SK4032003A3 - 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
- SK4032003A3 SK4032003A3 SK403-2003A SK4032003A SK4032003A3 SK 4032003 A3 SK4032003 A3 SK 4032003A3 SK 4032003 A SK4032003 A SK 4032003A SK 4032003 A3 SK4032003 A3 SK 4032003A3
- Authority
- SK
- Slovakia
- Prior art keywords
- methyl
- chlorophenyl
- bis
- methylsulfonyl
- azetidine
- Prior art date
Links
- 208000008589 Obesity Diseases 0.000 title abstract description 8
- 235000020824 obesity Nutrition 0.000 title abstract description 8
- 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
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 289
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 270
- -1 -COOR 5 Chemical group 0.000 claims description 215
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 128
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 112
- 125000000217 alkyl group Chemical group 0.000 claims description 91
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 72
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 67
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 61
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 60
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 60
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 56
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 28
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 28
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- 239000001301 oxygen Substances 0.000 claims description 28
- 239000011593 sulfur Chemical group 0.000 claims description 28
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 24
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 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 22
- 229960004425 sibutramine Drugs 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 229940124802 CB1 antagonist Drugs 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- SVSARCCKBMZNMR-UHFFFAOYSA-N [1-[2-[methyl-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethyl]amino]ethyl]pyridin-4-ylidene]methyl-oxoazanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1CCN(C)CCN1C=CC(=C[NH+]=O)C=C1 SVSARCCKBMZNMR-UHFFFAOYSA-N 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 12
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 12
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 229940124530 sulfonamide Drugs 0.000 claims description 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 9
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical group ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 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
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000004686 alkyl sulfanyl alkyl group Chemical group 0.000 claims description 7
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 7
- 230000003287 optical effect Effects 0.000 claims description 7
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 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 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 6
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- ZITKLNYNZGFLFM-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-4-methylsulfonylbenzamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 ZITKLNYNZGFLFM-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-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
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 150000003456 sulfonamides Chemical class 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- VKYOAPIHWDRWCF-VWLOTQADSA-N 4-[(s)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]-n,n-dimethylbenzamide Chemical compound C1=CC(C(=O)N(C)C)=CC=C1[C@@H](C=1C=CC(Cl)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 VKYOAPIHWDRWCF-VWLOTQADSA-N 0.000 claims description 5
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 5
- BIHRKCOQNANFPP-QHCPKHFHSA-N 1-[(s)-(4-chlorophenyl)-(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C1([C@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C(=CC(Cl)=CC=2)Cl)=CC=C(Cl)C=C1 BIHRKCOQNANFPP-QHCPKHFHSA-N 0.000 claims description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- MNLAVFKVRUQAKW-UHFFFAOYSA-N VR nerve agent Chemical compound CCN(CC)CCSP(C)(=O)OCC(C)C MNLAVFKVRUQAKW-UHFFFAOYSA-N 0.000 claims description 4
- AIZZQTVOXQNBPB-UHFFFAOYSA-N [4-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methanol Chemical compound C=1C(F)=CC(F)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(CO)=CC=1)C1=CC=C(Cl)C=C1 AIZZQTVOXQNBPB-UHFFFAOYSA-N 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
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 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
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- NVAZILBISPTELT-NRFANRHFSA-N 1-[(s)-(4-chlorophenyl)-thiophen-2-ylmethyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C1([C@@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(Cl)=CC=2)=CC=CS1 NVAZILBISPTELT-NRFANRHFSA-N 0.000 claims description 3
- SBNQHGQKWYWGIE-UHFFFAOYSA-N 1-[4-[3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]phenyl]piperazin-1-yl]-2-(methylamino)ethanone Chemical compound C1CN(C(=O)CNC)CCN1C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 SBNQHGQKWYWGIE-UHFFFAOYSA-N 0.000 claims description 3
- WKOAOEVZSBATJT-SSEXGKCCSA-N 1-[[4-[(r)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]-3,3-dimethylpiperidine Chemical compound C1C(C)(C)CCCN1CC1=CC=C([C@@H](N2CC(C2)=C(C=2C=C(F)C=C(F)C=2)S(C)(=O)=O)C=2C=CC(Cl)=CC=2)C=C1 WKOAOEVZSBATJT-SSEXGKCCSA-N 0.000 claims description 3
- FFVNJEJANVAWEH-UHFFFAOYSA-N 1-[bis(2-fluorophenyl)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=CC=1)F)C1=CC=CC=C1F FFVNJEJANVAWEH-UHFFFAOYSA-N 0.000 claims description 3
- VZWQRIMUBIPTIM-UHFFFAOYSA-N 1-[bis(3-fluorophenyl)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=C(F)C=CC=1)C1=CC=CC(F)=C1 VZWQRIMUBIPTIM-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- RGMVGFUHTMCAHQ-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]-3-[methylsulfonylmethylsulfonyl-[3-(trifluoromethylsulfanyl)phenyl]methylidene]azetidine Chemical compound C=1C=CC(SC(F)(F)F)=CC=1C(S(=O)(=O)CS(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 RGMVGFUHTMCAHQ-UHFFFAOYSA-N 0.000 claims description 3
- HBLQMBNUYUVOKF-UHFFFAOYSA-N 1-[bis(4-chlorophenyl)methyl]-n-[(3,5-difluorophenyl)methyl]azetidin-3-amine Chemical compound FC1=CC(F)=CC(CNC2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 HBLQMBNUYUVOKF-UHFFFAOYSA-N 0.000 claims description 3
- DSIMSFUZYRACNE-UHFFFAOYSA-N 1-[bis(4-fluorophenyl)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(F)=CC=1)C1=CC=C(F)C=C1 DSIMSFUZYRACNE-UHFFFAOYSA-N 0.000 claims description 3
- ZUJLEGLMCBXZBA-UHFFFAOYSA-N 1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC(OC)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 ZUJLEGLMCBXZBA-UHFFFAOYSA-N 0.000 claims description 3
- GXDNYOGWFZOREO-UHFFFAOYSA-N 1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C1=CC(C)=CC=C1C(C=1C=CC(C)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 GXDNYOGWFZOREO-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- HLOUATKBBLVAOQ-UHFFFAOYSA-N 2-(benzenesulfonyl)-n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]acetamide Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(NC(=O)CS(=O)(=O)C=2C=CC=CC=2)C1 HLOUATKBBLVAOQ-UHFFFAOYSA-N 0.000 claims description 3
- KSEYYUPAXNLWPF-IBGZPJMESA-N 2-[(s)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]-1,3-thiazole Chemical compound C1([C@@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(Cl)=CC=2)=NC=CS1 KSEYYUPAXNLWPF-IBGZPJMESA-N 0.000 claims description 3
- CEAFTNGPOKSUCY-UHFFFAOYSA-N 3-[(1-benzhydrylazetidin-3-ylidene)-methylsulfonylmethyl]benzamide Chemical compound C=1C=CC(C(N)=O)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 CEAFTNGPOKSUCY-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- 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 claims description 3
- MDIRSOMJVCIVSW-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-piperidin-1-ylbenzamide Chemical compound C=1C=CC(C(=O)NN2CCCCC2)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 MDIRSOMJVCIVSW-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- QQRVMMYVSMOPDG-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]phenol Chemical compound C=1C=CC(O)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 QQRVMMYVSMOPDG-UHFFFAOYSA-N 0.000 claims description 3
- MXUGPRCHGYVTST-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(2-methylbutyl)benzamide Chemical compound CCC(C)CNC(=O)C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 MXUGPRCHGYVTST-UHFFFAOYSA-N 0.000 claims description 3
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 claims description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- VKYOAPIHWDRWCF-RUZDIDTESA-N 4-[(r)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]-n,n-dimethylbenzamide Chemical compound C1=CC(C(=O)N(C)C)=CC=C1[C@H](C=1C=CC(Cl)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 VKYOAPIHWDRWCF-RUZDIDTESA-N 0.000 claims description 3
- GLXILTSCZKNOJQ-RUZDIDTESA-N 4-[(r)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]-n-ethylbenzamide Chemical compound C1=CC(C(=O)NCC)=CC=C1[C@H](C=1C=CC(Cl)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 GLXILTSCZKNOJQ-RUZDIDTESA-N 0.000 claims description 3
- HVBYMRXIWXCJAR-HSZRJFAPSA-N 4-[(r)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]benzamide Chemical compound C1([C@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(=CC=2)C(N)=O)=CC=C(Cl)C=C1 HVBYMRXIWXCJAR-HSZRJFAPSA-N 0.000 claims description 3
- NANRSOWQCYTYCU-UHFFFAOYSA-N 4-[4-[3-[(1-benzhydrylazetidin-3-ylidene)methylsulfonylmethyl]phenoxy]butyl]morpholine Chemical compound C1N(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1=CS(=O)(=O)CC(C=1)=CC=CC=1OCCCCN1CCOCC1 NANRSOWQCYTYCU-UHFFFAOYSA-N 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- WXNMZJIASLWWFS-UHFFFAOYSA-N C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(N(CC=2C=C3C=CC=NC3=CC=2)S(=O)=O)C1 Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(N(CC=2C=C3C=CC=NC3=CC=2)S(=O)=O)C1 WXNMZJIASLWWFS-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 3
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 3
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- NJUQAIXQRRQGRJ-UHFFFAOYSA-N 1-[3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]phenyl]-4-(2-methylpropyl)piperazine Chemical compound C1CN(CC(C)C)CCN1C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 NJUQAIXQRRQGRJ-UHFFFAOYSA-N 0.000 claims 1
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- FBWVTEZCNIQJRF-UHFFFAOYSA-N 1-[[4-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1CC1=CC=C(C(N2CC(C2)=C(C=2C=C(F)C=C(F)C=2)S(C)(=O)=O)C=2C=CC(Cl)=CC=2)C=C1 FBWVTEZCNIQJRF-UHFFFAOYSA-N 0.000 claims 1
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- JCXAARLJXDJMCB-UHFFFAOYSA-N 1-benzhydryl-3-[[3,5-bis(trifluoromethyl)phenyl]-methylsulfonylmethylidene]azetidine Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 JCXAARLJXDJMCB-UHFFFAOYSA-N 0.000 claims 1
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- OQODAQPQMPMKFB-UHFFFAOYSA-N 4-[3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]phenyl]-n-methylpiperazine-1-carboxamide Chemical compound C1CN(C(=O)NC)CCN1C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 OQODAQPQMPMKFB-UHFFFAOYSA-N 0.000 claims 1
- OIJLKMYMEOURJA-UHFFFAOYSA-N 4-[[4-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]morpholine Chemical compound C=1C(F)=CC(F)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(CN2CCOCC2)=CC=1)C1=CC=C(Cl)C=C1 OIJLKMYMEOURJA-UHFFFAOYSA-N 0.000 claims 1
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- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims 1
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- AIZZQTVOXQNBPB-DEOSSOPVSA-N [4-[(s)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methanol Chemical compound C1([C@@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(CO)=CC=2)=CC=C(Cl)C=C1 AIZZQTVOXQNBPB-DEOSSOPVSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims 1
- QKASKKMDZXXIET-UHFFFAOYSA-N methyl 3-[(1-benzhydrylazetidin-3-ylidene)-methylsulfonylmethyl]benzoate Chemical compound COC(=O)C1=CC=CC(C(=C2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)S(C)(=O)=O)=C1 QKASKKMDZXXIET-UHFFFAOYSA-N 0.000 claims 1
- XZLPOJOSMALGTC-QUZZAMIASA-N n-[(1s,3s,4r)-3-bicyclo[2.2.1]heptanyl]-n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]methanesulfonamide Chemical compound CS(=O)(=O)N([C@@H]1[C@@H]2CC[C@@H](C2)C1)C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 XZLPOJOSMALGTC-QUZZAMIASA-N 0.000 claims 1
- TWAKXQFGGJVBJY-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2,5-dimethoxybenzenesulfonamide Chemical compound COC1=CC=C(OC)C(S(=O)(=O)NC2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 TWAKXQFGGJVBJY-UHFFFAOYSA-N 0.000 claims 1
- XVKRTKCONIOYGB-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-3,4-dichlorobenzenesulfonamide Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(NS(=O)(=O)C=2C=C(Cl)C(Cl)=CC=2)C1 XVKRTKCONIOYGB-UHFFFAOYSA-N 0.000 claims 1
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- QGEIDYNVEYDOHV-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-n-methylquinoline-8-sulfonamide Chemical compound C=1C=CC2=CC=CN=C2C=1S(=O)(=O)N(C)C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 QGEIDYNVEYDOHV-UHFFFAOYSA-N 0.000 claims 1
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- ZVCQSDQDTCYOGI-UHFFFAOYSA-N n-[[4-[(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]-n-propan-2-ylpropan-2-amine Chemical compound C1=CC(CN(C(C)C)C(C)C)=CC=C1C(C=1C=CC(Cl)=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 ZVCQSDQDTCYOGI-UHFFFAOYSA-N 0.000 claims 1
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- 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
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent 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
- 239000002562 thickening agent Substances 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
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Abstract
Description
Kombinácia antagonistu receptora CBl a sibutramínu, farmaceutická kompozícia, ktorá ju obsahuje, a jej použitie pri liečbe obezityCombination of CB1 receptor antagonist and sibutramine, pharmaceutical composition containing it, and its use in the treatment of obesity
Oblasť technikyTechnical field
Predkladaný vynález sa týka kombinácie antagonistu receptora CBl a sibutramínu, farmaceutických prostriedkov, ktoré ju obsahujú, a jej použitia pri liečbe obezity.The present invention relates to a combination of a CB1 receptor antagonist and sibutramine, pharmaceutical compositions containing it, and its use in the treatment of obesity.
Doterajší stav technikyBACKGROUND OF THE INVENTION
Antagonisty receptora CBl sú známe pre svoj účinok na príjem potravy a ich použitie ako anorexigénne činidlá (G. Colombo a kol., Life Sciences, 63 (8), 113-117 (1998); J. Siamand a kol., Behavioural Pharmacol., 9, 179-181 (1998)).CB1 receptor antagonists are known for their effect on food intake and their use as anorexigenic agents (G. Colombo et al., Life Sciences, 63 (8), 113-117 (1998); J. Siamand et al., Behavioral Pharmacol. 9: 179-181 (1998)).
Sibutramín (BTS 54524; N-{1-[1-(4-chlórfenyl)cyklobutyl]-3-metylbutyl}-N,N-dimetylamín; Meridia®, Reductil®), jeho hydrát a jeho farmaceutický pŕijatelné soli a najmä jeho hydrochlorid, znižuje príjem potravy a používa sa pri liečbe obezity (WO 90/061110; D. H. Ryan a kol., Obesity Research, 3 (4), 553 (1995); H. C. Jackson a kol., British Journal of Pharmacology, 121, 1758 (1997); G. Fanghanel a kol., Inter. J. Obes., 24 (2), 144 (2000); G. A. Bray a kol., Obes. Res., 7 (2), 189 (1999)).Sibutramine (BTS 54524; N- {1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl} -N, N-dimethylamine; Meridia®, Reductil®), its hydrate and its pharmaceutically acceptable salts, and in particular its hydrochloride , decreases food intake and is used in the treatment of obesity (WO 90/061110; DH Ryan et al., Obesity Research, 3 (4), 553 (1995); HC Jackson et al., British Journal of Pharmacology, 121, 1758 ( G. Fanghanel et al., Inter J. Obes., 24 (2), 144 (2000); GA Bray et al., Obes. Res., 7 (2), 189 (1999)).
Podstata vynálezuSUMMARY OF THE INVENTION
Teraz sa zistilo, že kombinácia sibutramínu, jeho hydrátu a jeho farmaceutický prijateľných solí a antagonistu receptora CBl sa vyznačuje synergickým účinkom v znížení príjmu potravy, a preto sa používa pri liečbe obezity.It has now been found that the combination of sibutramine, its hydrate and its pharmaceutically acceptable salts and a CB1 receptor antagonist has a synergistic effect in reducing food intake and is therefore used in the treatment of obesity.
Kombinácia môže obsahovať aj niekolko antagonistov receptoraThe combination may also contain several receptor antagonists
CB1.CB1.
Z antagonistov CB1 sa môžu použiť najmä deriváty azetidinu sané vo WO 00/15609, WO 01/64633 a WO 01/64634 všeobecného opísané v< vzorca (I)Among the CB1 antagonists, in particular, the azetidine derivatives disclosed in WO 00/15609, WO 01/64633 and WO 01/64634 of general formula (I) may be used.
R (I) kde každá skupina R znamená reťazec A alebo BR (I) wherein each R is A or B
C = CH so2r‘ aleboC = CH with 2 r ';
II
C-CH (A)C-CH
R1 R 1
R2 R 2
R1 R 1
R2 znamená metylovú skupinu alebo etylovú skupinu, znamená buď aromatickú skupinu vybranú z fenylovej skupiny, naftylovej skupiny alebo indenylovej skupiny, pričom tieto aromatické skupiny môžu byť nesubstituovaná alebo substituované jedným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, skupinami -CO-alk, hydroxylovými skupinami, skupinami -COOR5, formylovými skupinami, trifluórmetylovými skupinami, trifluórmetylsulfanylovými skupinami, trifluórmetoxyskupinami, nitroskupinami, skupinami -WR6R7, skupinami -CO-NH-NR6R7, skupinami -N (alk) COORC, kyanoskupinami, skupinami -CONHR9, skupinami -CO-NR16R17, alkylsulfanylovými skupinami, hydroxyalkylovými skupinami, skupinami -O-alk-NR12R13 alebo alkyltioaikylovými skupinami, alebo heteroaromatickú skupinu, vybranú z benzofurylovej skupiny, benzotiazolylovej skupiny, benzotienylovej skupiny, benzoxazolylovej skupiny, chromanylovej skupiny, 2,3-dihydroxybenzofurylovej skupiny, 2,3-dihydrobenzotienylovej skupiny, in3 zofurylovej skupiny, 2,3-dihydrobenzotienylovej skupiny, indolinylovej skupiny, indolylovej skupiny, izochromanylovej skupiny, izochinolylovej skupiny, pyridylovej skupiny, chinolylovej skupiny, 1,2,3,4-tetrahydroizochinolylovej skupiny, I,2,3,4-tetrahydrochinolylovej skupiny, tiazoiylovej skupiny alebo tienylovej skupiny, pričom tieto heteroaromatické skupiny môžu byť nesubstituovaná alebo substituované atómom halogénu, alkylovou skupinou, alkoxyskupinou, skupinou -COOR5, trifluórmetylovou skupinou, trifluórmetylsulfanylovou skupinou, trifluórmetoxyskupinou, nitroskupinou, skupinou -NR6R7, skupinou -CO-NH-NR5R7, kyanoskupinou, skupinou -CONHR9, alkylsulfanylovou skupinou, hydroxyalkylovou skupinou alebo alkyltioalkylovou skupinou,R 2 represents a methyl or ethyl radical, means either an aromatic group selected from phenyl, naphthyl and indenyl, these aromatic groups may be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, -CO-alk, hydroxyl groups, -COOR 5 groups, formyl groups, trifluoromethyl groups, trifluoromethylsulfanyl groups, trifluoromethoxy groups, nitro groups, -WR 6 R 7 groups, -CO-NH-NR 6 R 7 groups, -N (alk) COOR C groups, cyano groups, -CONHR 9 groups, -CO-NR 16 R 17 groups, alkylsulfanyl groups, hydroxyalkyl groups, -O-alk-NR 12 R 13 groups or alkylthioalkyl groups, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl 2,3-dihydroxybenzofuryl j, 2,3-dihydrobenzothienyl, 3-isofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by a halogen atom, an alkyl group, an alkoxy group, -COOR 5 , a trifluoromethyl group, a trifluoromethylsulfanyl group, a trifluoromethoxy group, a nitro group, a nitro group, a nitro group, -NR 6 R 7 , -CO-NH-NR 5 R 7 , cyano, -CONHR 9 , alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
R3 a R4, ktoré sú rovnaké alebo rôzne predstavujú buď aromatickú skupinu vybranú z fenylovej skupiny, naftylovej skupiny alebo indenylovej skupiny, pričom tieto aromatické skupiny môžu byť nesubstituovaná alebo substituované jedným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, formylovými skupinami, hydroxylovými skupinami, trifluórmetylovými skupinami, trifluórmetoxyskupinami, skupinami -CO-alk, kyanoskupinami, skupinami -COOR5, skupinami -CONR10Rn, skupinami -CO-NH-NR6R7, alkylsulfanylovými skupinami, hydroxyalkýlovými skupinami, skupinami -alk-NR6R7 alebo alkyltioalkylovými skupinami, alebo heteroaromatickú skupinu vybranú z benzofurylovej skupiny, benzotiazolylovej skupiny, benzotienylovej skupiny, benzoxazolylovej skupiny, chromanylovej skupiny, 2,3-dihydrobenzofurylovej skupiny, 2,3-dihydrobenzotienylovej skupiny, furylovej skupiny, izochromanylove j skupiny, izochinolylovej skupiny, pyrolylovej skupiny, chinolylovej skupiny, 1,2,3,4-tetrahydroizochinolylovej skupiny, tiazoiylovej skupiny alebo tienylovej skupiny, pričom tieto heteroaromatické skupiny môžu byť nesubstituované alebo substituované jedným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, hy4 droxylovými skupinami, trifluórmetylovými skupinami, trifluórmetoxyskupinami, kyanoskupinami, skupinami -COOR5, skupinami -CO-NH-NR6R7, skupinami -CONR10RU, skupinami -alk-NR6R7, alkylsulfanylovými skupinami, hydroxyalkylovými skupinami alebo alkyltioalkylovými skupinami,R 3 and R 4 which are the same or different represent either an aromatic group selected from phenyl, naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups groups, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR 5, -CONR 10 R n, -CO-NH-NR 6 R 7, alkylmercapto, hydroxyalkyl, -alk-NR 6 R 7 or alkylthioalkyl, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isoquinromyl, pyrrolyl, ch inolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, trifluoromethyl groups, trifluoromethoxy groups, trifluoromethoxy groups, trifluoromethoxy groups , -COOR 5 group, a -CO-NH-NR 6 R 7, -CONR 10 R U, -alk-NR 6 R 7, alkylmercapto, hydroxyalkyl or alkylthioalkyl,
R3 je alkylová skupina alebo fenylová skupina pripadne substituovaná jedným alebo viacerými atómami halogénu,R 3 is an alkyl or phenyl optionally substituted with one or more halogen atoms,
R6 a R7, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka, alkylovú skupinu, skupinu -COOalk, cykloalkylovú skupinu, alkylcykloalkylovú skupinu, skupinu -alk-O-alk alebo hydroxyalkylovú skupinu, alebo R6 a R7 spoločne s atómom dusíka, na ktorý sa viažu, tvoria nasýtenú alebo nenasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry alebo atómu dusíka a prípadne substituovanú jednou alebo viacerými alkylovými skupinami, skupinami -CO-alk, skupinami -COOalk, skupinami -CONHalk, skupinami -CSNHalk, skupinami -CO-alk-NR14Rl3, oxoskupinami, hydroxyalkylovými skupinami, skupinami -alk-O-alk alebo skupinami -CO-NH2,R 6 and R 7 , which are the same or different, represent a hydrogen atom, an alkyl group, a -COOalk group, a cycloalkyl group, an alkylcycloalkyl group, an -alk-O-alk group or a hydroxyalkyl group, or R 6 and R 7 together with a nitrogen atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, -CO-alk-NR 14 R 13 groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups, or -CO-NH 2 groups,
R8 znamená alkylovú skupinu,R 8 represents an alkyl group,
R9 znamená atóm vodíka, alkylovú skupinu alebo alkylovú skupinu substituovanú dialkylaminoalkylovou skupinou, fenylovou skupinou, cykloalkylovou skupinou (prípadne substituovanou skupinou -COOalk) alebo nasýtenou alebo nenasýtenou monocyklickou alebo bicyklickou heterocyklickou skupinou obsahujúcou 3 až 10 členov, prípadne obsahujúcou jeden alebo viacero heteroatómov vybraných z atómu kyslíka, atómu síry a atómu dusíka a prípadne substituovanou jedným alebo viacerými alkylovými skupinami,R 9 represents a hydrogen atom, an alkyl group or an alkyl group substituted with a dialkylaminoalkyl group, a phenyl group, a cycloalkyl group (optionally substituted with -COOalk group) or a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members, optionally containing one or more heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and optionally substituted by one or more alkyl groups,
Rl0 a R11, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka alebo alkylovú skupinu, alebo R10 a R11 tvoria spoločne s atómom dusíka, na ktorý sa viažu, nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry a atómu dusíka a prípadne substituovanú jedným alebo viacerými alkylovými skupinami,R 10 and R 11 , which are the same or different, represent a hydrogen atom or an alkyl group, or R 10 and R 11 together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,
R12 a R13, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka, alkylovú skupinu alebo cykloalkylovú skupinu, alebo Ri2 a R13 tvoria spoločne s atómom dusíka, na ktorý sa viažu, nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry a atómu dusíka a prípadne substituovanú alkylovou skupinou, skupinou -CO-alk, skupinou -COOalk, skupinou -CONHalk, skupinou -CSNHalk, skupinou -CO-alk-NR14R15 alebo nasýtenou monocyklickou alebo bicyklickou heterocyklickou skupinou obsahujúcou 3 až 10 členov a obsahujúcou heteroatóm vybraný z atómu kyslíka, atómu síry a atómu dusíka,R 12 and R 13 , which are the same or different, represent a hydrogen atom, an alkyl group or a cycloalkyl group, or R 12 and R 13 together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members , optionally containing a further heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with alkyl, -CO-alk, -COOalk, -CONHalk, -CSNHalk, -CO-alk-NR 14 R 15 or a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members and containing a heteroatom selected from oxygen, sulfur and nitrogen,
R14 a R15, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka, alkylovú skupinu alebo skupinu -COOalk,R 14 and R 15 , which are the same or different, represent a hydrogen atom, an alkyl group or a -COOalk group,
R16 a R17 tvoria spoločne s atómom dusíka, na ktorý sa viažu, nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalšie heteroatómy vybrané z atómu kyslíka, atómu síry a atómu dusíka,R 16 and R 17 together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing further heteroatoms selected from oxygen, sulfur and nitrogen,
R' znamená atóm vodíka alebo skupinu -CO-alk, alebo R znamená skupinu CHR18, aR 'is H or -CO-alk, or R represents a CHR 18 radical, and
R18 znamená skupinu -NHCOR19 alebo skupinu -N (R20)-Y-R21,R 18 represents a radical -NHCOR 19 or -N (R 20) -YR 21,
Y je skupina CO alebo skupina SO2,Y is CO or SO 2 ,
R4 a R3, ktoré sú rovnaké alebo rôzne, predstavujú buď aromatickú skupinu vybranú z fenylovej skupiny, naftylovej skupiny alebo indenylovej skupiny, pričom tieto aromatické skupiny môžu byť nesubstituované alebo substituované jedným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, formylovými skupinami, hydroxylovými skupinami, trifluórmetylovými skupinami, trifluórmetoxyskupinami, skupinami -CO-alk, kyanoskupinami, skupinami -COOH, skupinami -COOalk, skupinami -CONR22R23, skupinami -CO-NH-NR24R25, alkylsulfanylovými skupinami, alkylsulfinylovými skupinami, alkylsulfonylovými skupinami, alkylsulfanylalkylovými skupinami, alkylsulfinylalkylovými skupinami, alkylsulfonylalkylovými skupinami, hydroxyalkylovými skupinami alebo skupinami -alk-NR22R23, alebo heteroaromatickú skupinu vybranú z benzofurylovej skupiny, benzotiazolylovej skupiny, benzotienylovej skupiny, benzoxazolylovej skupiny, chromanylovej skupiny, 2,3-dihydroxybenzofurylovej skupiny, 2,3-dihydrobenzotienylovej skupiny, pyrimidinylovej skupiny, furylovej skupiny, imidazolylovej skupiny, izochromanylovej skupiny, izochinolylovej skupiny, pyrolylovej skupiny, pyridylovej skupiny, chinolylovej skupiny, 1,2,3,4-tetrahydroizochinoiylovej skupiny, tiazolylovej skupiny alebo tienylovej skupiny, pričom tieto heteroaromatické skupiny môžu byt nesubstituované alebo substituované atómom halogénu, alkylovou skupinou, alkoxyskupinou, hydroxylovou skupinou, trifluórmetylovou skupinou, trifluórmetoxyskupinou, kyanoskupinou, skupinou -COOH, skupinou -COOalk, skupinou -CO-NH-NR24R25, skupinou -CONR22R23, skupinou-alk-NR24R25, alkylsulfanylovou skupinou, alkylsulfinylovou skupinou, alkylsulfonylovou skupinou, alkylsulfanylalkyiovou skupinou, alkylsulfinylakylovou skupinou, alkylsulfonylalkylovou skupinou alebo hydroxyalkylovou skupinou,R 4 and R 3 , which are the same or different, represent either an aromatic group selected from phenyl, naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, -CO-alk groups, cyano groups, -COOH groups, -COOalk groups, -CONR 22 R 23 groups, -CO-NH-NR 24 R 25 groups, alkylsulfanyl groups, alkylsulfinyl groups, alkylsulfonyl groups , alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR 22 R 23 groups, or a heteroaromatic group selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3- dihydroxybenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl wherein the heteroaromatic groups may be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR 24 R 25 , -CONR 22 R 23, the group-alk-NR 24 R 25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyiovou group, alkylsulfinylakylovou group, alkylsulfonylalkyl or hydroxyalkyl,
R19 znamená skupinu -alk-SO2R26, skupinu -alk-SO2-CH=CH-R26, skupinu Het1 substituovanú skupinou -SO2-R26 alebo fenylovú skupinu substituovanú skupinou -SO2-R26 alebo skupinou -alk-SO2-R26,R 19 represents an -alk-SO 2 R 26, -alk-SO 2 -CH = CH-R 26, Het 1 is substituted by -SO 2 R 26 or phenyl substituted by -SO 2 R 26 or -alk-SO 2 R 26 ,
R20 znamená atóm vodíka alebo alkylovú skupinu,R 20 represents a hydrogen atom or an alkyl group,
R21 znamená fenylalkylovú skupinu, skupinu Het1 alebo skupinuR 21 represents a phenylalkyl group, a Het 1 group or a group
Ar1,Ar 1 ,
R22 a R23, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka alebo alkylovú skupinu, alebo R22 a R23 tvoria spoločne s atómom dusíka, na ktorý sa viažu, nasýtenú monocyklickú alebo bicyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu i síry a atómu dusíka a prípadne substituovanú jedným alebo viacerými alkylovými skupinami,R 22 and R 23 , which are the same or different, represent a hydrogen atom or an alkyl group, or R 22 and R 23 together with the nitrogen atom to which they are attached form a saturated monocyclic or bicyclic group containing 3 to 10 members, optionally containing further a heteroatom selected from oxygen, sulfur and nitrogen, and optionally substituted with one or more alkyl groups,
R24 a R25, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka, alkylovú skupinu, skupinu -COOalk, cykloalkylovú skupinu, alkylcykloalkylovú skupinu, skupinu -alk-O-alk alebo hydroxyalkylovú skupinu, alebo R24 a R25 spoločne s atómom uhlíka, na ktorý sa viažu, tvoria nasýtenú alebo nenasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry alebo atómu dusíka a prípadne substituovanú jednou alebo viacerými alkylovými skupinami, skupinami -CO-alk, skupinami -COOalk, skupinami -CONHalk, skupinami -CSNHalk, oxoskupinami, hydroxyalkylovými skupinami, skupinami -alk-O-alk alebo skupinami -CO-NH2,R 24 and R 25 , which are the same or different, represent a hydrogen atom, an alkyl group, a -COOalk group, a cycloalkyl group, an alkylcycloalkyl group, an -alk-O-alk group or a hydroxyalkyl group, or R 24 and R 25 together with a carbon atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups or -CO-NH 2 groups,
R25 znamená alkylovú skupinu, skupinu Ar1 alebo skupinu Het1,R 25 represents an alkyl group, an Ar 1 group or a Het 1 group,
Ar1 znamená fenylovú skupinu, naftylovú skupinu alebo indenylovú skupinu, pričom tieto skupiny sú prípadne substituované jedným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, kyanoskupinami, skupinami -CO-alk, skupinami -COOH, skupinami -COOalk, skupinami -CONR27R28, skupinami -CO-NH-NR29R30, alkylsulfanylovými skupinami, alkylsulfinylovými skupinami, alkylsulfonylovými skupinami, skupinami -alk-NR29R30, skupinami -NR29R30, alkyltioalkylovými skupinami, formylovými skupinami, hydroxylovými skupinami, hydroxyalkylovými skupinami, skupinami Het, skupinami -O-alk-NH-cykloalkyl, trifluórmetoxyskupinami, trifluórmetylovými skupinami, skupinami -NH-CO-alk, skupinami -SO2NH2, skupinami -NH-COCH3, skupinami -NH-COOalk, skupinami Het alebo ešte dve susedné skupiny môžu tvoriť dioxymetylénovú skupinu,Ar 1 is phenyl, naphthyl or indenyl, these groups being optionally substituted by one or more halogen atoms, alkyl groups, alkoxy groups, cyano groups, -CO-alk groups, -COOH groups, -COOalk groups, -CONR 27 R groups 28 , -CO-NH-NR 29 R 30 , alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR 29 R 30 , -NR 29 R 30 , alkylthioalkyl, formyl, hydroxyl, hydroxyalkyl, Het groups, -O-alk-NH-cycloalkyl groups, trifluoromethoxy groups, trifluoromethyl groups, -NH-CO-alk groups, -SO 2 NH 2 groups, -NH-COCH 3 groups, -NH-COOalk groups, Het groups or two more adjacent groups may form a dioxymethylene group,
Het1 znamená nenasýtenú alebo nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 kruhových členov, obsahujúcu jeden alebo viacero heteroatómov vybraných z atómu kyslíka, atómu síry a atómu dusíka, ktorá je prípadne substituovaná jednou alebo viacerými alkylovými skupinami, alkoxyskupinami, vinylovými skupinami, stornami halogénu, alkoxykarbonylovými skupinami, oxoskupinami, hydroxylovými skupinami trifluórmetoxyskupinami alebo trifluórmetyiovými skupinami, pričom atómy dusíka heterccyklov sú prípadne v N-oxidovanej forme,Het 1 means an unsaturated or saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 ring members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, vinyl, vinyl halogen, alkoxycarbonyl, oxo, hydroxyl, trifluoromethoxy or trifluoromethyl groups, the nitrogen atoms of the heterocycles optionally being in the N-oxidized form,
R27 a R28, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka, alkylovú skupinu, alebo R27 a R28 spoločne s atómom uhlíka, na ktorý sa viažu, tvoria nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry alebo atómu dusíka a prípadne substituovanú jednou alebo viacerými alkylovými skupinami,R 27 and R 28 , which are the same or different, represent a hydrogen atom, an alkyl group, or R 27 and R 28 together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups,
R29 a R30, ktoré sú rovnaké alebo rôzne, predstavújú atóm vodíka, alkylovú skupinu, skupinu -COOalk, cykloalkylovú skupinu, alkylcykloalkylovú skupinu, skupinu -alk-O-alk alebo hydroxyalkylovú skupinu, alebo R29 a R30 spoločne s atómom uhlíka, na ktorý sa viažu, tvoria nasýtenú alebo nenasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry alebo atómu dusíka a prípadne substituovanú jednou alebo viacerými alkylovými skupinami, skupinami -CO-alk, skupinami -COOalk, skupinami -CONHalk, skupinami -CSNHalk, oxoskupinami, hydroxyalkylovými skupinami, skupinami -alk-O-alk alebo skupinami -CO-NH2, alebo R znamená skupinu CHR31, aR 29 and R 30 , which are the same or different, represent a hydrogen atom, an alkyl group, a -COOalk group, a cycloalkyl group, an alkylcycloalkyl group, an -alk-O-alk group or a hydroxyalkyl group, or R 29 and R 30 together with a carbon atom to which they are attached form a saturated or unsaturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl, -CO-alk, -COOalk groups, -CONHalk groups, -CSNHalk groups, oxo groups, hydroxyalkyl groups, -alk-O-alk groups or -CO-NH 2 groups, or R represents CHR 31 , and
R31 znamená skupinu -NR32R33, skupinu -NR32-CO-R33 alebo skupinu -NR32-SO2R3\ r4 a R3, ktoré sú rovnaké alebo rôzne, predstavujú buď aromatickú skupinu vybranú z fenylovej skupiny, naftylovej skupiny alebo indenylovej skupiny, pričom tieto aromatické skupiny môžu byť nesubstituované alebo substituované jedným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, formylovými skupinami, hydroxylovými skupinami, trifluórmetylovými skupinami, trifluórmetoxyskupinami, skupinami -CO-alk, kyanoskupinami, skupinami -COOH, skupinami -COOalk, skupinami -CONR22R23, skupinami -CO-NH-NR24R25, aikylsulfanylovými skupinami, alkyisulfinylovými skupinami, alkylsulfonyiovými skupinami, alkylsulfanylalkylovými skupinami, alkyisulfinylalkylovými skupinami, alkyisulfonylalkylovými skupinami, hydroxyalkylovými skupinami alebo skupinami -alk-NR7R8, alebo heteroaromatickú skupinu vybranú z benzofurylovej skupiny, benzotiazolylovej skupiny, benzotienylovej skupiny, benzoxazolylovej skupiny, chromanylove j skupiny, 2,3-dihydroxybenzofurylovej skupiny, 2,3-dihydrobenzotienylovej skupiny, furylovej skupiny, imidazolylovej skupiny, izochromanylovej skupiny, izochinoiylovej skupiny, pyrolylovej skupiny, pyridylovej skupiny, pyrimidinylovej skupiny, chinolylovej skupiny, 1,2,3,4-tetrahydroizochinolylovej skupiny, tiazolylovej skupiny alebo tienylovej skupiny, pričom tieto heteroaromatické skupiny môžu byť nesubstituované alebo substituované atómom halogénu, alkylovou skupinou, alkoxyskupinou, hydroxylovou skupinou, trifluórmetylovou skupinou, trifluórmetoxyskupinou, kyanoskupinou, skupinou -COOH, skupinou -COOalk, skupinou -CO-NH-NR24R25, skupinou -CONR22R23, skupinou-alk-NR24R25, alkyisulf anylovou skupinou, alkyisulfinylovou skupinou, alkylsulfonylovou skupinou, alkylsulfanylalkylovou skupinou, alkyisulfinylakylovou skupinou, alkyisulfonylalkyiovou skupinou alebo hydroxy10 alkylovou skupinou,R 31 represents -NR 32 R 33 , -NR 32 -CO-R 33, or -NR 32 -SO 2 R 3, R 4 and R 3 , which may be the same or different, represent either an aromatic group selected from a phenyl group , naphthyl or indenyl, which aromatic groups may be unsubstituted or substituted by one or more halogen atoms, alkyl groups, alkoxy groups, formyl groups, hydroxyl groups, trifluoromethyl groups, trifluoromethoxy groups, -CO-alk groups, cyano groups, -COOH groups, -COOalk groups, -CONR 22 R 23 groups, -CO-NH-NR 24 R 25 groups, alkylsulfanyl groups, alkyisulfinyl groups, alkylsulfonyl groups, alkylsulfanylalkyl groups, alkyisulfinylalkyl groups, alkyisulfonylalkyl groups, hydroxyalkyl groups or -alk-NR 7 groups 8 , or a heteroaromatic group selected from benzofuryl, benzothiazolylo benzothenyl, benzoxazolyl, chromanyl, 2,3-dihydroxybenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinolyl , 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl, wherein the heteroaromatic groups may be unsubstituted or substituted by a halogen atom, an alkyl group, an alkoxy group, a hydroxyl group, a trifluoromethyl group, a trifluoromethoxy group, a cyano group, a -COOH group, -COOalk, -CO-NH-NR 24 R 25 , -CONR 22 R 23 , -alk-NR 24 R 25 , alkyisulfanyl, alkyisulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkyisulfinylalkyl, alkyisulfonylalkyl, or hydroxy 10 an alkyl group u.
R32 znamená skupinu -C (R35) (R36)-Het2, skupinu -Het2, skupinu -C (R35) (R36)-Ar2, skupinu Ar2, cykloalkylovú skupinu alebo norbornylovú skupinu,R 32 is -C (R 35 ) (R 36 ) -Het 2 , -Het 2 , -C (R 35 ) (R 36 ) -Ar 2 , Ar 2 , cycloalkyl or norbornyl,
R33 znamená atóm vodíka, hydroxyalkylovú skupinu, skupinu -alk-COOalk, skupinu -alk-CONR22R23, skupinu -alk-NR22R23, alkoxyskupinu, skupinu Ar2, skupinu Het2, skupinu -CH2Ar2, skupinu -CH2Het2 alebo alkylovú skupinu prípadne substituovanú jedným alebo viacerými atómami halogénu,R 33 is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR 22 R 23 , -alk-NR 22 R 23 , alkoxy, Ar 2 , Het 2 , -CH 2 Ar 2 , - CH 2 Het 2 or an alkyl group optionally substituted by one or more halogen atoms,
R34 znamená hydroxyalkylovú skupinu, skupinu -alk-COOalk, skupinu -alk-CONR22R23, skupinu -alk-NR22R23, alkoxyskupinu, skupinu Ar2, skupinu Het2, skupinu -CH2Ar2, skupinu -CH2Het2 alebo alkylovú skupinu prípadne substituovanú jedným alebo viacerými atómami halogénu,R 34 represents a hydroxyalkyl, -alk-COOalk, -alk-CONR 22 R 23, -alk-NR 22 R 23, alkoxy, Ar 2, Het 2, -CH 2 Ar 2 group, or a group -CH2Het 2 an alkyl group optionally substituted by one or more halogen atoms,
R35 znamená atóm vodíka, hydroxyalkylovú skupinu, skupinu -alk-COOalk, skupinu -alk-CONR22R23, skupinu -alk-NR22R23, alkoxyalkylovú skupinu, skupinu Ar2, skupinu Het2, skupinu -CH2Ar2, skupinu -CH2Het2 alebo alkylovú skupinu prípadne substituovanú jedným alebo viacerými atómami halogénu,R 35 is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR 22 R 23 , -alk-NR 22 R 23 , alkoxyalkyl, Ar 2 , Het 2 , -CH 2 Ar 2 , -CH 2 Het 2 or an alkyl group optionally substituted by one or more halogen atoms,
R36 znamená atóm vodíka, hydroxyalkylovú skupinu, skupinu -alk-COOalk, skupinu -alk-CONR22R23, skupinu -alk-NR22R23, alkoxyalkylovú skupinu alebo alkylovú skupinu prípadne substituovanú jedným alebo viacerými atómami halogénu, alebo ešte R35 a R36 tvoria spoločne s atómom uhlíka, na ktorý sa viažu, nasýtený monocyklický alebo bicyklický kruh obsahujúci 3 až 10 členov, prípadne obsahujúci ďalší heteroatóm vybraný z atómu kyslíka, atómu síry a atómu dusíka a prípadne substituovaný jedným alebo viacerými alkylovými skupinami,R 36 is hydrogen, hydroxyalkyl, -alk-COOalk, -alk-CONR 22 R 23 , -alk-NR 22 R 23 , alkoxyalkyl or alkyl optionally substituted by one or more halogen atoms, or R 35 and R 36 together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic ring containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl groups,
Ar2 znamená fenylovú skupinu, naftylovú skupinu alebo indenylovú skupinu, pričom tieto skupiny sú prípadne substituované jed11 ným alebo viacerými atómami halogénu, alkylovými skupinami, alkoxyskupinami, kyanoskupinami, skupinami -CO-alk, skupinami -COOH, skupinami -COOalk, skupinami -CONR37R38, skupinami -CO-NH-NR39R40, alkylsulfanylovými skupinami, alkylsulfinylovými skupinami, alkylsulfonylovými skupinami, skupinami -alk-NR39R40, skupinami -NR39R40, alkyltioalkylovými skupinami, formylovými skupinami, trifluórmetylovými skupinami, trifluórmetoxyskupinami, skupinami Het, skupinami -O-alk-NH-cykloalkyl, skupinami -SO2NH2, hydroxylovými skupinami, hydroxyalkylovými skupinami, skupinami -NHCOalk, skupinami -NH-COOalk alebo na dvoch susedných atómoch uhlíka dioxymetylénovou skupinou,Ar 2 represents a phenyl group, a naphthyl group or an indenyl group, these groups being optionally substituted by one or more halogen atoms, alkyl groups, alkoxy groups, cyano groups, -CO-alk groups, -COOH groups, -COOalk groups, -CONR 37 groups R 38 , -CO-NH-NR 39 R 40 groups, alkylsulfanyl groups, alkylsulfinyl groups, alkylsulfonyl groups, -alk-NR 39 R 40 groups, -NR 39 R 40 groups, alkylthioalkyl groups, formyl groups, trifluoromethyl groups, trifluoromethoxy groups, Het groups, -O-alk-NH-cycloalkyl groups, -SO2NH2 groups, hydroxyl groups, hydroxyalkyl groups, -NHCOalk groups, -NH-COOalk groups or two adjacent carbon atoms with a dioxymethylene group,
Het2 znamená nenasýtenú alebo nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 kruhových členov, obsahujúcu jeden alebo viacero heteroatómov vybraných z atómu kyslíka, atómu síry a atómu dusíka, ktorá je prípadne substituovaná jednou alebo viacerými alkylovými skupinami, alkoxyskupinami, atómami halogénu, alkoxykarbonylovými skupinami, oxoskupinami alebo hydroxylovými skupinami, pričom atómy dusíka heterocyklov sú prípadne v N-oxidovanej forme,Het 2 means an unsaturated or saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 ring members, containing one or more heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl groups, oxo or hydroxyl groups, the nitrogen atoms of the heterocycles optionally being in the N-oxidized form,
R37 a R38, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka alebo alkylovú skupinu, alebo R37 a R38 spoločne s atómom uhlíka, na ktorý sa viažu, tvoria nasýtenú monocyklickú alebo bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry alebo atómu dusíka a prípadne substituovanú jednou alebo viacerými alkylovými skupinami,R 37 and R 38 , which are the same or different, represent a hydrogen atom or an alkyl group, or R 37 and R 38 together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing from 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted with one or more alkyl groups,
R39 a R40, ktoré sú rovnaké alebo rôzne, predstavujú atóm vodíka alebo alkylovú skupinu, alebo R39 a R40 spoločne s atómom uhlíka, na ktorý sa viažu, tvoria nasýtenú monocyklickú alebo ‘bicyklickú heterocyklickú skupinu obsahujúcu 3 až 10 členov, prípadne obsahujúcu ďalší heteroatóm vybraný z atómu kyslíka, atómu síry alebo atómu dusíka a prípadne substituovanú jednou alebo viacerými alkylovými skupinami, alk znamená alkylovú skupinu alebo alkylénovú skupinu, pričom alkylové, alkylénové a alkoxylové časti sú s priamym alebo rozvetveným reťazcom obsahujúcim 1 až 6 atómov uhlíka, a cykloalkylové skupiny obsahujú 3 až 10 atómov uhlíka, optické izoméry týchto zlúčenín a ich farmaceutický prijatelné soli s anorganickou alebo organickou kyselinou.R 39 and R 40 , which are the same or different, represent a hydrogen atom or an alkyl group, or R 39 and R 40 together with the carbon atom to which they are attached form a saturated monocyclic or bicyclic heterocyclic group containing 3 to 10 members, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen and optionally substituted by one or more alkyl groups, alk represents an alkyl group or an alkylene group, wherein the alkyl, alkylene and alkoxy groups are straight or branched chain containing 1 to 6 carbon atoms, and cycloalkyl groups contain 3 to 10 carbon atoms, the optical isomers of these compounds, and their pharmaceutically acceptable salts with an inorganic or organic acid.
Výhodnými azetidínovými derivátmi sú nasledovné zlúčeniny:Preferred azetidine derivatives are the following compounds:
l-benzhydryl-3-[(metylsulfonyl)(fenyl)metylén]azetidín, l-benzhydryl-3-[(3-metylfenyl) (metylsulfonyl) metylén]azetidín, l-benzhydryl-3-[(3-chlórfenyl)(metylsulfonyl)metylén]azetidín, l-benzhydryl-3-[(3,5-dichlórfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(2,5-dichlórfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(2,3-dichlórfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(3-fluórfenyl)(metylsulfonyl)metylén]azetidín, l-benzhydryl-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(3-brómfenyl)(metylsulfonyl)metylén]azetidín, l-benzhydryl-3-[(3-jódfenyl)(metylsulfonyl)metylén]azetidín, l-benzhydryl-3-[(metylsulfonyl)(3-trifluórmetoxyfenyl)metylén]-azetidín, l-benzhydryl-3-[(metylsulfonyl)(3-trifluórmetylfenyl)metylén]-azetidín, l-benzhydryl-3-{ [3,.5-bis (trifluórmetyl) fenyl] (metylsulfonyl) -metylén]azetidín, l-benzhydryl-3-[(3,5-dibrómfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(3-metoxykarbonylfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(3-kyanofenyl)(metylsulfonyl)metylén]azetidín, l-benzhydryl-3-[(3-karbamoylfenyl)(metylsulfonyl)metylén]-azetidín, l-benzhydryl-3-[(metylsulfonyl)(naft-l-yl)(metylsulfonyl)-metylén]azetidín,1-benzhydryl-3 - [(methylsulfonyl) (phenyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-chlorophenyl) (methylsulfonyl) ) methylene] azetidine, 1-benzhydryl-3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(2,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1 -benzhydryl-3 - [(2,3-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-fluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-bromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-iodophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethoxyphenyl) methylene] azetidine, 1-benzhydryl-3 - [(methylsulfonyl) (3-trifluoromethylphenyl) methylene] azetidine, 1-benzhydryl-3 - {[3, .5-bis (trifluoromethyl) phenyl] (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3,5-dibromophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-mee) 1-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine; 1-benzhydryl-3 - [(3-carbamoylphenyl) (methylsulfonyl) methylene] azetidine; 1-benzhydryl-3 - [(3-cyanophenyl) (methylsulfonyl) methylene] benzhydryl-3 - [(methylsulphonyl) (naphth-l-yl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl) (metylsulfonyl) -metylén]azetidín,1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-metoxyfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,1- [Bis (4-methoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-metylfenyl)metyl]-3-[(3, 5-difluórfenyl) (metylsulfonyl) -metylén]azetidín, {RS}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-1-[(4-metoxyfenyl)(fenyl)metyl]azetidín, (í?) — 3 — [(3,5-difluórfenyl)(metylsulfonyl)metylén]-1-[(4-metoxyfenyl)(fenyl)metyl]azetídín, (S)-3-[(3,5-difluórfenyl) (metylsulfonyl)metylén]-1-[(4-metoxyfenyl)(fenyl)metyl]azetidín,1- [bis (4-methylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, {RS} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] - 1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine, (R) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine (S) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] -1 - [(4-methoxyphenyl) (phenyl) methyl] azetidine,
1-[bis(4-trifluórmetoxyfenyl)metyl]-3-[(3,5-difluórfenyl)-(metylsulfonyl)metylén]azetidín,1- [bis (4-trifluoromethoxyphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine,
1-[bis(4-trifluórmetylfenyl)metyl]-3-[(3,5-difluórfenyl) -(metylsulfonyl)metylén]azetidín,1- [bis (4-trifluoromethylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyi)metyl·]-3-{[3,5-bis(trifluórmetyl)fenyl]-metylsulfonylmetylén}azetidín, (RS)-1-[(4-chlórfenyl)(2,4-dichlórfenyl)metyl]-3-[(3,5-difluór fenyl)(metylsulfonyl)metylén]azetidín, (í?) -1- [ (4-chlórfenyl) (2,4-dichlórfenyl)metyl] -3- [ (3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, (S)-1-[(4-chlórfenyl)(2,4-dichlórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, (FS)-1-{(4-chlórfenyl)[4-(hydroxymetyl)fenyl]metyl}-3-[(3,5-di fluórfenyl)(metylsulfonyl)metylén]azetidín, (Ä)-l-{(4-chlórfenyl) [4-(hydroxymetyl)fenyl]metyl)-3-[(3, 5-difluórfenyl)(metylsulfonyl)metylén]azetidín, (S)-l-{(4-chlórfenyl) [4-(hydroxymetyl)fenyl]metyl}-3-[(3, 5-difluórfenyl)(metylsulfonyl)metylén]azetidín, (FS)-l-{(4-chlórfenyl)[4-(pyrolidinylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, (F)-l-{(4-chlórfenyl)[4-(pyrolidinylmetyl)fenyl]metyl]-3- [ (3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín, (S)-1{(4-chlórfenyl)[4-(pyrolidinylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,1- [bis (4-chlorophenyl) methyl] -3 - {[3,5-bis (trifluoromethyl) phenyl] methylsulfonylmethylene} azetidine, (RS) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluoro phenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3) 5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (2,4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine (FS) -1 - {(4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {( 4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (hydroxymethyl)] phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (FS) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3 (5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (F) -1 - {(4-chlorophenyl) [4- (pyrrolidinylmethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 {(4-chloro r phenyl) [4- (pyrrolidinylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-(RS)-(4-chlórfenyl) [4-(3, 3-dimetylpiperid-l-ylmetyl)fenyl]-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,1- (RS) - (4-Chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-((Ä)-(4-chlórfenyl) [4-(3, 3-dimetylpiperid-l-ylmetyl)fenyl]-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, l-((S)-(4-chlórfenyl·) [4-(3,3-dimetylpiperid-l-ylmetyl)fenyl]151 - ((R) - (4-chlorophenyl) [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((S) - (4-chlorophenyl) - [4- (3,3-dimethylpiperid-1-ylmethyl) phenyl] 15
-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1—{(RS)-(4-chlórfenyl)[4-(tíomorfolín-4-ylmetyl)fenyljmetyl}-[(3, 5-difluórfenyl) (metylsulfonyl)metylén]azetidín, l-((F)-(4-chlórfenyl)[4-(tiomorfolin-4-ylmetyl)fenyl]metyl·}-3-[(3, 5-difluórfenyl) (metylsulfonyl)metylén]azetidín, l-{(S)-(4-chlórfenyl) [4-(tiomorfolin-4-ylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín, l-{(RS) -(4-chlórfenyl) [4-(N-etyl-N-cyklohexylaminometyl)fenyl] -metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, l-((F)-(4-chlórfenyl)[4-(N-etyl-N-cyklohexylaminometyl)fenyl]-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, l-{(S) -(4-chlórfenyl) [4- (N-etyl-N-cyklohexylaminometyl)fenyl]-metyl}-3-[(3, 5-difluórfenyl) (metylsulfonyl)metylén]azetidín,1 - {(RS) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((F) - (4- chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (thiomorpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (N-ethyl-N) -cyclohexylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ((F) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl)) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (N-ethyl-N-cyclohexylaminomethyl) phenyl] - methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-{{(FS) -(4-chlórfenyl){4-[(4-etoxykarbonylpiperaziny1)metyl]-fenylJmetyl}}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-azetidín, l-{{(R) ~(4-chlórfenyl) (4-[ (4-etoxykarbonylpiperazinyl)metyl]-fenylJmetyl)}}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-azetidín, l-({(S)-(4-chlórfenyl){4-[(4-etoxykarbonylpiperazinyl)metyl]-fenylJmetyl}}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-azetidín, l-{(FS)-(4-chlórfenyl)[4-(N-cyklopropyl-N-propylaminometyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-azetidín, l-{(F)-(4-chlórfenyl)[4-(N-cyklopropyl-N-propylaminometyl)-fenyl]metyl}-3-[(3, 5-difluórfenyl) (metylsulfonyl)metylén]-azetidín,1 - {{(FS) - (4-chlorophenyl) {4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - { {(R) - (4-chlorophenyl) (4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - ({( S) - (4-chlorophenyl) {4 - [(4-ethoxycarbonylpiperazinyl) methyl] phenyl] methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(FS) - ( 4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(F) - (4-chlorophenyl) ) [4- (N-Cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-((S)-(4-chlórfenyl)[4-(N-cyklopropyl-N-propylaminometyl)-fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]-azetidín, l-{(RS)-(4-chlórfenyl)[4-(diizopropylaminometyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,1 - ((S) - (4-chlorophenyl) [4- (N-cyclopropyl-N-propylaminomethyl) -phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- {(R) - (4-chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-{(R) -(4-chlórfenyl)-[4-(diizopropylaminometyl)fenyl]metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, l-{(S)-(4-chlórfenyl)[4-(diizopropylaminometyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén)azetidín,1 - {(R) - (4-chlorophenyl) - [4- (diisopropylaminomethyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4 chlorophenyl) [4- (diisopropylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene) azetidine,
1-{{ (RS) - (4-chlórfenyl){4-[bis(2-metoxyetyl·)aminometyl]fenyl}-metyl}}-3-[(3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín,1 - {{(RS) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-({(R)-(4-chlórfenyl){4-[bis(2-metoxyetyl)aminometyl]fenyl}-metyl]}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,1 - ({(R) - (4-chlorophenyl) {4- [bis (2-methoxyethyl) aminomethyl] -phenyl} -methyl]} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-{{(S)-(4-chlórfenyl)(4-[bis(2-metoxyetyl)aminometyl]fenyl}-metyl}}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, l-{(RS)-(4-chlórfenyl)[4-[di-n-propylaminometyl)fenyl]metyl}-3- [ (3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín,1 - {{(S) - (4-chlorophenyl) (4- [bis (2-methoxyethyl) aminomethyl] phenyl} methyl}} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-Chlorophenyl) [4- [di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1—{(R)-(4-chlórfenyl)[4-(di-n-propylaminometyl)fenyljmetyl)-3- [ (3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín, l-{(S)-(4-chlórfenyl)[4-(di-n-propylaminometyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín, l-{(RS)-(4-chlórfenyl)[4-(piperid-l-ylmetyl)fenyl]metyl}-3- [ (3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín, l-{ (R) - (4-chlórfenyl)[4-(piperid-l-ylmetyl)fenyl]metyl}-3- [ (3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín,1 - {(R) - (4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - ( 4-chlorophenyl) [4- (di-n-propylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4 - (piperid-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperid-1- ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-{(S)-(4-chlórfenyl) [4-(piperid-l-ylmetyl)fenyl]metyl)-3 - [ (3,5-difluórfenyl) (metylsulfonyl)metylén]azetidín,1 - {(S) - (4-Chlorophenyl) [4- (piperid-1-ylmethyl) phenyl] methyl) -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-((RS)-(4-chlórfenyl)[4-(4-metylpiperazin-l-ylmetyl)fenyl]-meťyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{ (í?) - (4-chlórfenyl) [4 - (4-metylpiperazin-l-ylmetyl) fenyl] -metyl}-3-[(3, 5-difluórfenyl) (metylsulfonyl)metylén]azetidin, l-{(S)-(4-chlórfenyl)[4-(4-metylpiperazin-l-ylmetyl)fenyl]-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin,1 - ((RS) - (4-chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1- { (R) - (4-Chlorophenyl) [4- (4-methylpiperazin-1-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) ) - (4-chlorophenyl) [4- (4-methylpiperazin-l-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-{(RS) -(4-chlórfenyl)[4-(morfolin-4-ylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{(F)-(4-chlórfenyl)[4-(morfolin-4-ylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl) (metylsulfonyl)metylén]azetidin, l-{(S)-(4-chlórfenyl)[4-(morfolin-4-ylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{(RS)-(4-chlórfenyl)(4-(dietylaminometyl)fenyl·]metyl}-3-[(3,5-difiuórfenyl)(metylsulfonyl)metylén]azetidin, l-{ (i?) - (4-chlórfenyl) [4- (dietylaminometyl) fenyl]metyl}-3- [ (3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{(S)-(4-chlórfenyl)[4-(dietylaminometyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{((RS)-(4-chlórfenyl)[4-(piperazin-2-on-4-ylmetyl)fenyl]-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{(Ä)-(4-chlórfenyl)[4-(piperazin-2-on-4-ylmetyl)fenyl]-metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-((S)-(4-chlórfenyl)[4-(piperazin-2-on-4-ylmetyl)fenyl]-metyl}-3—[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, l-{(RS)-(4-chlórfenyl)[4-(imidazol-l-ylmetyl)fenyl]metyl}-3- [ (3>, 5-difluórfenyl) (metylsulfonyl) metylén] azetidin,1 - {(RS) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(F) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (morpholin-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) (4- (diethylaminomethyl)) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (diethylaminomethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {((RS) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(R) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene ] azetidine, 1 - ((S) - (4-chlorophenyl) [4- (piperazin-2-one-4-ylmethyl) phenyl] methyl 1} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(RS) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3- [ (3,5,5-Difluorophenyl) (methylsulfonyl) methylene] azetidine,
1- { (jR) — (4-chlórfenyl) [4 - (imidazol-l-ylmetyl) fenyl] metyl} -3181 - {(R) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -318
-[(3,5-difluórfenyl) (metylsulfonyl·)metylén]azetidin, l-{(S)-(4-chlórfenyl)[4-(imidazol-1-ylmetyl)fenyl]metyl}-3-[(3,5-difluórfenyl) (metylsulfonyl)metylén]azetidin, (RS)-1-((4-chlórfenyl)[ 4-(N,N-dimetylkarbamoyl·)fenyl]metyl}-3-[(3, 5-difluórfenyl) (metylsulfonyl)metylén]azetidin, (R) -1-((4-chlórfenyl)[4-(N,N-dimetylkarbamoyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, (S) -l-{(4-chlórfenyl) [4- (N,N-dimetylkarbamoyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, (RS) — 1—{(4-chlórfenyl)[4-(N-etylkarbamoyl)fenyl]metyl)}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, (R) —1—{(4-chlórfenyl)[4-(N-etylkarbamoyl)fenyl]metyl}-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, (S) -1-{(4-chlórfenyl)[4-(N-etylkarbamoyl)fenyl]mety]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, (RS)-1-[(4-karbamoylfenyl)(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl) (metylsulfonyl)metylén]azetidin, (R) -1-[(4-karbamoylfenyl)(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin, (S) -1-[(4-karbamoylfenyl)(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidin,- [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, 1 - {(S) - (4-chlorophenyl) [4- (imidazol-1-ylmethyl) phenyl] methyl} -3 - [(3, 5-Difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - ((4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) ( methylsulfonyl) methylene] azetidine, (R) -1 - ((4-chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-Chlorophenyl) [4- (N, N-dimethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1- {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl)} - 3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - {(4-chlorophenyl) [ 4- (N-ethylcarbamoyl) phenyl] methyl} -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - {(4-chlorophenyl) [4- (N-ethylcarbamoyl) phenyl] methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-carbamo ylphenyl) (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-carbamoylphenyl) (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3,5-dichlórfenyl)(metylsulfonyl) -metylén]azetidin, l-benzhydryl-3-[(3-metylsulfanylfenyl)(metylsulfonyl)metylén]-azetidin, l-benzhydryl-3-[(3-metylsulfanylmetyl)fenyl)] (metylsulfonyl) -metylén)azetidin,1- [bis (4-chlorophenyl) methyl] -3 - [(3,5-dichlorophenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylphenyl) (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(3-methylsulfanylmethyl) phenyl)] (methylsulfonyl) methylene) azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3-kyanofenyl)(metylsulfonyl)-metylén]azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - [(3-cyanophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3-karbamoylfenyl)(metylsulfonyl)-metylén]azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - [(3-carbamoyl-phenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3-metoxyfenyl)(metylsulfonyl)-metylén]azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - [(3-methoxyphenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3-hydroxyfenyl)(metylsulfonyl)-metylén]azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - [(3-hydroxyphenyl) (methylsulphonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(metylsulfonyl)(3-pyrolidinylfenyl)metylén]azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulphonyl) (3-pyrrolidinylphenyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3-hydroxymetylfenyl)(metylsulfonyl )metylén]azetidín,1- [bis (4-chlorophenyl) methyl] -3 - [(3-hydroxymethylphenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-{(metylsulfonyl)[3-(N-piperidylkarbamoyl)fenyl]metylén}azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - {(methylsulfonyl) [3- (N-piperidylcarbamoyl) phenyl] methylene} azetidine,
1-[bis(4-chlórfenyl)metyi]-3-[(metylsulfonyl)(3-trifluórmetylsulf anylfenyl)(metylsulfonyl)metylén]azetidín,1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (3-trifluoromethylsulfanylphenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-fluórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)-metylén]azetidín,1- [Bis (4-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(2-fluórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)-metylén]azetidín,1- [Bis (2-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis (3-fluórfenyl)metyl]-3-[(3,5-difluórfenyl) (metylsulfonyl)-metylén]azetidín, (RS)-1-[(4-chlórfenyl)(tiazol-2-yl)metyl]-3-[(metylsulfonyl)-(fenyl)metylén]azetidín, (R)-1-[(4-chlórfenyl)(tiazol-2-yl)metyl]-3-[(metylsulfonyl)-(fenyl)metylén]azetidín, (S) — 1 -[ (4-chlórfenyl) (tiazol-2-yl) metyl]-3- [ (metylsulfonyl) 201- [bis (3-fluorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl ] -3 - [(methylsulfonyl) - (phenyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) - (phenyl) methylene] Azetidine, (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(methylsulfonyl) 20]
- (fenyl)metylén]azetidín, [RS)-1-[(4-chlórfenyl) (tlen-2-yl)metyl)-3-[(3,5-difluórfenyl)-(metylsulfonyl)metylén]azetidin, (R) -1-[(4-chlórfenyl) (tien-2-yl)metyl]-3-[(3,5-difluórfenyl)-(metylsulfonyl)metylén]azetidin, (S) -l-[(4-chlórfenyl) (tien-2-yl)metyl]-3-[(3,5-difluórfenyl)-(metylsulfonyl)metylén]azetidín, l-benzhydryl-3-[(etylsulfonyl)(fenyl)metylén]azetidín,- (phenyl) methylene] azetidine, [RS] -1 - [(4-chlorophenyl) (ethylen-2-yl) methyl) -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (R) ) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, 1-benzhydryl-3 - [(ethylsulfonyl) (phenyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-{{3-[N-(4-metylpiperazinyl)-karbamoyl]fenyl](metylsulfonyl)metylén}azetidín,1- [Bis (4-chlorophenyl) methyl] -3 - {{3- [N- (4-methylpiperazinyl) carbamoyl] phenyl] (methylsulfonyl) methylene} azetidine,
1-[bis(4-chlórfenyl)metyl]-3-{[3-(2,2-dimetylkarbohydrazido)-fenyl](metylsulfonyl)metylén}azetidin,1- [Bis (4-chlorophenyl) methyl] -3 - {[3- (2,2-dimetylkarbohydrazido) phenyl] (methylsulfonyl) methylene} azetidine,
1-[bis(tien-2-yl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)-metylén]azetidín,1- [bis (thien-2-yl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(p-tolyl)metyl]-3-[(metylsulfonyl)(fenyl)metylén]azetidín,1- [bis (p-tolyl) methyl] -3 - [(methylsulfonyl) (phenyl) methylene] azetidine,
1- [ (4-chlórfenyl) (4-hydroxymetylfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylén]azetidín,1 - [(4-chlorophenyl) (4-hydroxymethylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3-metylaminofenyl)(metylsulfonyl) metylén] azetidín, (RS)-1-[(4-chlórfenyl)(tiazol-2-yl)metyl]-3-[(3,5-difluórfenyl)- (metylsulfonyl)metylén]azetidín, (R) -1-[(4-chlórfenyl)(tiazol-2-yl)metyl]-3-[(3,5-difluórfenyl)- (metylsulfonyl)metylén]azetidín, (S) -1-[(4-chlórfenyl)(tiazol-2-yl)metyl]-3-[(3,5-difluórfenyl)- (metylsulfonyl)metylén]azetidín,1- [bis (4-chlorophenyl) methyl] -3 - [(3-methylaminophenyl) (methylsulfonyl) methylene] azetidine, (RS) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (R) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine, (S) -1 - [(4-chlorophenyl) (thiazol-2-yl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methylene] azetidine,
1- [bis(4-chlórfenyl)metyl]-3-[(metylsulfonyl) (2-metoxykarbonyltien-5-yl)metylén]azetidín, (RS)-1-[[bis(4-chlórfenyl)metyl]-3-hydroxy-3-[(metylsulfonyi)1- [bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (2-methoxycarbonylthien-5-yl) methylene] azetidine, (RS) -1 - [[bis (4-chlorophenyl) methyl] -3- hydroxy-3 - [(methylsulfonyl)
-(2-metoxykarbonyltieň-5-y1)metyl]azetidín,- (2-methoxycarbonylthien-5-y1) methyl] azetidine,
1-[bis(4-chlórfenyl) metyl]-3-[(2-izcbutylaminokarbonyltien-5-yl)(metylsulfonyi)metylén]azetidín,1- [bis (4-chlorophenyl) methyl] -3 - [(2-isobutylaminocarbonythien-5-yl) (methylsulfonyl) methylene] azetidine,
1-[bis(4-chlórfenyl) metyl]-3-[(3-metoxykarbonylfenyl)-(metylsulfonyi)metyl- (PS)]azetidin-3-ol,1- [bis (4-chlorophenyl) methyl] -3 - [(3-methoxycarbonylphenyl) - (methylsulfonyl) methyl- (PS)] azetidin-3-ol,
1-[bis(4-chlórfenyl)metyl]-3-[(metylsulfonyi)(pyrid-4-yl)-metyl-(RS)]azetidin-3-ol,1- [Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyrid-4-yl) methyl- (RS)] azetidin-3-ol,
1-[[bis(4-chlórfenyl)metyl]-3-[(metylsulfonyi)(pyrid-3-yl)-metyl-{RS)]azetidin-3-ol,1 - [[Bis (4-chlorophenyl) methyl] -3 - [(methylsulfonyl) (pyrid-3-yl) methyl {RS)] azetidin-3-ol,
3-({1-[bis(4-chlórfenyl) mety l]a zet idin-3-ylidén} metánsulf onylmetyl)-N-(3-morfolin-4-ylpropyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] and zetidin-3-ylidene} methanesulfonylmethyl) -N- (3-morpholin-4-ylpropyl) benzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén]metánsulfonyl metyl)-N-(3-dimetylaminopropyi)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N- (3-dimethylaminopropyl) benzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonyl metyl)-N-(2-(pyrolidin-l-yl)etyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2- (pyrrolidin-1-yl) ethyl) benzamide,
3- ({1- [bis (4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonylmetyl)-N-(2-dimetylamino-l-metyletyl)benzamid,3- ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-dimethylamino-1-methylethyl) benzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonyl metyl)-N-(piperidín-1-yl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (piperidin-1-yl) benzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén]metánsulfonyl metyl)-N-izobutylbenzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene] methanesulfonylmethyl) -N-isobutylbenzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-y1idén}metánsulfonyl metyl)-N-(3-imidazol-1-ylpropyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (3-imidazol-1-ylpropyl) benzamide,
3-({1-(bis(4-chlórfenyl)metyl]azetidin-3-ylidén]metánsulfonyl metyl)-N-(2-dimetylaminoetyl)benzamid,3 - ({1- (bis (4-chlorophenyl) methyl) azetidin-3-ylidene] methanesulfonylmethyl) -N- (2-dimethylaminoethyl) benzamide,
N'-metylhydrazid kyseliny 3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonylmetyl)benzoovej,3 '- ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) benzoic acid N'-methylhydrazide,
3-({1-[bis(4-chlórfenyl)metylazetidin-3-ylidén}metánsulfonylmetyl)-N-(2-morfolin-4-yletyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl-azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-morpholin-4-yl-ethyl) -benzamide,
3-({1-bis(4-chlórfenyl)metyl]azetidin-3-ylidén[metánsulfonyimetyl)-N-(l-etylpyrolidin-2-ylmetyl)benzamid,3 - ({1-bis (4-chlorophenyl) methyl] azetidin-3-ylidene [metánsulfonyimetyl) -N- (l-ethyl-pyrrolidin-2-ylmethyl) -benzamide,
3-({1-(bis(4-chlórfenyl)metyl]azetidin-3-ylidén(metánsulfonylmetyl)-N-(2,2-dimetylpropyl)benzamid,3 - ({1- (bis (4-chlorophenyl) methyl] azetidin-3-ylidene (methanesulfonylmethyl) -N- (2,2-dimethylpropyl) benzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfony1metyl)-N-(cyklohexylmetyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} metánsulfony1metyl) -N- (cyclohexylmethyl) -benzamide,
3-({1-[bis (4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonylmetyl)-N-(cyklopropylmetyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (cyclopropylmethyl) benzamide,
3-((1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonylmetyl) -N-(2-metylbutyl)benzamid,3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) -N- (2-methylbutyl) benzamide,
3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)metánsulfony1metyl)-N-(2-fenylpropyl)benzamid,3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) metánsulfony1metyl) -N- (2-phenylpropyl) benzamide,
- ({1- [bis (4-chlórfenyl)metyl]azetidin-3-ylidén[metánsulfonylmetyl)-N- (tetrahydrofuran-2-ylmetyl)benzamid,- ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) -N- (tetrahydrofuran-2-ylmethyl) benzamide,
3-((1-[bis (4-chlórfenyl)metyl]azetidin-3-ylidén[metánsulfonylmetyl)-N-(2,2-difenyletyl)benzamid,3 - ((1- [bis (4-chlorophenyl) methyl) azetidin-3-ylidene [methanesulfonylmethyl) -N- (2,2-diphenylethyl) benzamide,
3-((1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)metánsulfonylmetyl)-N-(2-etylbutyi)benzamid, metylester kyseliny 4-{[3-((1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén[metánsulfonylmetyl)benzoylamino]metyl}cyklohexánkarboxylovej,3 - ((1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) -N- (2-ethylbutyl) benzamide, 4 - {[3 - ((1- [bis (4- chlorophenyl) methyl] azetidin-3-ylidene [methanesulfonylmethyl) -benzoylamino] methyl} cyclohexanecarboxylate,
2-amino-l-(4-(3- ({l-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}-metánsulfonylmetyl)fenyl]piperazin-1-y1[etanón, terc-butylester kyseliny (2-{4-[3-({l-[bis(4-chlórfenyl)metyl]-azetidin-3-ylidén)metánsulfonylmetyl)fenyl]piperazin-l-yl)-2-oxoetyl)karbamovej, l-{4-[3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)-metánsulfonylmetyl)fenyl]piperazin-l-yl}-2-metylaminoetanón, terc-butylester kyseliny (2-{4-[3-({l-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)metánsulfonylmetyl)fenyl]piperazin-l-yl)-2-oxoetyl)-N-metylkarbamovej,2-Amino-1- (4- (3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -methanesulfonylmethyl) phenyl] piperazin-1-yl) ethanone, tert-butyl ester (2) - {4- [3 - ({1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-ylidene) -methanesulfonylmethyl) -phenyl] -piperazin-1-yl) -2-oxo-ethyl) -carbamic acid, 1- {4- [ 3 - ({1- [Bis (4-Chloro-phenyl) -methyl] -azetidin-3-ylidene) -methanesulfonylmethyl) -phenyl] -piperazin-1-yl} -2-methylamino-ethanone, tert-butyl ester (2- {4- [3- ({l- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazin-l-yl) -2-oxo-ethyl) -N-butyl ester,
N-metylamid kyseliny 4-[3-({[1-bis(4-chlórfenyl)metyl]-azetidin-3-ylidén)metánsulfonylmetylfenyl]piperazin-1-karbotioovej,4- [3 - ({[1-Bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethylphenyl] piperazine-1-carbothioic acid N-methylamide,
N-metylamid kyseliny 4-[3-({1-[bis(4-chlórfenyl)metyl]-azetidin-3-ylidén}metánsulfonylmetylfenyl]piperazín-1-karboxylovej, metylester kyseliny 4-[3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)metánsulfonylmetyl)fenyl]piperazín-1-karboxylovej,4- [3 - ({1- [Bis (4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethylphenyl] piperazine-1-carboxylic acid N-methylamide, methyl 4- [3 - ({1- [bis] (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazine-1-carboxylic acid,
1-[3-({1-[bi s(4-chlórfenyl)metyl]azetidin-3-ylidénImetánsulf onylmetyl) fenyl]-4-izobutylpiperazín, l-[3-({l-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)metánsulfonylmetyl)fenyl]-4-etylpiperazín,1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene-methanesulfonylmethyl) phenyl] -4-isobutylpiperazine, 1- [3 - ({1- [bis (4-chlorophenyl) methyl] ] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] -4-ethylpiperazine,
4-acetyl-1-[3-({1-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}-metánsulfonylmetyl)fenyl]piperazin, l-{4-[3-({l-[bis(4-chlórfenyl)metyl]azetidin-3-ylidén}metánsulfonylmetyl)fenyl]piperazin-l-yl}-2-dimetylaminoetanón, i4-acetyl-1- [3 - ({1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene} -methanesulfonylmethyl) phenyl] piperazine, 1- {4- [3 - ({1- [bis ( 4-chlorophenyl) methyl] azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazin-1-yl} -2-dimethylaminoethanone; i
1—[3—({1—[bis(4-chlórfenyl)metyl]azetidin-3-ylidén)metánI sulfonylmetyl)fenyl]piperazin, terc-butylester kyseliny 4-[3-({1-[bis(4-chlórfenyl)metyl]244- [3 - ({1- [Bis (4-chlorophenyl) -1- [bis (4-chlorophenyl) methyl] azetidin-3-ylidene) methanesulfonylmethyl) phenyl] piperazine, tert -butyl ester ) -methyl] 24
-azetidin-3-ylidén}metánsulfonylmetyl)fenyl]piperazín-l-karboxylovéj,azetidin-3-ylidene} methanesulfonylmethyl) phenyl] piperazine-l-carboxylic acid,
1-[bis(4-metoxykarbonylfenyl)metyl]-3-[(3,5-difluórfenyl)-(metylsulfonyl)metylén]azetidín,1- [Bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulphonyl) methylene] azetidine,
3- acetoxy-l-[bis (4 -metoxy karbonyl fenyl·) metyl] -3 - [ (3, 5-dif luórfenyl)(metylsulfonyl)metyl-(RS)]azetidín, (RS)-4-[4-((4-chlórfenyl){3-[(3,5-difluórfenyl)metánsulfony1metylén]azetidin-l-yl}metyl)benzyl]morfolín,3-Acetoxy-1- [bis (4-methoxycarbonylphenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl (RS)] azetidine, (RS) -4- [4- ((4-chlorophenyl) {3 - [(3,5-difluorophenyl) metánsulfony1metylén] azetidin-l-yl} methyl) benzyl] morpholine,
4- (4-{3-[(l-benzhydrylazetidin-3-ylidén)metánsulfonylmetyl]-fenoxy}butyl)morfolín,4- (4- {3 - [(1-benzhydrylazetidin-3-ylidene) methanesulfonylmethyl] -phenoxy} butyl) morpholine,
- (4-{3-[(l-benzhydrylazetidin-3-ylidén)metánsulfonylmetyl]-fenoxy}propyl)morfolín,- (4- {3 - [(1-benzhydrylazetidin-3-ylidene) methanesulfonylmethyl] -phenoxy} propyl) morpholine,
N-(1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}tíen-2-ylsulfónamid,N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} thien-2-ylsulfonamide,
N-(1- [bis(4-chlórfenyl)metyl]azetidin-3-yl}-4-metoxyfeny1sulfónamid,N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -4-methoxyphenylsulfonamide,
N-[4-(N-{l-[bis(4-chlórfenyl)metyl]azetidin-3-yl}sulfamoyi)-fenyl]acetamid,N- [4- (N- {l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} sulfamoyl) phenyl] acetamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-4-metylfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methylphenylsulfonamido,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3,4-dimetoxyfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dimetoxyfenylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3-fluórfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-fluorophenylsulfonamido,
N-{1- [bis(4-chlórfenyl)metyl]azetidin-3-yl}-3,4-dichlórfenyisulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-dichlorophenyisulfonamide,
N-(1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3-kyanofenylsulfónamid,N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-kyanofenylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-2,5-dimetoxyfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2,5-dimetoxyfenylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3-trifluórmetylfenylsulfdnamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-trifluórmetylfenylsulfdnamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl} naft-2-ylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-2-ylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}naft-l-ylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} naphth-l-ylsulfonamide,
N-[1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3,4-difluórfenylsulfónamid,N- [1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,4-difluórfenylsulfónamid,
N- {1- [bis (4-chlór f enyl) metyl] azetidin-3-yl }-1-metyl-lH-imidazol-4-ylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -1-methyl-1H-imidazol-4-ylsulfonamide,
N-[4-(N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-ylJsulfamoyl)-2-chlórfenyl]acetamid,N- [4- (N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-ylJsulfamoyl) -2-chlorophenyl] acetamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}pyrid-3-ylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} pyrid-3-ylsulfonamide,
N-{1-[bis (4-chlórfenylmetyl]azetidin-3-yl}-4-fluórfenylsulfónamid,N- {1- [bis (4-chlorophenylmethyl) azetidin-3-yl} -4-fluorophenylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}chinol-8-ylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} quinolin-8-ylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}fenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} phenylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}(fenylmetyl)sulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} (phenylmethyl) sulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3,5-difluórfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3,5-difluórfenylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}pyrid-2-y1sulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} pyridin-2-y1sulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-(3-fluór-5-pyrolidin-l-ylfenyl)sulfónamid, íN- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} - (3-fluoro-5-pyrrolidin-1-ylphenyl) sulfonamide;
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-metyl-4-fluór26 fenylsulfónamid,N- {1- [bis (4-chloro-phenyl) -methyl] -azetidin-3-yl} -N-methyl-4-fluoro-26-phenylsulfonamide,
N-{1-[bis[4-chlórfenyl)metyl]azetidin-3-yl}-N-metylchinol-8-ylsulfónamid,N- {1- [bis [4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl-quinolin-8-ylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-metylfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methylphenylsulfonamido,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-metyl(fenylmetyl) -sulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-methyl (phenylmethyl) sulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-3-sulfamoylfenylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3-sulfamoylfenylsulfónamid,
2-benzénsulfonyl-N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-acetamid,2-benzenesulfonyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -acetamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-2-(4-toluén-4-sulfonyl)acetamid, (3-chlór-4-metylsulfonyltiofén-2-karboxy)-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl]amid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -2- (4-toluene-4-sulfonyl) acetamide, (3-chloro-4-methylsulfonylthiophene-2-carboxy) - {1 - [bis (4-chlorophenyl) methyl] azetidin-3-yl] -amide,
N-{1- [bis (4-chlórfenyl)metyl]azetidin-3-yl}-3-(2-fenyletylénsulfonyl)propiónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -3- (2-phenylethylenesulfonyl) propionamide,
N-{1- [bis (4-chlórfenyl)metyl]azetidin-3-yl}-4-metylsulfonylbenzamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methylsulfonylbenzamide,
N-{1- [bis (4-chlórfenyl)metyl]azetidin-3-yl}-4-metánsulfonylbenzamid, (5-metylsulfonyltiofén-2-karboxy)-{1-[bis(4-chlórfenyl)-metyl]azetidin-3-yl}amid, (5-metylsulfonyl-3-metyl-4-vinyltiofén-2-karboxy){1-[bis-(4-chlórfenyl)metyl]azetidin-3-yl}amid, (RS)-N-{1-[(4-chlórfenyl)pyridin-3-ylmetyl]azetidin-3-yl}-3,5-difluórbenzénsulfónamid, (RS)-N-{1-[(4-chlórfenyl)pyrimidin-5-ylmetyl]azetidin-3-yl}-3,5'-difluórbenzénsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -4-methanesulfonylbenzamide, (5-methylsulfonylthiophene-2-carboxy) - {1- [bis (4-chlorophenyl) methyl] azetidine- 3-yl} amide, (5-Methylsulfonyl-3-methyl-4-vinylthiophene-2-carboxy) {1- [bis- (4-chlorophenyl) methyl] azetidin-3-yl} amide, (RS) -N- {1 - [(4-chlorophenyl) pyridin-3-ylmethyl] azetidin-3-yl} -3,5-difluorobenzenesulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidine 3-yl} -3,5'-difluoro-benzenesulfonamide,
N-{l-[bis(4-chlórfenyl)metyl]azetidin-3-yl)-N-(6-chlórpyrid-2-yl)metylsulfónamid,N- {l- [bis (4-chlorophenyl) methyl] azetidin-3-yl) -N- (6-chloropyrid-2-yl) methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(6-etylpyrid-2-yl)metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (6-ethyl-pyridin-2-yl) methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-chinol-6-ylmetylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-quinol-6-ylmetylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-y1}-N-chinol-5-y1metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N-quinolin-5-y1metylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-izochinol-5-ylmetylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-isoquinolin-5-ylmetylsulfónamid,
N-(1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-pyrid-3-ylmetylsulfónamid,N- (1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N-pyrid-3-ylmetylsulfónamid,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(pyrid-l-oxid-3-yl)metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-l-oxide-3-yl) methylsulfonamide,
N-(ÍR,2 S,4 S)-bicyklo[2,2,1]hept-2-yl-N-{l-[bis-(4-chlórfenyl·)-metylazetidin-3-yljmetylsulfónamid,N- (1R, 2S, 4S) -bicyclo [2.2.1] hept-2-yl-N- {1- [bis- (4-chloro-phenyl) -methyl-azetidin-3-yl] -methylsulfonamide,
N-(ÍR, 2R, 4S) -(bicyklo[2,2,1] hept-2-yl) -N-{1—(bis-(4-chlórfenyl) -metyl]azetidin-3-y1]metylsulfónamid,N- (1R, 2R, 4S) - (Bicyclo [2.2.1] hept-2-yl) -N- {1- (bis- (4-chloro-phenyl) -methyl] -azetidin-3-yl) -methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-y1}-N-(3,5-difluórfenyl)metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N- (3,5-difluorophenyl) methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-y1}-N-(tiazol-2-yl)-metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-y1} -N- (thiazol-2-yl) methylsulphonamide,
N-{ 1- [bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(3-metoxyfenyl)-metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-methoxyphenyl) methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl] azetidin-3-y1}-N-(3-hydroxyfenyl)28N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxyphenyl) 28
-metylsulfónamid,methylsulphonamide.
N-{1-[bis(4-chlorfenyl)metyl]azetidin-3-yl}-N-(3-hydroxymetyl fenyl)metylsulfónamid, etyl-N-{1-[bis (4-chlórfenyl)metyl]azetidin-3-yl}-N-(metylsulfonyl) -3-aminobenzoát,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3-hydroxymethylphenyl) methylsulfonamide, ethyl N- {1- [bis (4-chlorophenyl) methyl] azetidin-3 -yl} -N- (methylsulfonyl) -3-aminobenzoate,
N-{l-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(izobutylpiperid-4-yl)metylsulfónamid,N- {l- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (izobutylpiperid-4-yl) methylsulfonamide,
N-benzyl-N- {1- [bis (4-chlór f enyl) metyl]azetidin-3-yl }amín,N-benzyl-N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} amine,
N-{1-[bis(4-chlórfenyl)metyl]azetidín-3-yl}-N-(3,5-difluórbenzyl)amín,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) amine,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(3,5-difluórbenzyl)metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorobenzyl) methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(pyrid-3-ylmetyl)metylsulfónamid,N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (pyrid-3-ylmethyl) methylsulfonamide,
N-{1-[bis(4-fluórfenyl)metyl]azetidin-3-yl}—N—(3,5-difluórfenyl) metylsulfónamid, (RS)-N-{1-[(4-chlórfenyl)pyrid-3-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (P)-N-{1-[(4-chlórfenyl)pyrid-3-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (S)-N-{1-[(4-chlórfenyl)pyrid-3-ylmetyl]azetidín-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (RS)-N-(1-[(4-chlórfenyl)pyrid-4-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (R)-N-{1-[(4-chlórfenyl)pyrid-4-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (S)-N-{1-[(4-chlórfenyl)pyrid-4-ylmetyl]azetidin-3-yl}-N-(3,'5-dif luórfenyl)metylsulfónamid, {RS) —N—{1—[(4-chlórfenyl)pyrimidín-5-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (R) -N-{1-[(4-chlórfenyl)pyrimidín-5-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid, (S) -N-{1-[(4-chlórfenyl)pyrimidin-5-ylmetyl]azetidin-3-yl}-N-(3,5-difluórfenyl)metylsulfónamid,N- {1- [bis (4-fluorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrid-3 -ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (P) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N - (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-3-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, ( RS) -N- (1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (R) -N- {1 - [(4) (chlorophenyl) pyrid-4-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -N- {1 - [(4-chlorophenyl) pyrid-4-ylmethyl] azetidine- 3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (RS) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3 (R) -N- {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide, (S) -, 5-difluorophenyl) methylsulfonamide, (S) - N {1 - [(4-chlorophenyl) pyrimidin-5-ylmethyl] azetidin-3-yl} -N- (3,5-difluorophenyl) methylsulfonamide,
N-{1-[bis(4-chlórfenyl)metyl]azetidin-3-yl}-N-(3,5-difluórfenyl) benzylsulfónamid, ich optické izoméry a ich farmaceutický prijateľné soli s anorganickou alebo organickou kyselinou.N- {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} -N- (3,5-difluorophenyl) benzylsulfonamide, their optical isomers, and their pharmaceutically acceptable salts with an inorganic or organic acid.
A ešte najmä výhodné sú nasledovné azetidínové deriváty:And yet particularly preferred are the following azetidine derivatives:
1-[bis(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)-metyl-(RS)]azetidin-3-ol,1- [Bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methyl- (RS)] azetidin-3-ol,
3-acetoxy-l-[bis(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl)-(metylsulfonyl)metyl)metylsulfonylmetyl-(RS)]azetidín,3-acetoxy-l- [bis (4-chlorophenyl) methyl] -3 - [(3,5-difluorophenyl) - (methylsulfonyl) methyl) methylsulfonylmethyl (RS)] azetidine,
1-[bis(4-chlórfenyl)metyl]-3-[(3,5-difluórfenyl) (metylsulfonyl)-metylén]azetidín, ich optické izoméry a ich farmaceutický prijateľné soli s anorganickou alebo organickou kyselinou.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.
Ako príklady farmaceutický prijateľných solí azetidínových derivátov sa uvádzajú nasledovné soli: benzensulfonát, bromid, chlorid, citrát, etánsulfonát, fumarát, glukonát, jodát, izetionát, maleát, metánsulfonát, metylén-bis-3-oxynaftoát, nitrát, oxalat, pamoát, fosfát, salicylát, sukcinát, sulfát, vínan, teofylínacetát a p-toluénsulfonát.Examples of pharmaceutically acceptable salts of azetidine derivatives include: benzenesulfonate, bromide, chloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-3-oxynaphthate, nitrate, oxalate, pamoate, oxalate, pamoate, oxalate, pamoate salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.
Ďalšie antagonisty CB1 na použitie v kombináciách podľa predkladaného vynálezu sú napríklad pyrazolové deriváty opísané v EP 576 357, EP 658 546, EP 656 354, WO 97/19063 a WO 00/46209, benzotiofénové a benzofuránové deriváty opísané vo WO 96/02248 alebo sulfónamidy opísané vo WO 98/37061. Uvádzajú sa najmä produkty známe pod kódom SR141716 a LY320135.Other CB1 antagonists for use in the combinations of the present invention are, for example, the pyrazole derivatives described in EP 576 357, EP 658 546, EP 656 354, WO 97/19063 and WO 00/46209, the benzothiophene and benzofuran derivatives described in WO 96/02248 or sulfonamides described in WO 98/37061. Particular mention is made of the products known under the codes SR141716 and LY320135.
Príklady uskutočnenia vynálezuDETAILED DESCRIPTION OF THE INVENTION
Synergický účinok kombinácie sibutramínu a antagonistu CB1 na príjem potravy sa stanovil podlá nasledovného protokolu.The synergistic effect of the combination of sibutramine and CB1 antagonist on food intake was determined according to the following protocol.
Na štúdiu sa použili obézne potkany Fa/fa Zucker vo veku 7 týždňov a pochádzajúce od Iffa-Credo, Francúzsko. Tieto potkany sa umiestnili do jednotlivých klietok a vážili sa každý deň medzi 8 a 10 hodinou odpoludnia. V rovnakom čase sa vážilo aj množstvo potravy. Táto potrava (M20, Pietrement, Francúzsko) sa menila každý deň a potkany mali volný prístup k potrave počas 24 hodín. Potkany sa ošetrovali počas 1 týždňa vehikulom (miglyol 812N a 0,5 % metylcelulóza/0,2 % polysorbát 80) v dvoch po sebe idúcich podaniach. Potkany sa od 8 dňa ošetrovali orálnou cestou antagonistom CB1 (l-[bis(4-dichlórfenyl)metyl]-3-[(3,5-difluórfenyl)(metylsulfonyl)metylénjazetidín alebo sibutramínom (pozri nasledovnú tabuľku).The obese Fa / fa Zucker rats at 7 weeks of age from Iffa-Credo, France were used for the study. These rats were placed in individual cages and weighed every day between 8 and 10 pm. At the same time, the amount of food was weighed. This food (M20, Pietrement, France) was changed every day and the rats had free access to food for 24 hours. Rats were treated with vehicle (miglyol 812N and 0.5% methylcellulose / 0.2% polysorbate 80) for 1 week in two consecutive administrations. Rats were treated orally from day 8 with CB1 antagonist (1- [bis (4-dichlorophenyl) methyl] -3 - [(3,5-difluorophenyl) (methylsulfonyl) methylene-ketidine or sibutramine (see table below).
Sibutramín sa rozpustil v roztoku zmesi 0,5 % metylcelulóza/0, 2% polysorbát 80 a podal sa v dávke 3 mg/kg; antaaonista CB1 sa rozpustil v miglyole 812N (Huls, Allemagne, Nemecko) v množstve 0,6 mg/kg, a tieto dva produkty sa podali v objeme 1 ml/kg. Každá skupina sa skladala z 12 až 14 zvierat, vytvorili sa nasledovné skupiny a zvieratá sa ošetrovali každý deň počas 5 dní v dvoch po sebe idúcich podaniach.Sibutramine was dissolved in a solution of 0.5% methylcellulose / 0.2% polysorbate 80 and administered at a dose of 3 mg / kg; the CB1 antagonist was dissolved in miglyole 812N (Huls, Allemagne, Germany) at 0.6 mg / kg, and the two products were administered in a volume of 1 ml / kg. Each group consisted of 12-14 animals, the following groups were formed, and the animals were treated every day for 5 days in two consecutive administrations.
Spotreba potravín každého zvieraťa sa merala každý deň. Výsledky sú uvedené ako množstvo potravín spotrebovaných v priebehu ošetrovania uskutočňovaného počas 5 dní. Získané výsledky sú uvedené v nasledovnej tabulke.Food consumption of each animal was measured daily. The results are shown as the amount of food consumed during the treatment for 5 days. The results obtained are shown in the following table.
*p <,0,05 **p < 0,01 ***p< 0,001* p <, 0.05 ** p <0.01 *** p <0.001
Výsledky ukazujú, že v prípade zvierat, ktoré dostávali kom32 bináciu sibutramínu a antagonistu CB1 je zníženie v spotrebe potravy oveľa väčšie než v prípade zvierat, ktoré dostávali samotný sibutramín alebo samotný antagonista CB1.The results show that in animals receiving sibutramine and CB1 antagonist combinations, the reduction in food consumption is much greater than in animals receiving sibutramine alone or CB1 antagonist alone.
Zlúčeniny sa v kombinácii môžu podávať orálne, parenterálne, transdermálne alebo rektálne, buď súčasne, oddelene alebo postupne.The compounds may be administered orally, parenterally, transdermally, or rectally, either simultaneously, separately or sequentially.
Predkladaný vynález sa týka aj farmaceutických kompozícií obsahujúcich kombináciu sibutramínu, jeho hydrátu alebo jeho farmaceutický prijateľnej soli a antagonistu receptora CB1 v čistom stave s jedným alebo viacerými kompatibilnými riedidlami a/alebo pomocnými látkami a/alebo v kombinácii s iným farmaceutický prijateľným aktívnym produktom na súčasné, oddelené alebo postupné použitie.The present invention also relates to pharmaceutical compositions comprising a combination of sibutramine, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and a CB1 receptor antagonist in pure form with one or more compatible diluents and / or excipients and / or in combination with another pharmaceutically acceptable active product. separate or sequential use.
Ako tuhé kompozície na orálne podanie sa môžu použiť tablety, pilulky, prášky (tvrdé želatínové kapsule, vrecká) alebo granule. V týchto prostriedkoch sa aktívna zložka podľa vynálezu zmieša pod prúdom argónu s jedným alebo viacerými inertnými zrieďovadlami, ako je škrob, celulóza, sacharóza, laktóza alebo oxid kremičitý. Tieto kompozície môžu obsahovať aj iné látky než sú zrieďovadlá, napríklad mazadlá, ako jes stearát horečnatý alebo mastenec, farbivá, povlaky (tablety potiahnuté cukrom) alebo glazúru.As solid compositions for oral administration, tablets, pills, powders (hard gelatin capsules, sachets) or granules may be used. In these compositions, the active ingredient of the invention is mixed under one stream of argon with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica. These compositions can comprise substances other than diluents, e.g. a lubricant such as a magnesium stearate or talc, a coloring, a coating (sugar-coated tablets) or a glaze.
Ako kvapalné kompozície na orálne podanie sa môžu použiť farmaceutický prijateľné roztoky, suspenzie, emulzie, sirupy a elixíry obsahujúce inertné zrieďovadlá, ako je voda, etanol, glycerol, rastlinné oleje alebo parafínový olej. Kompozície môžu obsahovať aj iné látky než sú· zrieďovadlá, napríklad zmáčadlá, sladidlá, zahusťovadlá, aromáty alebo stabilizátory.As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil may be used. The compositions may also contain substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing agents.
Sterilnými kompozíciami na parenterálne podanie môžu byť výhodne roztoky, ktoré sú vodné alebo nevodné, suspenzie alebo emulzie. Ako rozpúšťadlo alebo vehikulum sa môže použiť voda, propyléngiykol, polyetylénglykol, rastlinné oleje, najmä olivovýThe sterile compositions for parenteral administration may preferably be solutions which are aqueous or non-aqueous, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, can be used as a solvent or vehicle.
I olej', in j ikovatelné organické estery, napríklad etyloleát, alebo iné organické rozpúšťadlá. Tieto kompozície môžu obsahovať pomocné látky, najmä zmáčadlá, izotonizačné látky, emulgátory, dispergátory a stabilizátory. Sterilizácia sa môže uskutočniť niekoľkými spôsobmi, napríklad sterilnou filtráciou, včlenením sterilizačných činidiel do prostriedku, ožiarením alebo zohriatím. Môžu sa pripraviť aj vo forme sterilných tuhých prostriedkov, ktoré sa môžu rozpustiť v čase použitia v sterilnej vode alebo inom injikovatelnom prostredí.Oil, injectable organic esters, for example ethyl oleate, or other organic solvents. These compositions may contain excipients, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization can be accomplished in several ways, for example by sterile filtration, incorporation of sterilizing agents into the composition, irradiation or heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or other injectable medium.
Kompozíciami na rektálne podanie sú čapíky alebo rektálne kapsule, ktoré obsahujú okrem aktívnej zložky pomocné látky, ako je kakaové maslo, polosyntetické glyceridy alebo polyetylénglykoly.Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
Farmaceutické kompozície zvyčajne obsahujú 0,5 až 10 mg sibutramínu a 0,1 až 200 mg antagonistu CB1.The pharmaceutical compositions usually contain 0.5 to 10 mg sibutramine and 0.1 to 200 mg CB1 antagonist.
Predkladaný vynález sa týka aj spôsobu liečenia obezity, ktorý spočíva v podaní pacientovi kombinácie podľa vynálezu buď súčasne alebo oddelene alebo po čiastkových dávkach.The present invention also relates to a method of treating obesity comprising administering to a patient a combination of the invention either simultaneously or separately or in divided doses.
Dávka závisí od požadovaného účinku, od trvania liečby a od cesty podania; vo všeobecnosti sa podáva dospelému pacientovi 1 až 15 mg sibutramínu denne pri orálnom podaní a 0,10 až 500 mg antagonistu CB1 denne pri orálnom podaní.The dose depends on the effect desired, the duration of treatment and the route of administration; in general, 1 to 15 mg sibutramine per day for oral administration and 0.10 to 500 mg CB1 antagonist per day for oral administration are administered to an adult patient.
Vo všeobecnosti ošetrujúci lekár stanoví vhodnú dávku podľa veku, hmotnosti a akéhokolvek ďalšieho faktora špecifického pre subjekt, ktorý sa má liečiť.Generally, the attending physician will determine the appropriate dose according to the age, weight and any other factor specific to the subject to be treated.
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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 |
PCT/FR2001/003022 WO2002028346A2 (en) | 2000-10-04 | 2001-10-01 | Association of the cb1 receptor antagonist and sibutramin, for treating obesity |
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