HRP20030249A2 - Association of the cb1 receptor antagonist and a sibutramin, pharmaceutical compositions containing same and use thereof for treating obesity - Google Patents
Association of the cb1 receptor antagonist and a sibutramin, pharmaceutical compositions containing same and use thereof for treating obesity Download PDFInfo
- Publication number
- HRP20030249A2 HRP20030249A2 HR20030249A HRP20030249A HRP20030249A2 HR P20030249 A2 HRP20030249 A2 HR P20030249A2 HR 20030249 A HR20030249 A HR 20030249A HR P20030249 A HRP20030249 A HR P20030249A HR P20030249 A2 HRP20030249 A2 HR P20030249A2
- Authority
- HR
- Croatia
- Prior art keywords
- methyl
- chlorophenyl
- methylsulfonyl
- bis
- azetidine
- Prior art date
Links
- 208000008589 Obesity Diseases 0.000 title abstract description 7
- 235000020824 obesity Nutrition 0.000 title abstract description 7
- 229940123158 Cannabinoid CB1 receptor antagonist Drugs 0.000 title abstract description 5
- 239000003555 cannabinoid 1 receptor antagonist Substances 0.000 title abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- -1 -COOR5 Chemical group 0.000 claims description 141
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 138
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 114
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 68
- 229910052757 nitrogen Inorganic materials 0.000 claims description 54
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 38
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 34
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 32
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 32
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000004429 atom Chemical group 0.000 claims description 30
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 30
- 229920006395 saturated elastomer Polymers 0.000 claims description 30
- 239000011593 sulfur Chemical group 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 30
- 125000002619 bicyclic group Chemical group 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 21
- 125000004414 alkyl thio group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- 150000003254 radicals Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 19
- 229940124802 CB1 antagonist Drugs 0.000 claims description 16
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 15
- 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 15
- 229960004425 sibutramine Drugs 0.000 claims description 14
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 12
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 12
- 150000001491 aromatic compounds Chemical class 0.000 claims description 12
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 12
- 150000002390 heteroarenes Chemical class 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
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 10
- 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 8
- 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 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004686 alkyl sulfanyl alkyl group Chemical group 0.000 claims description 8
- 125000004687 alkyl sulfinyl alkyl group Chemical group 0.000 claims description 8
- 125000004688 alkyl sulfonyl alkyl group Chemical group 0.000 claims description 8
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 8
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 8
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 8
- 230000003287 optical effect Effects 0.000 claims description 8
- 125000005493 quinolyl group Chemical group 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 7
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 6
- 125000002541 furyl 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
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
- ZGYFLQUPOCALIL-UHFFFAOYSA-N 1-benzhydryl-3-[methylsulfonyl-[3-(trifluoromethoxy)phenyl]methylidene]azetidine Chemical compound C=1C=CC(OC(F)(F)F)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZGYFLQUPOCALIL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 5
- 229940124530 sulfonamide Drugs 0.000 claims description 5
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 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
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- BIHRKCOQNANFPP-HSZRJFAPSA-N 1-[(r)-(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-HSZRJFAPSA-N 0.000 claims description 3
- NVAZILBISPTELT-OAQYLSRUSA-N 1-[(r)-(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-OAQYLSRUSA-N 0.000 claims description 3
- 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
- SDJUKPVOYHWILZ-UHFFFAOYSA-N 1-[3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]phenyl]pyrrolidine Chemical compound C=1C=CC(N2CCCC2)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 SDJUKPVOYHWILZ-UHFFFAOYSA-N 0.000 claims description 3
- SOPDUJWVNOSRDR-GDLZYMKVSA-N 1-[[4-[(r)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]piperidine Chemical compound C1([C@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(CN3CCCCC3)=CC=2)=CC=C(Cl)C=C1 SOPDUJWVNOSRDR-GDLZYMKVSA-N 0.000 claims description 3
- WKOAOEVZSBATJT-PMERELPUSA-N 1-[[4-[(s)-(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-PMERELPUSA-N 0.000 claims description 3
- FBWVTEZCNIQJRF-LJAQVGFWSA-N 1-[[4-[(s)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]-4-methylpiperazine Chemical compound C1CN(C)CCN1CC1=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 FBWVTEZCNIQJRF-LJAQVGFWSA-N 0.000 claims description 3
- ZGLXDYITFVRVCG-NDEPHWFRSA-N 1-[[4-[(s)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]pyrrolidine Chemical compound C1([C@@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(CN3CCCC3)=CC=2)=CC=C(Cl)C=C1 ZGLXDYITFVRVCG-NDEPHWFRSA-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
- HCYHNZJIUZTTFK-UHFFFAOYSA-N 1-[bis[4-(trifluoromethoxy)phenyl]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(OC(F)(F)F)=CC=1)C1=CC=C(OC(F)(F)F)C=C1 HCYHNZJIUZTTFK-UHFFFAOYSA-N 0.000 claims description 3
- COEFGPCJQSWIJQ-UHFFFAOYSA-N 1-benzhydryl-3-[(2,3-dichlorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C=CC(Cl)=C(Cl)C=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 COEFGPCJQSWIJQ-UHFFFAOYSA-N 0.000 claims description 3
- ZXMARMGTUBBFHE-UHFFFAOYSA-N 1-benzhydryl-3-[(2,5-dichlorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C(Cl)=CC=C(Cl)C=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZXMARMGTUBBFHE-UHFFFAOYSA-N 0.000 claims description 3
- USKXXLXCEAKGIL-UHFFFAOYSA-N 1-benzhydryl-3-[(3,5-dichlorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C(Cl)=CC(Cl)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 USKXXLXCEAKGIL-UHFFFAOYSA-N 0.000 claims description 3
- BEZKBMXRTCXDEK-UHFFFAOYSA-N 1-benzhydryl-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)C1=CC=CC=C1 BEZKBMXRTCXDEK-UHFFFAOYSA-N 0.000 claims description 3
- IHEGLFXGTJAGNN-UHFFFAOYSA-N 1-benzhydryl-3-[(3-bromophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C=CC(Br)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 IHEGLFXGTJAGNN-UHFFFAOYSA-N 0.000 claims description 3
- ATLHMTLEQJOFKX-UHFFFAOYSA-N 1-benzhydryl-3-[(3-chlorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C=CC(Cl)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ATLHMTLEQJOFKX-UHFFFAOYSA-N 0.000 claims description 3
- CXVCKVBWGQDVAX-UHFFFAOYSA-N 1-benzhydryl-3-[(3-fluorophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C=CC(F)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 CXVCKVBWGQDVAX-UHFFFAOYSA-N 0.000 claims description 3
- ZEHGNVXHYPKEHO-UHFFFAOYSA-N 1-benzhydryl-3-[(3-iodophenyl)-methylsulfonylmethylidene]azetidine Chemical compound C=1C=CC(I)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 ZEHGNVXHYPKEHO-UHFFFAOYSA-N 0.000 claims description 3
- VGLYSTYECJHDJB-UHFFFAOYSA-N 1-benzhydryl-3-[(3-methylphenyl)-methylsulfonylmethylidene]azetidine Chemical compound CC1=CC=CC(C(=C2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)S(C)(=O)=O)=C1 VGLYSTYECJHDJB-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- OFVJVEPORFCDQL-UHFFFAOYSA-N 1-benzhydryl-3-[ethylsulfonyl(phenyl)methylidene]azetidine Chemical compound C=1C=CC=CC=1C(S(=O)(=O)CC)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 OFVJVEPORFCDQL-UHFFFAOYSA-N 0.000 claims description 3
- DYAHYJVGFCXPLL-UHFFFAOYSA-N 1-benzhydryl-3-[methylsulfonyl(phenyl)methylidene]azetidine Chemical compound C=1C=CC=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC=CC=1)C1=CC=CC=C1 DYAHYJVGFCXPLL-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
- UYMOXHDJOGNHGD-LJQANCHMSA-N 2-[(r)-(4-chlorophenyl)-[3-[methylsulfonyl(phenyl)methylidene]azetidin-1-yl]methyl]-1,3-thiazole Chemical compound C1([C@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=NC=CS1 UYMOXHDJOGNHGD-LJQANCHMSA-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
- UYMOXHDJOGNHGD-IBGZPJMESA-N 2-[(s)-(4-chlorophenyl)-[3-[methylsulfonyl(phenyl)methylidene]azetidin-1-yl]methyl]-1,3-thiazole Chemical compound C1([C@@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)=NC=CS1 UYMOXHDJOGNHGD-IBGZPJMESA-N 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 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
- VGMIYPGXWOUQFS-XMMPIXPASA-N 3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]-1-[(r)-(4-methoxyphenyl)-phenylmethyl]azetidine Chemical compound C1=CC(OC)=CC=C1[C@@H](C=1C=CC=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 VGMIYPGXWOUQFS-XMMPIXPASA-N 0.000 claims description 3
- VGMIYPGXWOUQFS-DEOSSOPVSA-N 3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]-1-[(s)-(4-methoxyphenyl)-phenylmethyl]azetidine Chemical compound C1=CC(OC)=CC=C1[C@H](C=1C=CC=CC=1)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 VGMIYPGXWOUQFS-DEOSSOPVSA-N 0.000 claims description 3
- WWFZLYVGAVYSHR-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-(2-morpholin-4-ylethyl)benzamide Chemical compound C=1C=CC(C(=O)NCCN2CCOCC2)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 WWFZLYVGAVYSHR-UHFFFAOYSA-N 0.000 claims description 3
- FRPWVAZATMLFSJ-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-(3-morpholin-4-ylpropyl)benzamide Chemical compound C=1C=CC(C(=O)NCCCN2CCOCC2)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 FRPWVAZATMLFSJ-UHFFFAOYSA-N 0.000 claims description 3
- QOFJARYKNHCFOP-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-(4-methylpiperazin-1-yl)benzamide Chemical compound C1CN(C)CCN1NC(=O)C1=CC=CC(C(=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(C)(=O)=O)=C1 QOFJARYKNHCFOP-UHFFFAOYSA-N 0.000 claims description 3
- UOUGWWQPFUAXGJ-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-[2-(dimethylamino)ethyl]benzamide Chemical compound CN(C)CCNC(=O)C1=CC=CC(C(=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(C)(=O)=O)=C1 UOUGWWQPFUAXGJ-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
- 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
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- 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
- NVWZAORPAUTJDW-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(2,2-dimethylpropyl)benzamide Chemical compound CC(C)(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 NVWZAORPAUTJDW-UHFFFAOYSA-N 0.000 claims description 3
- HZLYURCOFSSNJH-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(2,2-diphenylethyl)benzamide Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N(C1)CC1=CS(=O)(=O)CC1=CC=CC(C(=O)NCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 HZLYURCOFSSNJH-UHFFFAOYSA-N 0.000 claims description 3
- LJMMGNDPDWRUDG-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(2-ethylbutyl)benzamide Chemical compound CCC(CC)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 LJMMGNDPDWRUDG-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
- QYGSMFQHYQQGGR-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(2-methylpropyl)benzamide Chemical compound CC(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 QYGSMFQHYQQGGR-UHFFFAOYSA-N 0.000 claims description 3
- CNMDTGYRPPZEBQ-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(cyclohexylmethyl)benzamide Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N(C1)CC1=CS(=O)(=O)CC1=CC=CC(C(=O)NCC2CCCCC2)=C1 CNMDTGYRPPZEBQ-UHFFFAOYSA-N 0.000 claims description 3
- NVLVGHQEGLQVIL-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-(cyclopropylmethyl)benzamide Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N(C1)CC1=CS(=O)(=O)CC1=CC=CC(C(=O)NCC2CC2)=C1 NVLVGHQEGLQVIL-UHFFFAOYSA-N 0.000 claims description 3
- KTDXDPJKASEDKT-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-[(1-ethylpyrrolidin-2-yl)methyl]benzamide Chemical compound CCN1CCCC1CNC(=O)C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 KTDXDPJKASEDKT-UHFFFAOYSA-N 0.000 claims description 3
- BWZFAJHFKSCWLS-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-[1-(dimethylamino)propan-2-yl]benzamide Chemical compound CN(C)CC(C)NC(=O)C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 BWZFAJHFKSCWLS-UHFFFAOYSA-N 0.000 claims description 3
- OZHYCUGWABHDFR-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]-n-[3-(dimethylamino)propyl]benzamide Chemical compound CN(C)CCCNC(=O)C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 OZHYCUGWABHDFR-UHFFFAOYSA-N 0.000 claims description 3
- ZUQQILFPHCUUQO-UHFFFAOYSA-N 3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]methylsulfonylmethyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CS(=O)(=O)C=C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ZUQQILFPHCUUQO-UHFFFAOYSA-N 0.000 claims description 3
- PGHBUQMOEMEUNT-UHFFFAOYSA-N 3-n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]benzene-1,3-disulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(S(=O)(=O)NC2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)=C1 PGHBUQMOEMEUNT-UHFFFAOYSA-N 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
- GLXILTSCZKNOJQ-VWLOTQADSA-N 4-[(s)-(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-VWLOTQADSA-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
- OIJLKMYMEOURJA-MUUNZHRXSA-N 4-[[4-[(r)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]morpholine Chemical compound C1([C@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(CN3CCOCC3)=CC=2)=CC=C(Cl)C=C1 OIJLKMYMEOURJA-MUUNZHRXSA-N 0.000 claims description 3
- OIJLKMYMEOURJA-NDEPHWFRSA-N 4-[[4-[(s)-(4-chlorophenyl)-[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]methyl]phenyl]methyl]morpholine Chemical compound C1([C@@H](N2CC(C2)=C(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(CN3CCOCC3)=CC=2)=CC=C(Cl)C=C1 OIJLKMYMEOURJA-NDEPHWFRSA-N 0.000 claims description 3
- RYNSGDFWBJWWSZ-UHFFFAOYSA-N 4-[[6-methoxy-2-(4-methoxyphenyl)-3-benzofuranyl]-oxomethyl]benzonitrile Chemical compound C1=CC(OC)=CC=C1C1=C(C(=O)C=2C=CC(=CC=2)C#N)C2=CC=C(OC)C=C2O1 RYNSGDFWBJWWSZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- PSZFVCAQCDIBRW-UHFFFAOYSA-N 5-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]-n-(2-methylpropyl)thiophene-2-carboxamide Chemical compound S1C(C(=O)NCC(C)C)=CC=C1C(S(C)(=O)=O)=C1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 PSZFVCAQCDIBRW-UHFFFAOYSA-N 0.000 claims description 3
- QBQRVMHAUZKPEQ-UHFFFAOYSA-N CC1=CSC(S(C)(=O)=O)=C1C=C.NC(C1)C(C(O)=O)N1C(C(C=C1)=CC=C1Cl)C(C=C1)=CC=C1Cl Chemical compound CC1=CSC(S(C)(=O)=O)=C1C=C.NC(C1)C(C(O)=O)N1C(C(C=C1)=CC=C1Cl)C(C=C1)=CC=C1Cl QBQRVMHAUZKPEQ-UHFFFAOYSA-N 0.000 claims description 3
- XQCLHPYLUJPZBT-UHFFFAOYSA-N CS(C1=CSC=C1Cl)(=O)=O.NC(C1)C(C(O)=O)N1C(C(C=C1)=CC=C1Cl)C(C=C1)=CC=C1Cl Chemical compound CS(C1=CSC=C1Cl)(=O)=O.NC(C1)C(C(O)=O)N1C(C(C=C1)=CC=C1Cl)C(C=C1)=CC=C1Cl XQCLHPYLUJPZBT-UHFFFAOYSA-N 0.000 claims description 3
- PGDDYDAGRXBVAI-UHFFFAOYSA-N FC1=CC(F)=CC(CN(C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(=O)=O)=C1 Chemical compound FC1=CC(F)=CC(CN(C2CN(C2)C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)S(=O)=O)=C1 PGDDYDAGRXBVAI-UHFFFAOYSA-N 0.000 claims description 3
- NAXUDNAEIIAYRQ-UHFFFAOYSA-N [3-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]phenyl]methanol Chemical compound C=1C=CC(CO)=CC=1C(S(=O)(=O)C)=C(C1)CN1C(C=1C=CC(Cl)=CC=1)C1=CC=C(Cl)C=C1 NAXUDNAEIIAYRQ-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- AIZZQTVOXQNBPB-XMMPIXPASA-N [4-[(r)-(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-XMMPIXPASA-N 0.000 claims description 3
- 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 description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 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 description 3
- GSURFFSJZXJJQJ-UHFFFAOYSA-N methyl 4-[[3-[(3,5-difluorophenyl)-methylsulfonylmethylidene]azetidin-1-yl]-(4-methoxycarbonylphenyl)methyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C(C=1C=CC(=CC=1)C(=O)OC)N(C1)CC1=C(S(C)(=O)=O)C1=CC(F)=CC(F)=C1 GSURFFSJZXJJQJ-UHFFFAOYSA-N 0.000 claims description 3
- WHWRHLAHKVGQMU-UHFFFAOYSA-N methyl 5-[[1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-methylsulfonylmethyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1C(S(C)(=O)=O)=C1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 WHWRHLAHKVGQMU-UHFFFAOYSA-N 0.000 claims description 3
- XZLPOJOSMALGTC-XKDCRVNJSA-N n-[(1s,3r,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-XKDCRVNJSA-N 0.000 claims description 3
- TUHDYGZZOSVEIS-UHFFFAOYSA-N n-[1-[(4-chlorophenyl)-pyridin-3-ylmethyl]azetidin-3-yl]-n-(3,5-difluorophenyl)methanesulfonamide Chemical compound C=1C(F)=CC(F)=CC=1N(S(=O)(=O)C)C(C1)CN1C(C=1C=NC=CC=1)C1=CC=C(Cl)C=C1 TUHDYGZZOSVEIS-UHFFFAOYSA-N 0.000 claims description 3
- TUHDYGZZOSVEIS-JOCHJYFZSA-N n-[1-[(r)-(4-chlorophenyl)-pyridin-3-ylmethyl]azetidin-3-yl]-n-(3,5-difluorophenyl)methanesulfonamide Chemical compound C1([C@@H](N2CC(C2)N(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=NC=CC=2)=CC=C(Cl)C=C1 TUHDYGZZOSVEIS-JOCHJYFZSA-N 0.000 claims description 3
- SIQYQDZVTXFIHU-JOCHJYFZSA-N n-[1-[(r)-(4-chlorophenyl)-pyridin-4-ylmethyl]azetidin-3-yl]-n-(3,5-difluorophenyl)methanesulfonamide Chemical compound C1([C@H](N2CC(C2)N(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(Cl)=CC=2)=CC=NC=C1 SIQYQDZVTXFIHU-JOCHJYFZSA-N 0.000 claims description 3
- LXSJIKMOZWBXLC-OAQYLSRUSA-N n-[1-[(r)-(4-chlorophenyl)-pyrimidin-5-ylmethyl]azetidin-3-yl]-n-(3,5-difluorophenyl)methanesulfonamide Chemical compound C1([C@@H](N2CC(C2)N(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=NC=NC=2)=CC=C(Cl)C=C1 LXSJIKMOZWBXLC-OAQYLSRUSA-N 0.000 claims description 3
- SIQYQDZVTXFIHU-QFIPXVFZSA-N n-[1-[(s)-(4-chlorophenyl)-pyridin-4-ylmethyl]azetidin-3-yl]-n-(3,5-difluorophenyl)methanesulfonamide Chemical compound C1([C@@H](N2CC(C2)N(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=CC(Cl)=CC=2)=CC=NC=C1 SIQYQDZVTXFIHU-QFIPXVFZSA-N 0.000 claims description 3
- LXSJIKMOZWBXLC-NRFANRHFSA-N n-[1-[(s)-(4-chlorophenyl)-pyrimidin-5-ylmethyl]azetidin-3-yl]-n-(3,5-difluorophenyl)methanesulfonamide Chemical compound C1([C@H](N2CC(C2)N(S(=O)(=O)C)C=2C=C(F)C=C(F)C=2)C=2C=NC=NC=2)=CC=C(Cl)C=C1 LXSJIKMOZWBXLC-NRFANRHFSA-N 0.000 claims description 3
- IPJQIXUTBWDAKL-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-1-phenylmethanesulfonamide Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC(Cl)=CC=1)N1CC(NS(=O)(=O)CC=2C=CC=CC=2)C1 IPJQIXUTBWDAKL-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
- PIJIMSMSLQEXCB-UHFFFAOYSA-N n-[1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2-(4-methylphenyl)sulfonylacetamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)CC(=O)NC1CN(C(C=2C=CC(Cl)=CC=2)C=2C=CC(Cl)=CC=2)C1 PIJIMSMSLQEXCB-UHFFFAOYSA-N 0.000 claims description 3
- 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 description 3
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Prikazani izum se odnosi na kombinaciju -antagonista receptora CB1 i sibutramina, farmaceutske pripravke u čijem se sastavu nalaze, te njihovu primjenu u liječenju debljine. The presented invention relates to the combination of the CB1 receptor antagonist and sibutramine, the pharmaceutical preparation in which they are included, and their use in the treatment of obesity.
Antagonisti receptora CB1 poznati su po njihovom učinku na unos hrane, te njihovoj primjeni kao sredstva za mršavljenje (G. COLOMBO i sur., Life Sciences, 63 (8), 113-117 (1998); J. SIAMAND i sur., Begavioural Pharmacol., 9, 179-181 (1998)). CB1 receptor antagonists are known for their effect on food intake, and their use as a weight loss agent (G. COLOMBO et al., Life Sciences, 63 (8), 113-117 (1998); J. SIAMAND et al., Behavioural Pharmacol., 9, 179-181 (1998)).
Sibutramin (BTS 54524; N-{1-[1-(4-klorofenil)ciklobutil]-3-metilbutil}-N,N-dimetilamin; MeridiaR, ReductilR), njegov hidrat, te njegove farmaceutski prihvatljive soli, a osobito njegov klorhidrat smanjuje unos hrane i koristan je u liječenju debljine (WO90/061110; D.H. RYAN i sur., Obesity Research, 3(4), 553 (1995); H.C. JACKSON i sur., British Journal of Pharmacology, 121, 1758(1997); G. FANGHANEL i sur., Inter.J.Obes., 24(2), 144(2000); G.A. BRAY i sur., Obes.Res., 7 (2) 189(1999)). Sibutramine (BTS 54524; N-{1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl}-N,N-dimethylamine; MeridiaR, ReductilR), its hydrate, and its pharmaceutically acceptable salts, especially its hydrochloride reduces food intake and is useful in the treatment of obesity (WO90/061110; D.H. RYAN et al., Obesity Research, 3(4), 553 (1995); H.C. JACKSON et al., British Journal of Pharmacology, 121, 1758(1997) ; G. FANGHANEL et al., Inter.J.Obes., 24(2), 144(2000); G.A. BRAY et al., Obes.Res., 7 (2) 189(1999)).
Sada je pronađena kombinacija sibutramina, njegova hidrata i njegovih farmaceutski prihvatljivih soli s antagonistom CB1 receptora u obliku sinergističnog učinka na smanjenje unosa hrane, te su tako korisni u liječenju debljine. A combination of sibutramine, its hydrates and its pharmaceutically acceptable salts with a CB1 receptor antagonist has now been found to have a synergistic effect on reducing food intake, thus being useful in the treatment of obesity.
Kombinacija se isto tako odnosi na više antagonista CB1 receptora. The combination also refers to multiple CB1 receptor antagonists.
Među CB1 antagonistima, mogu se osobito koristiti derivati azetidina opisani u WO 00/15609, WO 01/64633, WO 01/64634 formule: Among CB1 antagonists, the azetidine derivatives described in WO 00/15609, WO 01/64633, WO 01/64634 of the formula can be used in particular:
[image] [image]
u kojoj where
R predstavlja ili lanac (A), (B) i R represents either chain (A), (B) and
[image] [image]
R1 predstavlja metilni ili etilni radikal, R1 represents a methyl or ethyl radical,
R2 predstavlja ili aromatski prsten odabran između.fenila, naftila ili indenila, navedeni aromatski spojevi mogu biti supstituirani ili ne supstituirani različitim halogenima, alkil, alkoksi, -CO-alk, hidroksi, -COOR5, formil, trifluorometil, trifluorometilsulfanil, trifluorometoksi, nitro, -NR6R7, -CO-NH-NR6R7, -N(alk)COOR8, cijano, -CONHR9, -CO-NR16R17, alkilsulfanil, hidroksialkil, -O-alk-NR12R13 ili alkiltioalkil ili heteroaromatskim spojem odabranim između ciklo benzofurila, benzotiazolila, benzotienila, benzoksazolila, kromanila, 2,3-dihidrobenzofurila, 2,3-dihidrobenzotienila, indolinila, indolila, izokromanila, izokinolila, piridila, kinolila, 1,2,3,4-tetrahidroizokinolila, 1,2,3,4-tetrahidrokinolila, tiazolila, tienila, navedeni heteroaromatski spojevi mogu biti supstituirani ili ne supstituirani halogenom, alkilom, alkoksi, -COOR5, trifluorometilom, trifluorometilsulfanilom, trifluorometoksi, nitro, -NR6R7, -CO-NH-NR6R7, cijano, -CONHR9, alkilsulfanilom, hidroksialkiom ili alkiltioalkilom, R2 represents either an aromatic ring selected from phenyl, naphthyl or indenyl, the said aromatic compounds may be substituted or unsubstituted by various halogens, alkyl, alkoxy, -CO-alk, hydroxy, -COOR5, formyl, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR6R7, -CO-NH-NR6R7, -N(alk)COOR8, cyano, -CONHR9, -CO-NR16R17, alkylsulfanyl, hydroxyalkyl, -O-alk-NR12R13 or alkylthioalkyl or a heteroaromatic compound selected from cyclobenzofuryl, benzothiazolyl, benzothienyl , benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl, isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl , thienyl, said heteroaromatic compounds may be substituted or unsubstituted by halogen, alkyl, alkoxy, -COOR5, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro, -NR6R7, -CO-NH-NR6R7, cyano, -CONHR9, alkylsulfanyl, hydroxyalkyl or al alkylthioalkyl,
R3 i R4 identični ili različiti, predstavljaju bilo aromatski spoj odabran između fenila, naftila ili indenila, navedeni aromatski spojevi mogu biti ne supstituirani ili supstituirani jednim ili više halogenom, alkilom, alkoksi, formilom, hidroksi, trifluorometilom, trifluorometoksi, -CO-alk, cijano, -COOR5, -CONR10R11, -CO-NH-NR6R7, alkilsulfanilom, hidroksialkilom, -alk-NR6R7 ili alkiltioalkilom; ili heteroaromatskim spojem odabranim između ciklo benzofurila, benzotiazolila, benzotienila, benzoksazolila, kromanila, 2,3-dihidrobenzofurila, 2,3-dihidrobenzotienila, furila, izokromanila, izokinolila, pirolila, kinolila, 1,2,3,4-tetrahidroizokinolila, tiazolila, tienila, navedeni heteroaromatski spojevi mogu biti supstituirani ili ne supstituirani halogenom, alkilom, alkoksi, hidroksi, trifluorometilom, trifluorometoksi, cijano, -COOR5, -CO-NH-NR6R7, -CONR10R11, -alk-NR6R7, alkilsulfanilom, hidroksialkiom ili alkiltioalkilom, R3 and R4 identical or different, represent either an aromatic compound selected from phenyl, naphthyl or indenyl, said aromatic compounds can be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOR5, -CONR10R11, -CO-NH-NR6R7, alkylsulfanyl, hydroxyalkyl, -alk-NR6R7 or alkylthioalkyl; or a heteroaromatic compound selected from cyclobenzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl, thienyl, said heteroaromatic compounds may be substituted or unsubstituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOR5, -CO-NH-NR6R7, -CONR10R11, -alk-NR6R7, alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
R5 je alkilni radikal ili fenil po izboru supstituiran jednim ili više halogenih atoma, R5 is an alkyl radical or phenyl optionally substituted by one or more halogen atoms,
R6 i R7, identični ili različiti predstavljaju atom vodika ili radikal alkil, -COOalk, cikloalkil, alkilcikloalkil, -alk-O-alk, hidroksialkil ili isto tako R6 i R7 zajedno s atomom dušika na koji su vezani tvore heterociklički mono ili biciklički, zasićeni ili nezasićeni prsten s 3 do 10 atoma, koji po izboru sadrži drugi heteroatom odabran između kisika, sumpora i dušika, te koji je po izboru supstituiran jednim ili više alkilnih radikala, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15, okso, hidroksialkilom, -alk-O-alk, -CO-NH2, R6 and R7, identical or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk, hydroxyalkyl or also R6 and R7 together with the nitrogen atom to which they are attached form heterocyclic mono or bicyclic, saturated or an unsaturated ring with 3 to 10 atoms, which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted by one or more alkyl radicals, -COalk, -COOalk, -CO-NHalk, -CS-NHalk , -CO-alk-NR14R15, oxo, hydroxyalkyl, -alk-O-alk, -CO-NH2,
R8 predstavlja alkilni radikal, R8 represents an alkyl radical,
R9 predstavlja atom vodika, ili alkilni radikal ili alkil supstituiran s dialkilamino, fenilom, cikloalkilom (po izboru supstituiran s -COOalk) ili heterociklički mono ili biciklički spoj, zasićen ili nezasićen s 3 do 10 atoma u lancu, koji sadrži po izboru jedan ili više heteroatoma odabrana između kisika, sumpora i dušika, te koji je po izboru supstituiran jednim ili više alkilnih radikala, R9 represents a hydrogen atom, or an alkyl radical or an alkyl substituted with dialkylamino, phenyl, cycloalkyl (optionally substituted with -COOalk) or a heterocyclic mono or bicyclic compound, saturated or unsaturated with 3 to 10 atoms in the chain, optionally containing one or more heteroatom selected from oxygen, sulfur and nitrogen, and optionally substituted by one or more alkyl radicals,
R10 i R11, identični ili različiti predstavljaju atom vodika ili radikal alkil, a isto tako R10 i R11 tvore zajedno s atomom dušika na koji su vezani tvore heterociklički mono ili biciklički, zasićeni ili nezasićeni prsten s 3 do 10 atoma u lancu, koji po izboru sadrži drugi heteroatom odabran između kisika, sumpora i dušika, te koji je po izboru supstituiran alkilnim radikalom, R10 and R11, identical or different, represent a hydrogen atom or an alkyl radical, and also R10 and R11 together with the nitrogen atom to which they are attached form a heterocyclic mono or bicyclic, saturated or unsaturated ring with 3 to 10 atoms in the chain, which optionally contains a second heteroatom selected from oxygen, sulfur and nitrogen, and optionally substituted with an alkyl radical,
R12 i R13, identični ili različiti predstavljaju atom vodika ili radikal alkil, cikloalkil ili isto tako R12 i R13 zajedno s atomom dušika na koji su vezani tvore heterociklički mono ili biciklički, zasićeni ili nezasićeni prsten s 3 do 10 atoma, koji po izboru sadrži drugi heteroatom odabran između kisika, sumpora i dušika, te koji je po izboru supstituiran alkilnim radikala, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15, ili heterociklički mono ili biciklički zasićeni spoj koji ima od 3 do 10 atoma, te koji sadrži heteroatom odabran između kisika, sumpora i dušika, R12 and R13, identical or different, represent a hydrogen atom or an alkyl radical, cycloalkyl or also R12 and R13 together with the nitrogen atom to which they are attached form a heterocyclic mono or bicyclic, saturated or unsaturated ring with 3 to 10 atoms, which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted by an alkyl radical, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, -CO-alk-NR14R15, or a heterocyclic mono or bicyclic saturated compound having from 3 to 10 atoms, and containing a heteroatom selected from oxygen, sulfur and nitrogen,
R14 i R15, identični ili različiti predstavljaju atom vodika ili radikal alkil ili -COOalk, R14 and R15, identical or different, represent a hydrogen atom or an alkyl radical or -COOalk,
R16 i R17 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni spoj koji ima od 3 do 10 atoma, te po izboru sadrži drugi heteroatom odabran između kisika, sumpora i dušika, R16 and R17 form together with the nitrogen atom to which they are attached a heterocyclic mono or bicyclic saturated compound having from 3 to 10 atoms, and optionally containing another heteroatom selected from oxygen, sulfur and nitrogen,
R' predstavlja atom vodika ili radikal -CO-alk, ili R' represents a hydrogen atom or a -CO-alk radical, or
R predstavlja radikal CHR18, a R represents the radical CHR18, a
R18 predstavlja radikal –NHCOR19 ili -N(R20)-Y-R21, R18 represents the radical –NHCOR19 or -N(R20)-Y-R21,
Y je CO ili SO2, Y is CO or SO2,
R4 i R3, identični ili različiti, predstavljaju aromatski spoj odabran između fenila, naftila i indenila, a navedeni aromatski mogu biti ne supstituirani ili supstituirani jednim ili više halogena, alkilom, alkoksi, formilom, hidroksi, trifluorometilom, trifluorometoksi, -CO-alk, cijano, -COOH, -COOalk, CONR22R23, -CO-NH-NR24R25, alkilsulfanilom, alkilsulfinilom, alkilsulfonilom, alkilsulfanilalkilom, alkilsulfinilalkilom, alkilsulfonilalkilom, hidroskialkilom, ili -alk-NR22R23; ili heteroaromatskim spojem odabranim između cikličkih benzofurila, benzotiazolila, benzotienila, benzoksazolila, kromanila, 2,3-dihidrobenzofurila, 2,3-dihidrobenzotienila, pirimidinila, furila, imidazolila, izokromanila, izokinolila, pirolila, piridila, kinolila, 1,2,3,4-tetrahidroizokinolila, tiazolila i tienila, navedeni heteroatomi mogu biti ne supstituirani ili supstituirani halogenom, alkilom, alkoksi, hidroksi, trifluorometilom, trifluorometoksi, cijano, -COOH, -COOalk, -CO-NH-NR24R25, -CONR22R23, alk-NR24R25, alkilsulfanilom, alkilsulfinilom, alkilsulfonilom, alkilsulfanilalkilom, alkilsulfinilalkilom, alkilsulfonilalkilom ili hidroksialkilom, R4 and R3, identical or different, represent an aromatic compound selected from phenyl, naphthyl and indenyl, and said aromatic can be unsubstituted or substituted by one or more halogens, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, CONR22R23, -CO-NH-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, or -alk-NR22R23; or a heteroaromatic compound selected from cyclic benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3, 4-tetrahydroisoquinolyl, thiazolyl and thienyl, said heteroatoms can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR24R25, -CONR22R23, alk-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
R19 predstavlja radikal -alk-SO2-R26, -alk-SO2-CH=CH-R26, Heti supstituiran s -SO2-R26 ili fenil supstituiran s -SO2-R26 ili alk-SO2-R26, R19 represents the radical -alk-SO2-R26, -alk-SO2-CH=CH-R26, Heti substituted with -SO2-R26 or phenyl substituted with -SO2-R26 or alk-SO2-R26,
R20 predstavlja atom vodika ili alkilni radikal, R21 predstavlja fenilalkilni radikal, Het1 ili Ar1, R20 represents a hydrogen atom or an alkyl radical, R21 represents a phenylalkyl radical, Het1 or Ar1,
R22 i R23, identični ili različiti, predstavljaju atom vodika ili alkilni radikal ili isto tako R22 i R23 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni spoj s 3 do 10 atoma, koji sadrži eventualno drugi heteroatom odabran između kisika, sumpora i dušika, te koji je eventualno supstituiran jednim ili više alkilom, R22 and R23, identical or different, represent a hydrogen atom or an alkyl radical or likewise R22 and R23 form together with the nitrogen atom to which they are attached a heterocyclic mono- or bicyclic saturated compound with 3 to 10 atoms, possibly containing another heteroatom selected from oxygen, of sulfur and nitrogen, and which is optionally substituted by one or more alkyl,
R24 i R25, identični ili različiti, predstavljaju atom vodika ili alkilni radikal, -COOalk, cikloalkil, alkilcikloalkil, -alk-O-alk ili hidroksialkil ili isto tako R24 i R25 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni ili nezasićeni spoj s 3 do 10 atoma, koji eventualno sadrži drugi heteroatom odabran između kisika, sumpora i dušika, te koji eventualno supstituiran jednim ili više alkilom, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, okso, hidroksialkilom, -alk-O-alk ili -CO-NH2, R24 and R25, identical or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl or also R24 and R25 form together with the nitrogen atom to which they are attached heterocyclic mono or bicyclic saturated or an unsaturated compound with 3 to 10 atoms, which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl , -alk-O-alk or -CO-NH2,
R26 predstavlja alkilni radikal, Ar1 ili Het1, R26 represents an alkyl radical, Ar1 or Het1,
Ar1 predstavlja fenilni radikal, naftil ili indenil, navedeni radikali mogu eventualno biti supstituirani jednim ili više halogenom, alkilom, alkoksi, cijano, -CO-alk, -COOH, -COOalk, -CONR27R28, -CO-NH-NR29NR28, alkilsulfanilom, alkilsulfinilom, alkilsulfonilom, -alk-NR29R30, -NR29R30, alkiltioalkil, formil, hidroksi, hidroksialkil, Het, -O-alk-NH-cikloalkil, OCF3, CF3, -NH-CO-alk, -SO2-NH2, -NH-COCH3, -NH-COOalk, Het ili isto tako na dva susjedna atoma ugljika s dioksimetilenom, Ar1 represents a phenyl radical, naphthyl or indenyl, the mentioned radicals can possibly be substituted by one or more halogen, alkyl, alkoxy, cyano, -CO-alk, -COOH, -COOalk, -CONR27R28, -CO-NH-NR29NR28, alkylsulfanyl, alkylsulfinyl , alkylsulfonyl, -alk-NR29R30, -NR29R30, alkylthioalkyl, formyl, hydroxy, hydroxyalkyl, Het, -O-alk-NH-cycloalkyl, OCF3, CF3, -NH-CO-alk, -SO2-NH2, -NH-COCH3 , -NH-COOalk, Het or likewise on two adjacent carbon atoms with dioxymethylene,
Het1 predstavlja heterociklički mono ili biciklički nezasićeni ili zasićeni spoj, s 3 do 10 atoma, te koji sadrži jedan ili nekoliko heteroatoma odabrana između kisika, sumpora i dušika eventualno supstituiranih jednim ili više alkilom, alkoksi, vinilom, halogenom, alkoksikarbonilom, okso, hidroksi, OCF3 ili CF3, heterocikli s dušikom mogu eventualno biti u njihovom N-oksidiranom obliku, Het1 represents a heterocyclic mono or bicyclic unsaturated or saturated compound, with 3 to 10 atoms, and containing one or several heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted by one or more alkyl, alkoxy, vinyl, halogen, alkoxycarbonyl, oxo, hydroxy, OCF3 or CF3, heterocycles with nitrogen may possibly be in their N-oxidized form,
R27 i R28, identični ili različiti, predstavljaju atom vodika ili alkilni radikal ili isto tako R27 i R28 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni spoj s 3 do 10 atoma, koji sadrži eventualno drugi heteroatom odabran između kisika, sumpora i dušika, te koji je eventualno supstituiran jednim ili više alkilom, R27 and R28, identical or different, represent a hydrogen atom or an alkyl radical or also R27 and R28 form together with a nitrogen atom to which they are attached a heterocyclic mono- or bicyclic saturated compound with 3 to 10 atoms, possibly containing another heteroatom selected from oxygen, of sulfur and nitrogen, and which is optionally substituted by one or more alkyl,
R29 i R30, identični ili različiti, predstavljaju atom vodika ili alkilni radikal, -COOalk, cikloalkil, alkilcikloalkil, -alk-O-alk ili hidroksialkil ili isto tako R29 i R30 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni ili nezasićeni spoj s 3 do 10 atoma, koji eventualno sadrži drugi heteroatom odabran između kisika, sumpora i dušika, te koji eventualno supstituiran jednim ili više alkilom, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, okso, hidroksialkilom, -alk-O-alk ili -CO-NH2, R29 and R30, identical or different, represent a hydrogen atom or an alkyl radical, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl or also R29 and R30 form together with the nitrogen atom to which they are attached heterocyclic mono or bicyclic saturated or an unsaturated compound with 3 to 10 atoms, which optionally contains another heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted by one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl , -alk-O-alk or -CO-NH2,
ili R predstavlja CHR31 i or R represents CHR31 and
R31 predstavlja radikal -N(R32)R33, -N (R32) -CO-R33, -N(R32)-SO2R34, R31 represents the radical -N(R32)R33, -N (R32) -CO-R33, -N(R32)-SO2R34,
R4 i R3, identični ili različiti, predstavljaju aromatski spoj odabran između fenila, naftila i indenila, a navedeni aromatski spojevi mogu biti ne supstituirani ili supstituirani jednim ili više halogenom, alkilom, alkoksi, formilom, hidroksi, trifluorometilom, trifluorometoksi, -CO-alk, cijano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24R25, alkilsulfanilom, alkilsulfinilom, alkilsulfonilom, alkilsulfanilalkilom, alkilsulfinilalkilom, alkilsulfonilalkilom, hidroskialkilom, ili -alk-NR7R8; ili heteroaromatskim spojem odabranim između cikličkih benzofurila, benzotiazolila, benzotienila, benzoksazolila, kromanila, 2,3-dihidrobenzofurila, 2,3-dihidrobenzotienila, pirimidinila, furila, imidazolila, izokromanila, izokinolila, pirolila, piridila, kinolila, 1,2,3,4-tetrahidroizokinolila, tiazolila i tienila, navedeni heteroatomi mogu biti ne supstituirani ili supstituirani halogenom, alkilom, alkoksi, hidroksi, trifluorometilom, trifluorometoksi, cijano, -COOH, -COOalk, -CO-NH-NR24R25, -CONR22R23, alk-NR24R25, alkilsulfanilom, alkilsulfinilom, alkilsulfonilom, alkilsulfanilalkilom, alkilsulfinilalkilom, alkilsulfonilalkilom ili hidroksialkilom, R4 and R3, identical or different, represent an aromatic compound selected from phenyl, naphthyl and indenyl, and said aromatic compounds can be unsubstituted or substituted by one or more halogen, alkyl, alkoxy, formyl, hydroxy, trifluoromethyl, trifluoromethoxy, -CO-alk , cyano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, or -alk-NR7R8; or a heteroaromatic compound selected from cyclic benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3, 4-tetrahydroisoquinolyl, thiazolyl and thienyl, said heteroatoms can be unsubstituted or substituted by halogen, alkyl, alkoxy, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR24R25, -CONR22R23, alk-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl,
R32 predstavlja radikal -C(R35)(R36)-Het2, -Het2, -C(R35)(R36)-Ar2, Ar2, cikloalkil ili norbornil, R32 represents the radical -C(R35)(R36)-Het2, -Het2, -C(R35)(R36)-Ar2, Ar2, cycloalkyl or norbornyl,
R33 predstavlja atom vodika ili radikal hidroksialkil, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoksi, Ar2, Het2, -CH2-Ar2, -CH2Het2 ili alkil eventualno supstituiran jednim ili više halogenom, R33 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoxy, Ar2, Het2, -CH2-Ar2, -CH2Het2 or alkyl optionally substituted by one or more halogens,
R34 predstavlja radikal hidroksialkil, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoksi, Ar2, Het2, -CH2-Ar2, -CH2Het2 ili alkil eventualno supstituiran jednim ili više halogenom, R34 represents the radical hydroxyalkyl, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoxy, Ar2, Het2, -CH2-Ar2, -CH2Het2 or alkyl optionally substituted by one or more halogens,
R35 predstavlja atom vodika ili radikal hidroksialkil, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoksialkil, Ar2, Het2, -CH2-Ar2, -CH2Het2 ili alkil eventualno supstituiran jednim ili više halogenom, R35 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoxyalkyl, Ar2, Het2, -CH2-Ar2, -CH2Het2 or alkyl optionally substituted by one or more halogens,
R36 predstavi ja atom vodika ili radikal hidroksialkil, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoksialkil ili alkil eventualno supstituiran jednim ili više halogenom, R36 represents a hydrogen atom or a hydroxyalkyl radical, -alk-COOalk, -alk-CONR22R23, -alk-NR22R23, alkoxyalkyl or alkyl optionally substituted by one or more halogens,
ili isto tako R35 i R36 tvore zajedno s atomom ugljika na koji su vezani heterociklički mono ili biciklički zasićeni spoj koji ima od 3 do 10 atoma, te koji sadrži drugi heteroatom odabran između kisika, sumpora i dušika, te koji je eventualno supstituiran jednim ili više alkila, or also R35 and R36 form together with the carbon atom to which they are attached a heterocyclic mono or bicyclic saturated compound having from 3 to 10 atoms, and which contains another heteroatom selected from oxygen, sulfur and nitrogen, and which is optionally substituted by one or more alkyl,
Ar2 predstavlja fenilni radikal, naftil ili indenil, navedeni različiti radikali mogu eventualno biti supstituirani jednim ili više halogenom, alkilom, alkoksi, -CO-alk, cijano, -COOH, -COOalk, -CONR37R38, -CO-NH-NR39NR40, alkilsulfanilom, alkilsulfinilom, alkilsulfonilom, -alk-NR29R30, -NR39R40, alkiltioalkilom, formilom, CF3, OCF3, Het, -O-alk-NH-cikloalkilom, -SO2-NH2, hidroksi, hidroksialkilom, -NHCOalk, -NHCOOalk, ili isto tako na dva susjedna atoma ugljika s dioksimetilenom, Ar2 represents a phenyl radical, naphthyl or indenyl, the mentioned different radicals can possibly be substituted by one or more halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR37R38, -CO-NH-NR39NR40, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, -alk-NR29R30, -NR39R40, alkylthioalkyl, formyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl, -SO2-NH2, hydroxy, hydroxyalkyl, -NHCOalk, -NHCOOalk, or likewise two adjacent carbon atoms with dioxymethylene,
Het2 predstavlja heterociklički mono ili biciklički nezasićeni ili zasićeni spoj, s 3 do 10 atoma, te koji sadrži jedan ili nekoliko heteroatoma odabrana između kisika, sumpora i dušika eventualno supstituiranih jednim ili više alkilom, alkoksi, halogenom, alkoksikarbonilom, okso, hidroksi, heterocikli s dušikom mogu eventualno biti u njihovom N-oksidnom obliku, Het2 represents a heterocyclic mono or bicyclic unsaturated or saturated compound, with 3 to 10 atoms, and which contains one or several heteroatoms selected from oxygen, sulfur and nitrogen optionally substituted by one or more alkyl, alkoxy, halogen, alkoxycarbonyl, oxo, hydroxy, heterocycles with with nitrogen they may possibly be in their N-oxide form,
R37 i R38, identični ili različiti, predstavljaju atom vodika ili alkilni radikal ili isto tako R37 i R38 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni spoj s 3 do 10 atoma, koji sadrži eventualno drugi heteroatom odabran između kisika, sumpora i dušika, te koji je eventualno supstituiran jednim ili više alkilom, R37 and R38, identical or different, represent a hydrogen atom or an alkyl radical or also R37 and R38 form together with a nitrogen atom to which they are bound a heterocyclic mono- or bicyclic saturated compound with 3 to 10 atoms, possibly containing another heteroatom selected from oxygen, of sulfur and nitrogen, and which is optionally substituted by one or more alkyl,
R39 i R40, identični ili različiti, predstavljaju atom vodika ili alkilni radikal ili isto tako R39 i R40 tvore zajedno s atomom dušika na koji su vezani heterociklički mono ili biciklički zasićeni spoj s 3 do 10 atoma, koji sadrži eventualno drugi heteroatom odabran između kisika, sumpora i dušika, te koji je eventualno supstituiran jednim ili više alkilom, R39 and R40, identical or different, represent a hydrogen atom or an alkyl radical, or likewise R39 and R40 form together with a nitrogen atom to which they are attached a heterocyclic mono- or bicyclic saturated compound with 3 to 10 atoms, possibly containing another heteroatom selected from oxygen, of sulfur and nitrogen, and which is optionally substituted by one or more alkyl,
alk predstavlja alkilni radikal ili alkilen, alk represents an alkyl radical or alkylene,
radikali i dijelovi alkila i alkilena i radikali i dijelovi alkoksi dolaze u obliku ravnog ili razgranatog lanca, te sadrže od 1 do 6 atoma ugljika, te cikloalkilne radikale sa 3 do 10 atoma ugljika, optički izomeri navedenih spojeva i njihove soli mineralnih kiselina ili farmaceutski prihvatljive organske tvari. radicals and parts of alkyl and alkylene and radicals and parts of alkoxy come in the form of a straight or branched chain, and contain from 1 to 6 carbon atoms, and cycloalkyl radicals with 3 to 10 carbon atoms, optical isomers of the mentioned compounds and their salts of mineral acids or pharmaceutically acceptable organic substances.
Povoljni derivati azetidina su slijedeći: Favorable derivatives of azetidine are the following:
1-benzhidril-3-[(metilsulfonil)(fenil)metilen]azetidin, 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
1-benzhidril-3-[(3-metilfenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-klorofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3,5-diklorofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(2,5-diklorofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(2,3-diklorofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-fluorofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-bromofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-jodofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(metilsulfonil)(3-trifluorometoksifenil)metilen]azetidin, 1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidine,
1-benzhidril-3-[(metilsulfonil)(3-trifluorometilfenil)metilen]azetidin, 1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetidine,
1-benzhidril-3-{[3,5-bis(trifluorometil)fenil](metilsulfonil)metilen}azetidin, 1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidine,
1-benzhidril-3-[(3,5-dibromofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-metoksikarbonilfenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-cijanofenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-karbamoilfenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(metilsulfonil)(naftil-1-il)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(methylsulfonyl)(naphthyl-1-yl)(methylsulfonyl)methylene]azetidine,
1-[bis-(4-klorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis-(4-metoksifenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis-(4-metilfenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-3-[(3,5-difluorofenil)(metilsulfonil)metilen]-1-[(4-metoksifenil)(fenil)metil)]azetidin, (R,S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,
(R)-3-[(3,5-difluorofenil)(metilsulfonil)metilen]-1-[(4-metoksifenil)(fenil)metil]azetidin, (R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,
(S)-3-[(3,5-difluorofenil)(metilsulfonil)metilen]-1-[(4-metoksifenil)(fenil)metil]azetidin, (S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,
1-[bis-(4-trifluorometoksifenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis-(4-trifluorometilfenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis-(4-klorofenil)metil]-3-[(3,5-bis(trifluorometil)fenil]metilsulfonil metilen} azetidin, 1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-bis(trifluoromethyl)phenyl]methylsulfonyl methylene} azetidine,
(R,S)-1-[(4-klorofenil)(2,4-diklorofenil) metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-klorofenil)(2,4-diklorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-klorofenil)(2,4-diklorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-{(4-klorofenil)[4-(hidroksimetil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-klorofenil)[4- (hidroksimetil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-klorofenil)[4-(hidroksimetil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-{(4-klorofenil)[4-(pirolidilmetil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-klorofenil)[4- (pirolidilmetil) fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-klorofenil)[4-(pirolidilmetil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(3,3-dimetil-piperidin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(3,3-dimethyl-piperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl) methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(3,3-dimetil-piperidin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(3,3-dimethyl-piperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(S)-(4-klorofenil)[4-(3,3-dimetil-piperidin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(3,3-dimethyl-piperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(R,S)-(4-klorofenil)[4-(tiomorfolin-4-il-metil)fenil]metil-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(thiomorpholin-4-yl-methyl)phenyl]methyl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(tiomorfolin-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(tiomorfolin-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(N-etil-N-cikloheksil-aminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(N-etil-N-cikloheksil-aminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(N-etil-N-cikloheksil-aminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(R,S)-(4-klorofenil)(4-[(4-etoksikarbonilpiperazinil)metil]fenil}metil}}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{{(R,S)-(4-chlorophenyl)(4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(R)-(4-klorofenil){4-[(4-etoksikarbonilpiperazinil)metil]fenil}metil}}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-klorofenil){4-[(4-etoksikarbonilpiperazinil)metil]fenil}metil}}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(N-ciklopropil-N-propil-aminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(N-ciklopropil-N-propil-aminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(N-ciklopropil-N-propil-aminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(diizopropilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(diizopropilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(diizopropilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(R,S)-(4-klorofenil){4-[bis-(2-metoksietil)aminometil]fenil}metil}}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{{(R,S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine ,
1-{{(R)-(4-klorofenil){4-[bis-(2-metoksietil)aminometil]fenil}metil}}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-klorofenil){4-[bis-(2-metoksietil)aminometil]fenil}metil}}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(di-n-propilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(di-n-propilaminometil)feniljmetil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenylmethyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(di-n-propilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(piperidin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(piperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(piperidin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(piperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(piperidin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(piperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(4-metil-piperazin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(4-methyl-piperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(R)-(4-klorofenil)[4-(4-metil-piperazin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(4-methyl-piperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(4-metil-piperazin-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(4-methyl-piperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(morfolin-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(morfolin-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(morfolin-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(dietilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(dietilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(dietilaminometil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(piperazin-2-on-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(R)-(4-klorofenil)[4-(piperazin-2-on-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4-(piperazin-2-on-4-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R,S)-(4-klorofenil)[4-(imidazol-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R,S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-klorofenil)[4-(imidazol-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-klorofenil)[4- (imidazol-1-il-metil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-{(4-klorofenil)[4-(N,N-dimetilkarbamoil)feniljmetil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenylmethyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-klorofenil)[4-(N,N-dimetilkarbamoil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-klorofenil)[4-(N,N-dimetilkarbamoil)feniljraetil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenylethyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-{(4-klorofenil)[4-(N-etilkarbamoil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-klorofenil)[4-(N-etilkarbamoil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-klorofenil)[4-(N-etilkarbamoil)fenil]metil}-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-[(4-karbamoilfenil)(4-klorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-karbamoilfenil)(4-klorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-karbamoilfenil)(4-klorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-metilsulfanilfenil)(metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(3-metilsulfanilfenil)fenil)](metilsulfonil)metilen]azetidin, 1-benzhydryl-3-[(3-methylsulfanylphenyl)phenyl)](methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-cijanofenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-karbamoilfenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-metoksifenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-hidroksifenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(metilsulfonil)(3-pirolidinilfenil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-hidroksimetilfenil)-(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)-(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-{(metilsulfonil)[3-(N-piperidilkarbamoil)fenil]metilen}azetidin, 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,
1-[bis(4-klorofenil)metil]-3-{(metilsulfonil)[3-(N-piperidilkarbamoil)fenil]metilen}azetidin, 1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,
1-[bis(4-klorofenil)metil]-3-[(metilsulfonil)(3-trifluorometilsulfanilfenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-fluorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(2-fluorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(3-fluorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-[(4-klorofenil)(tiazol-2-il)metil]-3-[(metilsulfonil)(fenil)metilen]azetidin, (R,S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(R)-1-[(4-klorofenil)(tiazol-2-il)metil]-3-[(metilsulfonil)(fenil)metilen]azetidin, (R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(S)-1-[(4-klorofenil)(tiazol-2-il)metil]-3-[(metilsulfonil)(fenil)metilen]azetidin, (S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(R,S)-1-[(4-klorofenil)(tien-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-klorofenil)(tien-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-klorofenil)(tien-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhidril-3-[(etilsulfonil)(fenil)metilen]azetidin, 1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-{{3-[N-(4-metilpiperazinil)karbamoil]fenil}(metilsulfonil)metilen}azetidin, 1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)methylene}azetidine,
1-[bis(4-klorofenil)metil]-3-{[3-(2,2-dimetilkarbohidrazido) fenil](metilsulfonil)metilen}azetidin, 1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)methylene}azetidine,
1-[bis(tien-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil; metilen]azetidin, 1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl; methylene]azetidine,
1-[bis(p-tolil) metil]-3-[(metilsulfonil)(fenil)metilen]azetidin, 1-[bis(p-tolyl) methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
1-[(4-klorofenil)(4-hidroksimetilfenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[(4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-metilaminofenil)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine,
(R,S)-1-[(4-klorofenil)(tiazol-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R,S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-klorofenil)(tiazol-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-klorofenil)(tiazol-2-il)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, (S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(metilsulfonil)(2-metoksikarboniltien-5-il)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-hidroksi-3-[(metilsulfonil)(2-metoksikarboniltien-5-il)metilen]azetidin-(RS), 1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine-(RS),
1-[bis(4-klorofenil)metil]-3-[(2-izobutilaminokarboniltien-5-il)(metilsulfonil)metilen]azetidin, 1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-klorofenil)metil]-3-[(3-metoksikarbonilfenil)(metilsulfonil)metil-(RS)]azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,
1-[bis(4-klorofenil)metil]-3-[(metilsulfonil)(piridin-4-il)metil-(RS)]azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)]azetidin-3-ol,
1-[bis(4-klorofenil)metil]-3-[(metilsulfonil)(piridin-3-il)metil-(RS)]azetidin-3-ol, 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)]azetidin-3-ol,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(3-morfolin-4-il-propil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(3-morpholin-4-yl-propyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N- (3-dimetilamino-propil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(3-dimethylamino-propyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N- (2-pirolidin-1-il-etil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-pyrrolidin-1-yl-ethyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2-dimetilamino-1-metil-etil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-dimethylamino-1-methyl-ethyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-piperidin-1-il-benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-piperidin-1-yl-benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-izobutil-benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-isobutyl-benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(3-imidazol-1-il-propil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(3-imidazol-1-yl-propyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N- (2-dimetilamino-etil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-dimethylamino-ethyl)benzamide,
N'-metil-hidrazid 3-({1-[bis-(4-klorofenil)metil]azetidin-3-ili-den}-metansulfonil-metil)benzojeve kiseline, N'-methyl-hydrazide 3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)benzoic acid,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2-morfolin-4-il-etil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-morpholin-4-yl-ethyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(1-etil-pirolidin-2-ilmetil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(1-ethyl-pyrrolidin-2-ylmethyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2,2-dimetil-propil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2,2-dimethyl-propyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-cikloheksilmetil-benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-cyclohexylmethyl-benzamide,
3-({1-[bis (4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-ciklopropiImetil-benzamid, 3-({1-[bis (4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-cyclopropylmethyl-benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2-metil-butil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-methyl-butyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2-fenil-propil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-phenyl-propyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(tetrahidro-furan-2-ilmetil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(tetrahydro-furan-2-ylmethyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2,2-difenil-etil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2,2-diphenyl-ethyl)benzamide,
3-({1-[bis(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)N-(2-etil-butil)benzamid, 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)N-(2-ethyl-butyl)benzamide,
metilni ester 4-{[3-({1-[bis-(4-klorofenil)metil]azetidin-3-ili-den}-metansulfonil-metil)benzoilamino]metil}-cikloheksankarboksilne kiseline, 4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)benzoylamino]methyl}-cyclohexanecarboxylic acid methyl ester,
2-amino-1-{4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-il}-etanon, 2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazin-1-yl}-ethanone,
terc butil ester (2-{4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-il}-2-okso-etil)karbaminske kiseline, tert-butyl ester (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazin-1-yl}-2-oxo- ethyl) carbamic acid,
1-{4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-il}-2-metilamino-etanon, 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazin-1-yl}-2-methylamino-ethanone,
terc butil ester (2-{4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-il}-2-okso-etil)-N-metil-karbaminske kiseline, tert-butyl ester (2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazin-1-yl}-2-oxo- ethyl)-N-methyl-carbamic acid,
N-metilamid 4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-karbotioične kiseline, N-methylamide 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazine-1-carbothioic acid,
N-metilamid 4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-karboksilne kiseline, N-methylamide 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazine-1-carboxylic acid,
metilni ester 4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-karboksilne kiseline, 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazine-1-carboxylic acid methyl ester,
l-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]-4-izobutil-piperazin, 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]-4-isobutyl-piperazine,
l-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]-4-etil-piperazin, 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]-4-ethyl-piperazine,
4-acetil l-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin, 4-acetyl l-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazine,
l-{4-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]-piperazin-1-il}-2-dimetilamino-etanon, 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]-piperazin-1-yl}-2-dimethylamino-ethanone,
l-[3-({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin, 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazine,
terc-butil ester 4-[3- ({1-[bis-(4-klorofenil)metil]azetidin-3-iliden}-metansulfonil-metil)fenil]piperazin-1-karboksilne 4-[3- ({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonyl-methyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester
kiseline, acid,
1-[bis-(4-metoksikarbonilfenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
3-acetoksi-1-[bis-(4-metoksikarbonilfenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metil-(RS)]azetidin, 3-acetoxy-1-[bis-(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidine,
(RS)-4-[4-((4-klorofenil)(3-[(3,5-difluorofenil) metansulfonil-metilen]azetidin-1-il}-metil)-benzil]morfolin, (RS)-4-[4-((4-chlorophenyl)(3-[(3,5-difluorophenyl)methanesulfonyl-methylene]azetidin-1-yl}-methyl)-benzyl]morpholine,
4-(4-{3-[(1-benzhidril-azetidin-3-iliden)metansulfonil-metil]fenoksi}butil)morfolin, 4-(4-{3-[(1-benzhydryl-azetidin-3-ylidene)methanesulfonyl-methyl]phenoxy}butyl)morpholine,
4-(4-{3-[(1-benzhidril-azetidin-3-iliden)metansulfonil-metil]fenoksi}propil)morfolin, 4-(4-{3-[(1-benzhydryl-azetidin-3-ylidene)methanesulfonyl-methyl]phenoxy}propyl)morpholine,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-tien-2-il-sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-thien-2-yl-sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-4-metoksifenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methoxyphenylsulfonamide,
N-[4-(N-{1-[bis(4-klorofenil)metil]azetidin-3-il}sulfamoil)fenil]acetamid, N-[4-(N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}sulfamoyl)phenyl]acetamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-4-metilfenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methylphenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3,4-dimetoksifenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,4-dimethoxyphenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3-fluorofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-fluorophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3,4-diklorofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,4-dichlorophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3-cijanofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-cyanophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-2,5-dimetoksifenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2,5-dimethoxyphenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3-trifluorometilfenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-trifluoromethylphenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-naft-2-il-sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-naphth-2-yl-sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-naft-1-il-sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-naphth-1-yl-sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3,4-difluorofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,4-difluorophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-1-metil-1-H-imidazol-4-il-sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-methyl-1-H-imidazol-4-yl-sulfonamide,
N-[4-(N-{1- [bis (4-klorofenil)metil]azetidin-3-il}sulfamoil)-2-klorofenil]acetamid, N-[4-(N-{1- [bis (4-chlorophenyl)methyl]azetidin-3-yl}sulfamoyl)-2-chlorophenyl]acetamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-pirid-3-il-sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-pyrid-3-yl-sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-4-fluorofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-fluorophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}kinol-8-ilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}quinol-8-ylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}fenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}phenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-(fenilmetil)sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(phenylmethyl)sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3,5-difluorofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3,5-difluorophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}pirid-2-ilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid-2-ylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-(3-fluoro-5-pirolidin-1-il-fenil)sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3-fluoro-5-pyrrolidin-1-yl-phenyl)sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-N-metil-4-fluorofenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-4-fluorophenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-N-metil-kinol-8-ilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-quinol-8-ylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-N-metil-fenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-phenylsulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-N-metil-(fenilmetil)sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methyl-(phenylmethyl)sulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3-sulfamoilfenilsulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-sulfamoylphenylsulfonamide,
2-benzensulfonil-N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-acetamid, 2-benzenesulfonyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-acetamide,
N-{1-[bis(4-klorofenil)metil]-azetidin-3-il}-2-(toluen-4-sulfonil)-acetamid, N-{1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(toluene-4-sulfonyl)-acetamide,
(3-kloro-4-metilsulfonil-tiofen-2-karboksi)-{1-[bis(4-klorofenil)metil]azetidin-3-il}-amid, (3-chloro-4-methylsulfonyl-thiophene-2-carboxy)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-amide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-3-(2-fenil-etilensulfonil)-propionamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-3-(2-phenyl-ethylenesulfonyl)-propionamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-4-metilsulfonil-benzamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methylsulfonyl-benzamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-4-metansulfonil-benzamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-4-methanesulfonyl-benzamide,
(5-metilsulfonil-tiofen-2-karboksi)-{1-[bis(4-klorofenil)metil]azetidin-3-il}-amid, (5-methylsulfonyl-thiophene-2-carboxy)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-amide,
(5-metilsulfonil-3-metil-4-vinil-tiofen-2-karboksi)-{1-[bis(4-klorofenil)metil]azetidin-3-il}-amid, (5-methylsulfonyl-3-methyl-4-vinyl-thiophene-2-carboxy)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-amide,
(RS)-N-{1-[(4-kloro-fenil)piridin-3-il-metil]azetidin-3-il}-3,5-difluoro-benzensulfonamid, (RS)-N-{1-[(4-chloro-phenyl)pyridin-3-yl-methyl]azetidin-3-yl}-3,5-difluoro-benzenesulfonamide,
(RS)-N-{1-[(4-kloro-fenil)pirimidin-5-il-metil]azetidin-3-il}-3,5-difluoro-benzensulfonamid, (RS)-N-{1-[(4-chloro-phenyl)pyrimidin-5-yl-methyl]azetidin-3-yl}-3,5-difluoro-benzenesulfonamide,
N-{1-[bis(4-klorofenil)metil]azetidin-3-il}-N-(6-kloropiriđ-2-il)-metil-sulfonamid, N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6-chloropyrid-2-yl)-methyl-sulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-kinol-6-il-metil-sulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-6-yl-methyl-sulfonamide,
N-{1-[bis- (4-klorofenil)metil]azetidin-3-il}-N-kinol-5-il-metil-sulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-5-yl-methyl-sulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-izokino1-5-il-metil-sulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-isoquinol-5-yl-methyl-sulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-pirid-3-il-metil-sulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-yl-methyl-sulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(1-oksid-pirid-3-il)-metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1-oxid-pyrid-3-yl)-methylsulfonamide,
N-(1R,2S,4S)-biciklo[2,2,1]hept-2-il-N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-metilsulfonamid, N-(1R,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonamide,
N-(lR,2R,4S)-biciklo[2,2,1]hept-2-il-N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-metilsulfonamid, N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(3,5-difluorofenil)metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(tiazol-2-il)-metil sulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(thiazol-2-yl)-methyl sulfonamide,
N-{1-[bis-(4-klorofenil) metil]azetidin-3-il}-N-(3-metoksifenil)-metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-methoxyphenyl)-methylsulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(3-hidroksifenil)-metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-hydroxyphenyl)-methylsulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(3-hidroksimetil-fenil)-metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-hydroxymethyl-phenyl)-methylsulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(metilsulfonil)-3-aminobenzoat etila, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(methylsulfonyl)-3-aminobenzoate ethyl,
N-(l-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(1-izobutil-piperid-4-il)-metilsulfonamid, N-(1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1-isobutyl-piperid-4-yl)-methylsulfonamide,
N-benzil-N-{1-[bis(4-klorofenil)metil]azetidin-3-il}amin, N-benzyl-N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}amine,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(3,5-difluorobenzil)-amin, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)-amine,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(3,5-difluorobenzil)metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)methylsulfonamide,
N-{1-[bis-(4-klorofenil)metil]azetidin-3-il}-N-(pirid-3-il-metil)-metilsulfonamid, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-3-yl-methyl)-methylsulfonamide,
N-{1-[bis-(4-fluoro-fenil)-metil]-azetidin-3-il}- N-(3,5-difluorofenil)-metilsulfonamid, N-{1-[bis-(4-fluoro-phenyl)-methyl]-azetidin-3-yl}- N -(3,5-difluorophenyl)-methylsulfonamide,
(RS)-N-{1-[(4-klorofenil)-pirid-3-il-metil]-azetidin-3-il}-N-(3,5-difluorofenil)-metilsulfonamid, (RS)-N-{1-[(4-chlorophenyl)-pyrid-3-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(R)-N-{1-[(4-klorofenil)-pirid-3-il-metil]-azetidin-3-il}-N-(3,5-difluorofenil)-metilsulfonamid, (R)-N-{1-[(4-chlorophenyl)-pyrid-3-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(S) -N-U- [(4-klorofenil) -pirid-3-il-metil] -azetidin-3-il}-N-(3,5-difluorofenil)-metilsulfonamid, (S)-N-U-[(4-chlorophenyl)-pyrid-3-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(RS)-N-{1-[(4-klorofenil)-pirid-4-il-metil]-azetidin-3-il}-N-(3,5-difluorofenil)-metilsulfonamid, (RS)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(R)-N-{1-[(4-klorofenil)-pirid-4-il-metil]-azetidin-3-il}-N-(3, 5-difluorofenil)-metilsulfonamid, (R)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(S)-N-{1-[(4-klorofenil)-pirid-4-il-metil]-azetidin-3-il}-N-(3, 5-difluorofenil)-metilsulfonamid, (S)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(RS)-N-{1-[(4-klorofenil)-pirimidin-5-il-metil]-azetidin-3-11}-N-(3,5-difluorofenil)-metilsulfonamid, (RS)-N-{1-[(4-chlorophenyl)-pyrimidin-5-yl-methyl]-azetidin-3-11}-N-(3,5-difluorophenyl)-methylsulfonamide,
(R)-N-{1-[(4-klorofenil)-pirimidin-5-il-metil]-azetidin-3-il}-N-(3,5-difluorofenil)-metilsulfonamid, (R)-N-{1-[(4-chlorophenyl)-pyrimidin-5-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
(S)-N-{1-[(4-klorofenil)-pirimidin-5-il-metil]-azetidin-3-il}-N-(3,5-difluorofenil)-metilsulfonamid, (S)-N-{1-[(4-chlorophenyl)-pyrimidin-5-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,
N-{1- [bis (4-klorofenil) metil]azetidin-3-il}-N-(3,5-difluorofenil)-benzilsulfonamid, N-{1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-benzylsulfonamide,
te njihovi optički izomeri i njihove farmaceutski prihvatljive soli mineralnih ili organskih kiselina. and their optical isomers and their pharmaceutically acceptable salts of mineral or organic acids.
A još su osobito povoljni slijedeći derivati azetidina: And the following azetidine derivatives are particularly favorable:
{1-[bis-(4-klorofenil)-metil]-3-[(3,5-difluorofenil)(metilsulfonil)metil-(RS)]azetidin-3-ol, {1-[bis-(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,
3-acetoksi-1-[bis-(4-klorofenil)-metil]-3-[(3, 5-difluorofenil)(metilsulfonil)metil)-metil sulfonilmetil-(RS)]azetidin, 3-acetoxy-1-[bis-(4-chlorophenyl)-methyl]-3-[(3, 5-difluorophenyl)(methylsulfonyl)methyl)-methyl sulfonylmethyl-(RS)]azetidine,
1-[bis-(4-klorofenil)-metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin, 1-[bis-(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
te njihovi optički izomeri i njihove farmaceutski prihvatljive soli mineralnih ili organskih kiselina. and their optical isomers and their pharmaceutically acceptable salts of mineral or organic acids.
Kao primjeri farmaceutski prihvatljivih soli derivata azetidina, mogu se navesti slijedeće soli: benzensulfonat, bromhidrat, klorhidrat, citrat, etansulfonat, fumarat, glukonat, jodat, izetionat, maleat, metansulfonat, metilen-bis-β-oksonaftoat, nitrat, oksalat, pamoat, fosfat, salicilat, sukcinat, sulfat, tartarat, teofilinacetat i p-toluensulfonat. As examples of pharmaceutically acceptable salts of azetidine derivatives, the following salts can be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-β-oxonaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.
Ostali antagonisti CB1 koji se koriste, a mogu se povezati s prikazanim izumom su na primjer derivati pirazola opisani u EP576357, EP658546, EP656354, WO97/19063 i WO00/46209, derivati benzotiofena i benzofurana opisani u WO96/02248, arilsulfonamidi opisani u WO98/37061. Osobito se mogu navesti produkti poznati pod kodom SR141716 i LY320135. Other CB1 antagonists that are used and can be connected with the present invention are, for example, pyrazole derivatives described in EP576357, EP658546, EP656354, WO97/19063 and WO00/46209, benzothiophene and benzofuran derivatives described in WO96/02248, arylsulfonamides described in WO98/ 37061. In particular, the products known under the code SR141716 and LY320135 can be mentioned.
Sinergistički učinak sibutiramina i antagonista CB1 na konzumiranje hrane odren je prema slijedećem protokolu: The synergistic effect of sibutiramine and CB1 antagonists on food consumption was determined according to the following protocol:
Debeli Zucker štakori Fa/fa stari 7 tjedana koji dolaze iz Iffa-Credo, Francuska korišteni su u navedenom istraživanju. Štakori su smješteni u individualne kaveze, te vagani svakog dana između 8 i 10 sati u jutro. Količina hrane je jednako izvagana svako jutro u isto vrijeme. Navedena hrana (M20, Pietrement, Francuska) je svako jutro promijenjena i štakori su slobodno mogli jesti tijekom 24 sata. Tijekom jednog tjedna svi štakori su obrađeni vehiklom (miglyol 812N i metilceluloza 0,5%/polisorbat 80 0,2%) u dvije uzastopne primjene. Od 8. dana štakori su obrađeni vehiklom, antagonistom CB1 (1-[bis-(4-klorofenil)metil]-3-[(3,5-difluorofenil)(metilsulfonil)metilen]azetidin) ili sibutraminom oralnim putem (vidjeti dolje navedenu tabelu). 7-week-old fat Zucker Fa/fa rats from Iffa-Credo, France were used in the above study. The rats were placed in individual cages and weighed every day between 8 and 10 in the morning. The amount of food was equally weighed every morning at the same time. The indicated food (M20, Pietrement, France) was changed every morning and the rats were allowed to eat freely for 24 hours. During one week, all rats were treated with vehicle (miglyol 812N and methylcellulose 0.5%/polysorbate 80 0.2%) in two consecutive applications. From day 8, rats were treated with vehicle, the CB1 antagonist (1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine) or sibutramine orally (see below table).
Sibutramin dolazi u obliku otopine u otopini metilceluloze 0,5%/polisorbat 80 0,2%, te je primjenjen u dozi od 3 mg/kg; antagonist CB1 dolazi u obliku otopine u miglyol 812N (Hüls, Njemačka) u dozi od 0,6 mg/kg, oba produkta su primjenjena u volumenu od l ml/kg. Svaka skupina se sastoji od 12 do 14 životinja. Slijedeće skupine se sastoje od životinja koje su hranjene tijekom pet dana u obliku dvije uzastopne primjene svakog dana. Sibutramine comes in the form of a solution in methylcellulose solution 0.5%/polysorbate 80 0.2%, and was administered in a dose of 3 mg/kg; the CB1 antagonist comes in the form of a solution in miglyol 812N (Hüls, Germany) at a dose of 0.6 mg/kg, both products were administered in a volume of 1 ml/kg. Each group consists of 12 to 14 animals. The following groups consist of animals that were fed for five days in the form of two consecutive applications each day.
[image] [image]
Svakoga dana je mjerena konzumacija hrane svake životinje. Rezultati su izraženi prosječnom količinom konzumirane hrane tijekom 5 dana trajanja postupka. Dobiveni rezultati su prikazani u slijedećoj tabeli. Food consumption of each animal was measured every day. The results are expressed as the average amount of food consumed during the 5 days of the procedure. The obtained results are presented in the following table.
[image] * p<0,05 ** p<0,01 *** p<0,0001 [image] * p<0.05 ** p<0.01 *** p<0.0001
Rezultati pokazuju da među životinjama koje su primale kombinaciju sibutramina i antagonista CB1 smanjenje unosa hrane je značajno manje u usporedbi koje su primale bilo samo sibutramin, bilo samo antagonist CB1. The results show that among the animals that received the combination of sibutramine and the CB1 antagonist, the reduction in food intake was significantly less compared to those that received either sibutramine alone or the CB1 antagonist alone.
Kombinirani spojevi se mogu primjeniti oralnim putem, parenteralno, transdermalno ili rektalno bilo simultano ili odvojeno ili raspoređeno tijekom vremena. The combined compounds can be administered orally, parenterally, transdermally or rectally either simultaneously or separately or distributed over time.
Prikazani izum se odnosi isto tako i na farmaceutske pripravke koji sadrže kombinaciju sibutramina, njegova hidrata ili jedne od njegovih farmaceutski prihvatljivih soli i antagonista receptora CB1 u čistom stanju ili s jednim ili više diluenata i/ili kompatibilnih i farmakološki prihvatljivih adjuvansa i/ili eventualno u kombinaciji s nekim drugim farmakološki kompatibilnim i fiziološki aktivnim produktom bilo u istovremenoj primjeni, bilo odvojeno, ili raspoređeno tijekom vremena. The presented invention also relates to pharmaceutical preparations containing a combination of sibutramine, its hydrate or one of its pharmaceutically acceptable salts and a CB1 receptor antagonist in its pure state or with one or more diluents and/or compatible and pharmacologically acceptable adjuvants and/or possibly in in combination with some other pharmacologically compatible and physiologically active product either in simultaneous application, either separately, or distributed over time.
Kao kruti pripravci za oralnu primjenu, mogu se koristiti tablete, pilule, prašci (gelatinske kapsule, tablete) ili granule. U navedenim pripravcima, aktivne komponente su umiješane u jednom ili više inertnih razrjeđivača, kao što je amidon, celuloza, saharoza, laktoza ili silicij, pod strujom argona. Navedeni pripravci mogu isto tako sadržavati druge supstance pored razrijeđivača, na primjer jedan ili više lubrifikans kao što je magnezijev stearat ili talk, boju, sredstvo za oblaganje (dragee) ili glazuru. As solid preparations for oral administration, tablets, pills, powders (gelatin capsules, tablets) or granules can be used. In the mentioned preparations, the active components are mixed in one or more inert diluents, such as starch, cellulose, sucrose, lactose or silicon, under a stream of argon. Said preparations may also contain other substances in addition to the diluent, for example one or more lubricants such as magnesium stearate or talc, color, coating agent (dragee) or glaze.
Kao tekući pripravci za oralnu primjenu, mogu se koristiti farmaceutski prihvatljive otopine, suspenzije, emulzije, sirupi i eliksiri koji sadrže inertne razrjeđivače kao što je voda, etanol, glicerol, vegetabilna ulja ili parafinsko ulje. Navedeni pripravci mogu sadržavati druge supstance pored razrjeđivača, na primjer produkte za vlaženje, zaslađivače, sredstva za povećanje gustoće, za poboljšanje okusa ili sredstva za stabilizaciju. As liquid preparations for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil can be used. Said preparations may contain other substances in addition to diluents, for example wetting agents, sweeteners, thickeners, flavor enhancers or stabilizers.
Sterilni pripravci za parenteralnu primjenu, mogu biti povoljnije vodene otopine ili ne vodene otopine, suspenzije ili emulzije. Kao solvent ili vehikl, mogu se koristiti voda, propilenglikol, polietilenglikol, biljna ulja, osobito maslinovo ulje, injektibilni organski esteri, na primjer etilni oleat ili drugi prikladni organski solventi. Navedeni pripravci mogu isto tako sadržavati adjuvanse, osobito sredstva za vlaženje, postizanje izotoničnosti, emulzifikatore, raspršivače i stabilizatore. Sterilizacija se može izvesti na nekoliko načina, na primjer aseptičkom filtracijom, inkorporacijom u pripravak sterilnih agensa, zračenjem ili zagrijavanjem. Isto se tako mogu pripraviti u obliku krutih sterilnih pripravaka koji se mogu otopiti u trenutku primjene u sterilnoj vodi ili bilo kojem drugom sterilnom sredstvu za injiciranje. Sterile preparations for parenteral administration may preferably be aqueous solutions or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents can be used. Said preparations may also contain adjuvants, especially means for wetting, achieving isotonicity, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by aseptic filtration, incorporation into the preparation of sterile agents, irradiation or heating. They can also be prepared in the form of solid sterile preparations that can be dissolved at the time of application in sterile water or any other sterile means for injection.
Pripravci za rektalnu primjenu su supozitoriji ili rektalne kapsule koje sadrže, osim aktivnog produkta, ekscipijense kao što je kakao putar, polusintetske gliceride ili polietilenglikole. Preparations for rectal administration are suppositories or rectal capsules that contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
Farmaceutski pripravci sadrže općenito od 0,5 do 10 mg sibutramina i od 0,1 do 200 mg antagonista CB1. The pharmaceutical preparations generally contain from 0.5 to 10 mg of sibutramine and from 0.1 to 200 mg of the CB1 antagonist.
Prikazani izum se odnosi isto tako i na postupak liječenja debljine koji se sastoji u primjeni kod bolesnika kombinacije u skladu s izumom bilo istovremeno, bilo odvojeno ili raspoređeno u vremenu. The presented invention also relates to the obesity treatment procedure, which consists in the application to the patient of the combination according to the invention, either simultaneously, separately or distributed over time.
Dozirenje ovisi o očekivanom učinku, o trajanju liječenja i o načinu primjene; ono se općenito kreće u rasponu od 1 do 15 mg sibutramina na dan za oralnu primjenu kod odraslih, te od 0,10 do 500 mg antagonista CB1 na dan za oralnu primjenu kod odraslih. The dosage depends on the expected effect, the duration of the treatment and the method of administration; it generally ranges from 1 to 15 mg of sibutramine per day for oral administration in adults, and from 0.10 to 500 mg of CB1 antagonists per day for oral administration in adults.
Općenito govoreći, liječnik određuje odgovarajući put primjene ovisno o dobi, težini i drugim karakteristikama osobe podvrgnute liječenju. Generally speaking, the doctor determines the appropriate route of administration depending on the age, weight and other characteristics of the person undergoing treatment.
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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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- 2001-10-01 WO PCT/FR2001/003022 patent/WO2002028346A2/en active IP Right Grant
- 2001-10-01 EP EP01974413A patent/EP1328269B2/en not_active Expired - Lifetime
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2003
- 2003-04-02 HR HR20030249A patent/HRP20030249A2/en not_active Application Discontinuation
- 2003-04-03 NO NO20031521A patent/NO20031521L/en not_active Application Discontinuation
- 2003-04-16 ZA ZA200303015A patent/ZA200303015B/en unknown
- 2003-04-17 BG BG107739A patent/BG107739A/en unknown
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