HRP20110312T1 - Supstituirani benzimidazoli i postupci pripreme - Google Patents
Supstituirani benzimidazoli i postupci pripreme Download PDFInfo
- Publication number
- HRP20110312T1 HRP20110312T1 HR20110312T HRP20110312T HRP20110312T1 HR P20110312 T1 HRP20110312 T1 HR P20110312T1 HR 20110312 T HR20110312 T HR 20110312T HR P20110312 T HRP20110312 T HR P20110312T HR P20110312 T1 HRP20110312 T1 HR P20110312T1
- Authority
- HR
- Croatia
- Prior art keywords
- trifluoromethyl
- methyl
- phenyl
- pyridin
- compound
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract 21
- 150000001556 benzimidazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract 66
- 125000000217 alkyl group Chemical group 0.000 claims abstract 26
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 24
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 18
- 150000003839 salts Chemical class 0.000 claims abstract 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract 11
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract 6
- 150000002148 esters Chemical class 0.000 claims abstract 6
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 6
- 229940002612 prodrug Drugs 0.000 claims abstract 6
- 239000000651 prodrug Substances 0.000 claims abstract 6
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims abstract 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract 4
- 230000003009 desulfurizing effect Effects 0.000 claims abstract 4
- 125000000524 functional group Chemical group 0.000 claims abstract 4
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract 3
- 150000001450 anions Chemical class 0.000 claims abstract 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 3
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract 3
- 125000001424 substituent group Chemical group 0.000 claims abstract 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract 3
- 239000002253 acid Substances 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 2
- 239000001257 hydrogen Substances 0.000 claims abstract 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims abstract 2
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract 2
- 125000006239 protecting group Chemical group 0.000 claims abstract 2
- 238000007363 ring formation reaction Methods 0.000 claims abstract 2
- 239000003638 chemical reducing agent Substances 0.000 claims 4
- 239000002798 polar solvent Substances 0.000 claims 4
- -1 3-trifluoromethyl-phenyl Chemical group 0.000 claims 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 claims 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- JDAPYAFPVKVBPF-UHFFFAOYSA-N n-(2-fluoro-5-pyridin-3-ylphenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC(C(=CC=1)F)=CC=1C1=CC=CN=C1 JDAPYAFPVKVBPF-UHFFFAOYSA-N 0.000 claims 2
- NVKYHJWQISEJQK-UHFFFAOYSA-N n-(2-fluoro-5-pyridin-4-ylphenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC(C(=CC=1)F)=CC=1C1=CC=NC=C1 NVKYHJWQISEJQK-UHFFFAOYSA-N 0.000 claims 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- BPMDDRXOVIYKRO-UHFFFAOYSA-N (4-ethylpiperazin-1-yl)-[2-[4-[1-methyl-2-[4-(trifluoromethyl)anilino]benzimidazol-5-yl]oxypyridin-2-yl]-1h-imidazol-5-yl]methanone Chemical compound C1CN(CC)CCN1C(=O)C1=CN=C(C=2N=CC=C(OC=3C=C4N=C(NC=5C=CC(=CC=5)C(F)(F)F)N(C)C4=CC=3)C=2)N1 BPMDDRXOVIYKRO-UHFFFAOYSA-N 0.000 claims 1
- RUQDVCHGGJZPBP-UHFFFAOYSA-N (4-ethylpiperazin-1-yl)-[2-[4-[2-[2-fluoro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-1h-imidazol-5-yl]methanone Chemical compound C1CN(CC)CCN1C(=O)C1=CN=C(C=2N=CC=C(OC=3C=C4N=C(NC=5C(=CC=C(C=5)C(F)(F)F)F)N(C)C4=CC=3)C=2)N1 RUQDVCHGGJZPBP-UHFFFAOYSA-N 0.000 claims 1
- QQZNCAXYRMMAFQ-UHFFFAOYSA-N 1-ethyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxy-n-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(CC)C=1NC1=CC=C(C(F)(F)F)C=C1 QQZNCAXYRMMAFQ-UHFFFAOYSA-N 0.000 claims 1
- LVNYFIASUPVQIV-UHFFFAOYSA-N 1-methyl-5-[2-(5-phenyl-1h-imidazol-2-yl)pyridin-4-yl]oxy-n-[4-(trifluoromethylsulfanyl)phenyl]benzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C=3C=CC=CC=3)=CC=C2N(C)C=1NC1=CC=C(SC(F)(F)F)C=C1 LVNYFIASUPVQIV-UHFFFAOYSA-N 0.000 claims 1
- ADEVTABMDFBPPG-UHFFFAOYSA-N 1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxy-n-[2-(trifluoromethyl)phenyl]benzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=CC=C1C(F)(F)F ADEVTABMDFBPPG-UHFFFAOYSA-N 0.000 claims 1
- DVJYMPYLFMEZMR-UHFFFAOYSA-N 1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxy-n-[3-(trifluoromethyl)phenyl]benzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=CC(C(F)(F)F)=C1 DVJYMPYLFMEZMR-UHFFFAOYSA-N 0.000 claims 1
- ZNKJEEFWTJMGCS-UHFFFAOYSA-N 1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxy-n-[4-(trifluoromethylsulfanyl)phenyl]benzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(SC(F)(F)F)C=C1 ZNKJEEFWTJMGCS-UHFFFAOYSA-N 0.000 claims 1
- YABJJWZLRMPFSI-UHFFFAOYSA-N 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1 YABJJWZLRMPFSI-UHFFFAOYSA-N 0.000 claims 1
- OZOMCNZBYFGHSP-UHFFFAOYSA-N 1-methyl-n-[4-(4-methylpiperazin-1-yl)phenyl]-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound C1CN(C)CCN1C(C=C1)=CC=C1NC1=NC2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N1C OZOMCNZBYFGHSP-UHFFFAOYSA-N 0.000 claims 1
- XJDIHOYNBOTGEN-UHFFFAOYSA-N 1-methyl-n-[4-(trifluoromethoxy)phenyl]-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(OC(F)(F)F)C=C1 XJDIHOYNBOTGEN-UHFFFAOYSA-N 0.000 claims 1
- LQQRMHCFUPBXAK-UHFFFAOYSA-N 2-[4-[1-methyl-2-[4-(trifluoromethyl)anilino]benzimidazol-5-yl]oxypyridin-2-yl]-1h-imidazole-5-carbonitrile Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C#N)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1 LQQRMHCFUPBXAK-UHFFFAOYSA-N 0.000 claims 1
- OFYJNFTZWLQOFC-UHFFFAOYSA-N 2-[4-[2-[2-fluoro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-1h-imidazole-5-carbonitrile Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C#N)=CC=C2N(C)C=1NC1=CC(C(F)(F)F)=CC=C1F OFYJNFTZWLQOFC-UHFFFAOYSA-N 0.000 claims 1
- MEGIOXIBNYRWDR-UHFFFAOYSA-N 2-[4-[2-[2-fluoro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-n-(2-hydroxyethyl)-1h-imidazole-5-carboxamide Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(=O)NCCO)=CC=C2N(C)C=1NC1=CC(C(F)(F)F)=CC=C1F MEGIOXIBNYRWDR-UHFFFAOYSA-N 0.000 claims 1
- OCZXHQKDRFDCRJ-UHFFFAOYSA-N 2-[[1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-yl]amino]-5-(trifluoromethyl)phenol Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1O OCZXHQKDRFDCRJ-UHFFFAOYSA-N 0.000 claims 1
- RLRHXLXCAWJBGX-UHFFFAOYSA-N 2-chloro-1,3-dimethyl-1,2-dihydroimidazol-1-ium;chloride Chemical compound [Cl-].CN1C=C[NH+](C)C1Cl RLRHXLXCAWJBGX-UHFFFAOYSA-N 0.000 claims 1
- KLTIMEXKPRJOIS-UHFFFAOYSA-N 2-chloro-1-methyl-2H-pyridine hydroiodide Chemical compound I.CN1C=CC=CC1Cl KLTIMEXKPRJOIS-UHFFFAOYSA-N 0.000 claims 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 1
- LEDHAWOWVPPJPN-UHFFFAOYSA-N 5-[[1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-yl]amino]-2-(trifluoromethyl)phenol Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C(O)=C1 LEDHAWOWVPPJPN-UHFFFAOYSA-N 0.000 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims 1
- 229910019213 POCl3 Inorganic materials 0.000 claims 1
- SHWSLZQDDYQHGI-UHFFFAOYSA-N [2-[4-[2-[2-fluoro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-4-(trifluoromethyl)-1h-imidazol-5-yl]methanol Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=C(CO)N=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC(C(F)(F)F)=CC=C1F SHWSLZQDDYQHGI-UHFFFAOYSA-N 0.000 claims 1
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical group CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims 1
- 235000010216 calcium carbonate Nutrition 0.000 claims 1
- 229910000019 calcium carbonate Inorganic materials 0.000 claims 1
- UEOHBSPCKMVSEZ-UHFFFAOYSA-N ethyl 2-[4-[2-[2-chloro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-5-(trifluoromethyl)-1h-imidazole-4-carboxylate Chemical compound N1C(C(F)(F)F)=C(C(=O)OCC)N=C1C1=CC(OC=2C=C3N=C(NC=4C(=CC=C(C=4)C(F)(F)F)Cl)N(C)C3=CC=2)=CC=N1 UEOHBSPCKMVSEZ-UHFFFAOYSA-N 0.000 claims 1
- XDYXHTQMOKHMDM-UHFFFAOYSA-N ethyl 2-[4-[2-[2-fluoro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-5-(trifluoromethyl)-1h-imidazole-4-carboxylate Chemical compound N1C(C(F)(F)F)=C(C(=O)OCC)N=C1C1=CC(OC=2C=C3N=C(NC=4C(=CC=C(C=4)C(F)(F)F)F)N(C)C3=CC=2)=CC=N1 XDYXHTQMOKHMDM-UHFFFAOYSA-N 0.000 claims 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims 1
- BEOWSPCVIHQXLI-UHFFFAOYSA-N methyl 2-[4-[2-[2-fluoro-5-(trifluoromethyl)anilino]-1-methylbenzimidazol-5-yl]oxypyridin-2-yl]-1h-imidazole-5-carboxylate Chemical compound N1C(C(=O)OC)=CN=C1C1=CC(OC=2C=C3N=C(NC=4C(=CC=C(C=4)C(F)(F)F)F)N(C)C3=CC=2)=CC=N1 BEOWSPCVIHQXLI-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- CYNCLJZSLURWDD-UHFFFAOYSA-N n-(2-chlorophenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=CC=C1Cl CYNCLJZSLURWDD-UHFFFAOYSA-N 0.000 claims 1
- NOBWZSLSVIUZAX-UHFFFAOYSA-N n-(2-ethylphenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CCC1=CC=CC=C1NC1=NC2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N1C NOBWZSLSVIUZAX-UHFFFAOYSA-N 0.000 claims 1
- PWWZOONQYQLJBE-UHFFFAOYSA-N n-(2-hydroxyethyl)-2-[4-[1-methyl-2-[4-(trifluoromethyl)anilino]benzimidazol-5-yl]oxypyridin-2-yl]-1h-imidazole-5-carboxamide Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(=O)NCCO)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1 PWWZOONQYQLJBE-UHFFFAOYSA-N 0.000 claims 1
- ZEUAXTRKGYORKF-UHFFFAOYSA-N n-(3-ethylphenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CCC1=CC=CC(NC=2N(C3=CC=C(OC=4C=C(N=CC=4)C=4NC(=CN=4)C(F)(F)F)C=C3N=2)C)=C1 ZEUAXTRKGYORKF-UHFFFAOYSA-N 0.000 claims 1
- FHQUGILIWIXMQJ-UHFFFAOYSA-N n-(4-bromophenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(Br)C=C1 FHQUGILIWIXMQJ-UHFFFAOYSA-N 0.000 claims 1
- UULHAECZZWRIHA-UHFFFAOYSA-N n-(4-chlorophenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(Cl)C=C1 UULHAECZZWRIHA-UHFFFAOYSA-N 0.000 claims 1
- UNNIFOKCWPGGRX-UHFFFAOYSA-N n-(4-ethylphenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound C1=CC(CC)=CC=C1NC1=NC2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N1C UNNIFOKCWPGGRX-UHFFFAOYSA-N 0.000 claims 1
- JOJYJDOMFMIRKR-UHFFFAOYSA-N n-(4-tert-butylphenyl)-1-methyl-5-[2-(5-methyl-4-phenyl-1h-imidazol-2-yl)pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CC=1NC(C=2N=CC=C(OC=3C=C4N=C(NC=5C=CC(=CC=5)C(C)(C)C)N(C)C4=CC=3)C=2)=NC=1C1=CC=CC=C1 JOJYJDOMFMIRKR-UHFFFAOYSA-N 0.000 claims 1
- UKHGHPIFGONHOV-UHFFFAOYSA-N n-(4-tert-butylphenyl)-1-methyl-5-[2-[4-phenyl-5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=C(N=3)C=3C=CC=CC=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(C)(C)C)C=C1 UKHGHPIFGONHOV-UHFFFAOYSA-N 0.000 claims 1
- GWKBJILKCSXHMY-UHFFFAOYSA-N n-(5-tert-butyl-2-chlorophenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC(C(C)(C)C)=CC=C1Cl GWKBJILKCSXHMY-UHFFFAOYSA-N 0.000 claims 1
- BCSZFWZJIFOMKQ-UHFFFAOYSA-N n-(5-tert-butyl-2-fluorophenyl)-1-methyl-5-[2-(5-methyl-4-phenyl-1h-imidazol-2-yl)pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CC=1NC(C=2N=CC=C(OC=3C=C4N=C(NC=5C(=CC=C(C=5)C(C)(C)C)F)N(C)C4=CC=3)C=2)=NC=1C1=CC=CC=C1 BCSZFWZJIFOMKQ-UHFFFAOYSA-N 0.000 claims 1
- KLUQUTDAFSUQQQ-UHFFFAOYSA-N n-(5-tert-butyl-2-fluorophenyl)-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC(C(C)(C)C)=CC=C1F KLUQUTDAFSUQQQ-UHFFFAOYSA-N 0.000 claims 1
- LOOGBSGPMZTHIX-UHFFFAOYSA-N n-[2-chloro-4-(trifluoromethyl)phenyl]-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC=C(C(F)(F)F)C=C1Cl LOOGBSGPMZTHIX-UHFFFAOYSA-N 0.000 claims 1
- KBSLJFGAYBKSLV-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-1-methyl-5-[2-(5-methyl-4-phenyl-1h-imidazol-2-yl)pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CC=1NC(C=2N=CC=C(OC=3C=C4N=C(NC=5C(=CC=C(C=5)C(F)(F)F)Cl)N(C)C4=CC=3)C=2)=NC=1C1=CC=CC=C1 KBSLJFGAYBKSLV-UHFFFAOYSA-N 0.000 claims 1
- QPYNIFPLONQWGU-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-1-methyl-5-[2-[4-phenyl-5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=C(N=3)C=3C=CC=CC=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC(C(F)(F)F)=CC=C1Cl QPYNIFPLONQWGU-UHFFFAOYSA-N 0.000 claims 1
- PYBSLQNYWLNLKV-UHFFFAOYSA-N n-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-5-[2-(5-methyl-4-phenyl-1h-imidazol-2-yl)pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CC=1NC(C=2N=CC=C(OC=3C=C4N=C(NC=5C(=CC=C(C=5)C(F)(F)F)F)N(C)C4=CC=3)C=2)=NC=1C1=CC=CC=C1 PYBSLQNYWLNLKV-UHFFFAOYSA-N 0.000 claims 1
- OCTPLXRWWSCLMD-UHFFFAOYSA-N n-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-5-[2-[4-phenyl-5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=C(N=3)C=3C=CC=CC=3)C(F)(F)F)=CC=C2N(C)C=1NC1=CC(C(F)(F)F)=CC=C1F OCTPLXRWWSCLMD-UHFFFAOYSA-N 0.000 claims 1
- VDWDZORLKMAOGO-UHFFFAOYSA-N n-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-5-[2-[5-methyl-4-[3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CC=1NC(C=2N=CC=C(OC=3C=C4N=C(NC=5C(=CC=C(C=5)C(F)(F)F)F)N(C)C4=CC=3)C=2)=NC=1C1=CC=CC(C(F)(F)F)=C1 VDWDZORLKMAOGO-UHFFFAOYSA-N 0.000 claims 1
- BUGGWNWJASBPFW-UHFFFAOYSA-N n-[2-fluoro-5-(trifluoromethyl)phenyl]-1-methyl-5-[2-[5-methyl-4-[4-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound CC=1NC(C=2N=CC=C(OC=3C=C4N=C(NC=5C(=CC=C(C=5)C(F)(F)F)F)N(C)C4=CC=3)C=2)=NC=1C1=CC=C(C(F)(F)F)C=C1 BUGGWNWJASBPFW-UHFFFAOYSA-N 0.000 claims 1
- XGBGLHMBKUDHSN-UHFFFAOYSA-N n-[2-fluoro-5-(trifluoromethyl)phenyl]-6-methoxy-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C=2C=C(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)C(OC)=CC=2N(C)C=1NC1=CC(C(F)(F)F)=CC=C1F XGBGLHMBKUDHSN-UHFFFAOYSA-N 0.000 claims 1
- SMPKBRUCIWKACB-UHFFFAOYSA-N n-[4-fluoro-3-(oxolan-3-yl)phenyl]-1-methyl-5-[2-[5-(trifluoromethyl)-1h-imidazol-2-yl]pyridin-4-yl]oxybenzimidazol-2-amine Chemical compound N=1C2=CC(OC=3C=C(N=CC=3)C=3NC(=CN=3)C(F)(F)F)=CC=C2N(C)C=1NC(C=1)=CC=C(F)C=1C1CCOC1 SMPKBRUCIWKACB-UHFFFAOYSA-N 0.000 claims 1
- 150000007530 organic bases Chemical class 0.000 claims 1
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 235000011118 potassium hydroxide Nutrition 0.000 claims 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical group [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims 1
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
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Abstract
Postupak za pripremu spoja formule (I) ili njegovog tautomera, stereoizomera, estera, prolijeka ili farmaceutski prihvatljive solinaznačen time, da svaki R1 jest nezavisno odabran od hidroksi, halo, C1 6 alkila, C1 6 alkoksi, (C1 6 alkil) sulfanila, (C1 6 alkil) sulfonila, cikloalkila, heterocikloalkila, fenila i heteroarila; R2 jest C1 6 alkil, ili halo (C1 6 alkil); svaki R3 je nezavisno odabran od halo, C1 6 alkila i C1 6 alkoksi; svaki R4 je nezavisno odabran od hidroksi, C1 6 alkila, C1-6 alkoksi, halo, heterocikloalkilkarbonila, karboksila, (C1 6 alkoksi) karbonila, aminokarbonila, C1 6 alkilaminokarbonila, karbonitrila, cikloalkila, heterocikloalkila, fenila, i heteroarila; u čemu R1, R2, R3 i R4, mogu po izboru biti supstituirani jednim ili više supstituenata, nezavisno odabranih od hidroksi, halo, C1 6 alkila, halo (C1 6alkil), C1 6 alkoksi i halo (C1 6 alkoksi); a jest 1, 2, 3, 4 ili 5; b jest 0, 1, 2 ili 3; c jest 1 ili 2; koji postupak obuhvaća: (a) dovođenje u reakciju spoja formule (II) sa spojem formule (III) da se dobije spoj formule (IV) u čemu Q je NH2 ili NO2; jedan od L1 ili L2 jest halo, a drugi od L1 ili L2 jest OH ili njegov anion; Z jest cijano, COOR5, CH2OR5, CHO ili imidazol-2-il, supstituiran jednom ili dvije R4 skupine, i u čemu R5 jest vodik ili hidroksi zaštitna skupina; (b) kada u spoju formule (IV) Z jest cijano, COOR5 ili CH2OR5, pretvaranje navedenog spoja u spoj formule (IV), u čemu Z jest CHO; (c) kada u spoju formule (IV) Z jest cijano, pretvaranje cijano funkcionalne skupine u amidino funkcionalnu skupinu i dovođenje navedene amidino funkcionalne skupine u reakciju sa spojem formule (Va) pod uvjetima formiranja imidazolnog prstena; ili kada u spoju formule (IV) Z jest CHO, dovođenje u reakciju navedenog spoja sa spojem formule (Vb) da se dobije spoj formule (VI) u čemu Xa u formuli (Va) jest odlazeća skupina i R4p i R4q u formuli (Vb) su nezavisno H ili R4, uz uvjet da barem jedan od R4p i R4q jest R4, a Xb je =O ili =NHOH i uz uvjet da c jest 1 kada se spoj formule (VI) priprema iz spoja formule (Va); (d) kada u spoju formule (VI) Q jest NO2, pretvaranje navedenog spoja u spoj formule (VI), u čemu Q jest NH2; (e) dovođenje u reakciju spoja formule (VI), u čemu Q jest NH2, sa spojem formule (VII) da se dobije spoj formule (VIII) ili njegov tautomer(f) dovođenje u reakciju spoja formule (VIII) ili njegovog tautomera s desulfurirajućim agensom da se postigne zatvaranje prstena i dobije spoj formule (I); (g) po izboru, dovođenje u reakciju spoja formule (I) ili njegovog tautomera s kiselinom da dade prvu farmaceutski prihvatljivu sol; (h) po izboru, pretvaranje prve farmaceutski prihvatljive soli spoja formule (I) ili njegovog tautomera u drugu farmaceutski prihvatljivu sol; i (i) po izboru, pretvaranje spoja formule (I) ili njegovog tautomera ili njegove farmaceutski prihvatljive soli u ester ili prolijek formule (I). Patent sadrži još 15 patentnih zahtjeva.
Claims (16)
1. Postupak za pripremu spoja formule (I) ili njegovog tautomera, stereoizomera, estera, prolijeka ili farmaceutski prihvatljive soli
[image]
naznačen time, da svaki R1 jest nezavisno odabran od hidroksi, halo, C16 alkila, C16 alkoksi, (C16 alkil) sulfanila, (C16 alkil) sulfonila, cikloalkila, heterocikloalkila, fenila i heteroarila;
R2 jest C16 alkil, ili halo (C16 alkil);
svaki R3 je nezavisno odabran od halo, C16 alkila i C16 alkoksi;
svaki R4 je nezavisno odabran od hidroksi, C16 alkila, C1-6 alkoksi, halo, heterocikloalkilkarbonila, karboksila, (C16 alkoksi) karbonila, aminokarbonila, C16 alkilaminokarbonila, karbonitrila, cikloalkila, heterocikloalkila, fenila, i heteroarila;
u čemu R1, R2, R3 i R4, mogu po izboru biti supstituirani jednim ili više supstituenata, nezavisno odabranih od hidroksi, halo, C16 alkila, halo (C16alkil), C16 alkoksi i halo (C16 alkoksi);
a jest 1, 2, 3, 4 ili 5;
b jest 0, 1, 2 ili 3;
c jest 1 ili 2;
koji postupak obuhvaća:
(a) dovođenje u reakciju spoja formule (II) sa spojem formule (III) da se dobije spoj formule (IV)
[image]
u čemu Q je NH2 ili NO2; jedan od L1 ili L2 jest halo, a drugi od L1 ili L2 jest OH ili njegov anion; Z jest cijano, COOR5, CH2OR5, CHO ili imidazol-2-il, supstituiran jednom ili dvije R4 skupine, i u čemu R5 jest vodik ili hidroksi zaštitna skupina;
(b) kada u spoju formule (IV) Z jest cijano, COOR5 ili CH2OR5, pretvaranje navedenog spoja u spoj formule (IV), u čemu Z jest CHO;
(c) kada u spoju formule (IV) Z jest cijano, pretvaranje cijano funkcionalne skupine u amidino funkcionalnu skupinu i dovođenje navedene amidino funkcionalne skupine u reakciju sa spojem formule (Va) pod uvjetima formiranja imidazolnog prstena; ili kada u spoju formule (IV) Z jest CHO, dovođenje u reakciju navedenog spoja sa spojem formule (Vb) da se dobije spoj formule (VI)
[image]
u čemu Xa u formuli (Va) jest odlazeća skupina i R4p i R4q u formuli (Vb) su nezavisno H ili R4, uz uvjet da barem jedan od R4p i R4q jest R4,a Xb je =O ili =NHOH i uz uvjet da c jest 1 kada se spoj formule (VI) priprema iz spoja formule (Va);
(d) kada u spoju formule (VI) Q jest NO2, pretvaranje navedenog spoja u spoj formule (VI), u čemu Q jest NH2;
(e) dovođenje u reakciju spoja formule (VI), u čemu Q jest NH2,sa spojem formule (VII) da se dobije spoj formule (VIII) ili njegov tautomer
[image]
(f) dovođenje u reakciju spoja formule (VIII) ili njegovog tautomera s desulfurirajućim agensom da se postigne zatvaranje prstena i dobije spoj formule (I);
(g) po izboru, dovođenje u reakciju spoja formule (I) ili njegovog tautomera s kiselinom da dade prvu farmaceutski prihvatljivu sol;
(h) po izboru, pretvaranje prve farmaceutski prihvatljive soli spoja formule (I) ili njegovog tautomera u drugu farmaceutski prihvatljivu sol; i
(i) po izboru, pretvaranje spoja formule (I) ili njegovog tautomera ili njegove farmaceutski prihvatljive soli u ester ili prolijek formule (I).
2. Postupak prema patentnom zahtjevu 1, naznačen time, da se dio (a) izvodi s organskom ili anorganskom bazom u polarnom otapalu.
3. Postupak prema patentnom zahtjevu 2, naznačen time, da se anorganska baza odabire iz skupine koja se sastoji od NaOH, KOH, CaCO3 i K2CO3.
4. Postupak prema patentnom zahtjevu 2, naznačen time, da se polarno otapalo odabire iz skupine koja se sastoji od dimetilsulfoksida i dimetilformamida.
5. Postupak prema patentnom zahtjevu 1, naznačen time, da dio (b) sadrži reagiranje spoja formule (IV), kada Z jest COOR5, s redukcijskim agensom.
6. Postupak prema patentnom zahtjevu 5, naznačen time, da R5 jest terc-butil.
7. Postupak prema patentnom zahtjevu 5, naznačen time, da redukcijski agens jest diizobutilaluminijev hidrid.
8. Postupak prema patentnom zahtjevu 1, naznačen time, da se dio (c) izvodi s NH4OH u polarnom otapalu.
9. Postupak prema patentnom zahtjevu 8, naznačen time, da polarno otapalo jest smjesa etilacetata i etanola.
10. Postupak prema patentnom zahtjevu 1, naznačen time, da da dio (d) sadrži reagiranje spoja formule (VI), kada Q jest NO2, s redukcijskim agensom.
11. Postupak prema patentnom zahtjevu 10, naznačen time, da redukcijski agens jest natrijev ditionit.
12. Postupak prema patentnom zahtjevu 1, naznačen time, da se dio (e) izvodi u acetonitrilu.
13. Postupak prema patentnom zahtjevu 1, naznačen time, da se desulfurirajući agens u dijelu (f) odabire iz skupine koja se sastoji od FeCl3, 2-kloro-1-metilpiridin jodida, 2-kloro-1,3-dimetilimidazol klorida i POCl3.
14. Postupak za pripremu spoja formule (I) ili njegovog tautomera, stereoizomera, estera, prolijeka ili farmaceutski prihvatljive soli
[image]
naznačen time, da svaki R1 jest nezavisno odabran od hidroksi, halo, C16 alkila, C16 alkoksi, (C16 alkil) sulfanila, (C16 alkil) sulfonila, cikloalkila, heterocikloalkila, fenila i heteroarila;
R2 jest C16 alkil ili halo (C16 alkil);
svaki R3 jest nezavisno odabran od halo, C16 alkila i C16 alkoksi;
svaki R4 jest nezavisno odabran od hidroksi, C16 alkila, C1-6 alkoksi, halo, heterocikloalkilkarbonila, karboksila, (C16 alkoksi) karbonila, aminokarbonila, C16 alkilaminokarbonila, karbonitrila, cikloalkila, heterocikloalkila, fenila i heteroarila;
u čemu R1, R2, R3 i R4, mogu po izboru biti supstituirani jednim ili više supstituenata, nezavisno odabranih od hidroksi, halo, C16 alkila, halo (C16alkil), C16 alkoksi i halo (C16 alkoksi);
a jest 1, 2, 3, 4 ili 5;
b jest 0, 1, 2 ili 3;
c jest 1 ili 2;
koji postupak sadrži:
dovođenje u reakciju spoja formule (XIII) sa spojem formule (XIV) da se dobije spoj formule (I)
[image]
u čemu jedan od L3 ili L4 jest halo, a drugi od L3 ili L4 jest OH ili njegov anion; ili
dovođenje spoja formule (XV) u reakciju sa spojem formule (Vb) da se dobije spoj formule (I)
[image]
u čemu R4p i R4q su nezavisno H ili R4 uz uvjet da barem jedan od R4p i R4q jest R4, aXb jest =O ili =NHOH; ili
dovođenje spoja formule (VIII) ili njegovog tautomera u reakciju s desulfurirajućim agensom da se postigne zatvaranje prstena i dobije spoj formule (I)
[image]
15. Postupak prema patentnom zahtjevu 1, naznačen time, da je spoj formule (I) odabran iz skupine koja sadrži
{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(4-trifluorometil-fenil)-amin,
(2-fluoro-5-piridin-3-il-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2- fluoro-5-piridin-4-il-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-terc-butil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(3-trifluorometil-fenil)-amin,
(3-etil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-kloro-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-etil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-kloro-3-trifluorometil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-fluoro-3-trifluorometil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(4-trifluorometoksi-fenil)-amin,
(2-fluoro-5-trifluorometil-fenil)-(1-metil-5-{2-[5-metil-4-(3-trfiluorometilfenil)-1H-imidazol-2-il]-piridin-4-iloksi}-1H-benzoimidazol-2-il)-amin,
(2-fluoro-5-trifluorometil-fenil)-(1-metil-5-{2-[5-metil-4-(4-trifluorometilfenil)-1H-imidazol-2-il]-piridin-4-iloksi}-1H-benzoimidazol-2-il)-amin,
2-{4-[2-(2-fluoro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-5-trifluorometil-1H-imidazol-4-karboksilna kiselina etil ester,
(2-{4-[2-(2-fluoro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-5-trifluorometil-1H-imidazol-4-il)-metanol,
2-{4-[1-metil-2-(4-trifluorometil-fenilamino)-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-karbonitril,
(3-terc-butil-fenil)-{1-metil-5-[2-(5-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(5-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(4-trifluorometilsulfanil-fenil)-amin,
(3-terc-butil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
[4-fluoro-3-(tetrahidro-furan-3-il)-fenil]-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-bromo-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-fluoro-3-izopropil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(4-trifluorometilsulfanil-fenil)-amin,
(2-fluoro-5-izopropil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-fluoro-5-trifluorometil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(5-terc-butil-2-fluoro-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-fluoro-5-trifluorometil-fenil)-{1-metil-5-[2-(5-metil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-fluoro-5-piridin-3-il-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
2-{4-[2-(2-fluoro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-karbonitril,
(2-kloro-4-trifluorometil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2il)piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(5-terc-butil-2-kloro-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-fluoro-5-piridin-4-il-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-fluoro-5-trifluorometil-fenil)-{1-metil-5-[2-(4-fenil-5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-kloro-5-trifluorometil-fenil)-{1-metil-5-[2-(4-fenil-5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(4-fenil-5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(3-trifluorometil-fenil)-amin,
(3-etil-fenil)-{1-metil-5-[2-(4-fenil-5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-terc-butil-fenil)-{1-metil-5-[2-(4-fenil-5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-kloro-5-trifluorometil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-fluoro-5-trifluorometil-fenil)-{1-metil-5-[2-(5-metil-4-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-kloro-5-trifluorometil-fenil)-{1-metil-5-[2-(5-metil-4-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-terc-butil-fenil)-{1-metil-5-[2-(5-metil-4-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(5-metil-4-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(3-trifluorometil-fenil)-amin,
(5-terc-butil-2-fluoro-fenil)-{1-metil-5-[2-(5-metil-4-fenil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
[4-(4-metil-piperazin-1-il)-fenil]-{-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
2-{4-[2-(2-fluoro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-karboksilna kiselina metil ester,
2-{4-[2-(2-kloro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-5-trifluorometil-1H-imidazol-4-karboksilna kiselina etil ester,
(2-fluoro-4-trifluorometil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2-kloro-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(2,5-dimetoksi-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(3,5-dimetoksi-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(2-trifluorometil-fenil)-amin,
(2-etil-fenil)-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
(4-etil-piperazin-1-il)-(2-{4-[2-(2-fluoro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-il)-metanon,
2-{4-[2-(2-fluoro-5-trifluorometil-fenilamino)-1-metil-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-karboksilna kiselina (2-hidroksi-etil)-amid,
{1-etil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(2-fluoro-5-trifluorometil-fenil)-amin,
(2-fluoro-5-trifluorometil-fenil)-{6-metoksi-1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-amin,
{6-metoksi-1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(4-trifluorometil-fenil)-amin,
(4-etil-piperazin-1-il)-(2-{4-[1-metil-2-(4-trifluorometil-fenilamino)-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-il)-metanon,
{1-etil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-il}-(4-trifluorometil-fenil)-amin,
2-{4-[1-metil-2-(4-trifluorometil-fenilamino)-1H-benzoimidazol-5-iloksi]-piridin-2-il}-3H-imidazol-4-karboksilna kiselina (2-hidroksi-etil)-amid,
2-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-ilamino}-5-trifluorometil-fenol, i
3-{1-metil-5-[2-(5-trifluorometil-1H-imidazol-2-il)-piridin-4-iloksi]-1H-benzoimidazol-2-ilamino}-6-trifluorometil-fenol;
ili tautomer, stereoizomer, ester, prolijek ili njihova farmaceutski prihvatljiva sol.
16. Postupak prema bilo kojem od patentnih zahtjeva 1 ili 14, naznačen time, da spoj (I) jest spoj formule (IXa) ili njegov tautomer (IXb)
[image]
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2008
- 2008-01-28 IL IL189080A patent/IL189080A/en not_active IP Right Cessation
- 2008-02-03 IL IL189194A patent/IL189194A/en not_active IP Right Cessation
- 2008-02-07 CR CR9716A patent/CR9716A/es not_active Application Discontinuation
- 2008-02-21 EC EC2008008210A patent/ECSP088210A/es unknown
- 2008-02-25 CU CU20080027A patent/CU23784B7/es not_active IP Right Cessation
- 2008-02-25 EC EC2008008218A patent/ECSP088218A/es unknown
- 2008-02-28 TN TNP2008000088A patent/TNSN08088A1/en unknown
- 2008-02-28 TN TNP2008000089A patent/TNSN08089A1/en unknown
- 2008-02-28 HN HN2008000317A patent/HN2008000317A/es unknown
- 2008-03-11 MA MA30737A patent/MA29915B1/fr unknown
- 2008-03-11 MA MA30738A patent/MA29772B1/fr unknown
- 2008-03-26 NO NO20081476A patent/NO20081476L/no not_active Application Discontinuation
- 2008-05-05 US US12/151,995 patent/US7767820B2/en not_active Expired - Fee Related
- 2008-07-24 HK HK08108224.3A patent/HK1117519A1/xx not_active IP Right Cessation
- 2008-07-25 HK HK08108275.1A patent/HK1117523A1/xx not_active IP Right Cessation
- 2008-12-05 US US12/315,779 patent/US7732465B2/en active Active
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2010
- 2010-04-13 US US12/759,578 patent/US8592459B2/en active Active
- 2010-06-18 US US12/818,971 patent/US20100256375A1/en not_active Abandoned
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2011
- 2011-04-29 HR HR20110312T patent/HRP20110312T1/hr unknown
- 2011-06-27 CY CY20111100607T patent/CY1111871T1/el unknown
- 2011-12-06 CY CY20111101214T patent/CY1112157T1/el unknown
- 2011-12-15 HR HR20110939T patent/HRP20110939T1/hr unknown
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2012
- 2012-12-03 JP JP2012264552A patent/JP2013060457A/ja not_active Withdrawn
- 2012-12-03 JP JP2012264553A patent/JP2013060458A/ja active Pending
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