TWI419882B - Vr1之苯并咪唑調節劑 - Google Patents
Vr1之苯并咪唑調節劑 Download PDFInfo
- Publication number
- TWI419882B TWI419882B TW096115519A TW96115519A TWI419882B TW I419882 B TWI419882 B TW I419882B TW 096115519 A TW096115519 A TW 096115519A TW 96115519 A TW96115519 A TW 96115519A TW I419882 B TWI419882 B TW I419882B
- Authority
- TW
- Taiwan
- Prior art keywords
- phenyl
- benzimidazol
- vinyl
- trifluoromethyl
- benzenesulfonamide
- Prior art date
Links
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 197
- 150000001875 compounds Chemical class 0.000 claims description 176
- -1 aminosulfonylamino Chemical group 0.000 claims description 105
- 229910052799 carbon Inorganic materials 0.000 claims description 100
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 58
- 125000003545 alkoxy group Chemical group 0.000 claims description 56
- 229920002554 vinyl polymer Polymers 0.000 claims description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- 125000005843 halogen group Chemical group 0.000 claims description 39
- 208000002193 Pain Diseases 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 19
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 18
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 18
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims description 18
- 230000001404 mediated effect Effects 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 15
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 claims description 15
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 claims description 15
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 13
- PHPYXVIHDRDPDI-UHFFFAOYSA-N 2-bromo-1h-benzimidazole Chemical compound C1=CC=C2NC(Br)=NC2=C1 PHPYXVIHDRDPDI-UHFFFAOYSA-N 0.000 claims description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 13
- 150000001299 aldehydes Chemical class 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 206010065390 Inflammatory pain Diseases 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 230000003197 catalytic effect Effects 0.000 claims description 12
- 229940005991 chloric acid Drugs 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical class OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 7
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 208000005298 acute pain Diseases 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 239000004305 biphenyl Substances 0.000 claims description 7
- 235000010290 biphenyl Nutrition 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 230000001684 chronic effect Effects 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 208000004550 Postoperative Pain Diseases 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- PASWFOTTYAJBNR-JXMROGBWSA-N 2-[6-fluoro-2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1h-benzimidazol-5-yl]phenol Chemical compound OC1=CC=CC=C1C(C(=C1)F)=CC2=C1NC(\C=C\C=1C=CC(=CC=1)C(F)(F)F)=N2 PASWFOTTYAJBNR-JXMROGBWSA-N 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- YJPSUAGGJKRFRD-UHFFFAOYSA-N 2-[1-(2-phenylethynyl)benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(N(C=N2)C#CC=3C=CC=CC=3)C2=C1 YJPSUAGGJKRFRD-UHFFFAOYSA-N 0.000 claims description 3
- GNBVSCWQHRHPOS-KPKJPENVSA-N 2-[2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(=CC=2)C(F)(F)F)=N2)C2=C1 GNBVSCWQHRHPOS-KPKJPENVSA-N 0.000 claims description 3
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- PHBDKKIHETWYOU-JXMROGBWSA-N [2-[6-chloro-2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1h-benzimidazol-5-yl]phenyl]methanol Chemical compound OCC1=CC=CC=C1C(C(=C1)Cl)=CC2=C1NC(\C=C\C=1C=CC(=CC=1)C(F)(F)F)=N2 PHBDKKIHETWYOU-JXMROGBWSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 2
- MAHSFTCGIOZKAF-MDWZMJQESA-N 1-[2-[2-[(e)-2-[4-(trifluoromethylsulfonyl)phenyl]ethenyl]-3h-benzimidazol-5-yl]phenyl]ethanol Chemical compound CC(O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(=CC=2)S(=O)(=O)C(F)(F)F)=N2)C2=C1 MAHSFTCGIOZKAF-MDWZMJQESA-N 0.000 claims description 2
- BVVORTPCTWMIFI-MDWZMJQESA-N 1-[2-[2-[(e)-2-[4-(trifluoromethylsulfonyl)phenyl]ethenyl]-3h-benzimidazol-5-yl]phenyl]ethanone Chemical compound CC(=O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(=CC=2)S(=O)(=O)C(F)(F)F)=N2)C2=C1 BVVORTPCTWMIFI-MDWZMJQESA-N 0.000 claims description 2
- AQMXQOTTWVAIFI-UHFFFAOYSA-N 1-[2-[2-[2-[4-(trifluoromethylsulfonyl)phenyl]ethyl]-3h-benzimidazol-5-yl]phenyl]ethanol Chemical compound CC(O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(=CC=2)S(=O)(=O)C(F)(F)F)=N2)C2=C1 AQMXQOTTWVAIFI-UHFFFAOYSA-N 0.000 claims description 2
- OEDVPJOHKMEERN-KPKJPENVSA-N 2-[2-[(e)-2-[4-(trifluoromethoxy)phenyl]ethenyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(OC(F)(F)F)=CC=2)=N2)C2=C1 OEDVPJOHKMEERN-KPKJPENVSA-N 0.000 claims description 2
- QFCXDPRWLCRUGV-KPKJPENVSA-N 2-[2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-3h-benzimidazol-5-yl]benzamide Chemical compound NC(=O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(=CC=2)C(F)(F)F)=N2)C2=C1 QFCXDPRWLCRUGV-KPKJPENVSA-N 0.000 claims description 2
- BKBFEWSBNAYARN-UHFFFAOYSA-N 2-[2-[1-(2-phenylethynyl)benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(N(C=N2)C#CC=3C=CC=CC=3)C2=C1 BKBFEWSBNAYARN-UHFFFAOYSA-N 0.000 claims description 2
- JXRBFIZVMBNSFX-GXDHUFHOSA-N 2-[2-[2-[(e)-2-quinolin-6-ylethenyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=C3C=CC=NC3=CC=2)=N2)C2=C1 JXRBFIZVMBNSFX-GXDHUFHOSA-N 0.000 claims description 2
- CWSNBNRBBOOWDE-UHFFFAOYSA-N 2-[2-[2-[2-[4-(trifluoromethyl)phenyl]cyclopropyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(=N2)C3C(C3)C=3C=CC(=CC=3)C(F)(F)F)C2=C1 CWSNBNRBBOOWDE-UHFFFAOYSA-N 0.000 claims description 2
- BRLXLXKMAJHYAM-UHFFFAOYSA-N 2-[2-[2-[2-[4-(trifluoromethyl)phenyl]ethyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(=CC=2)C(F)(F)F)=N2)C2=C1 BRLXLXKMAJHYAM-UHFFFAOYSA-N 0.000 claims description 2
- SMULEHKLKQBAGG-UHFFFAOYSA-N 2-[2-[2-[4-(trifluoromethyl)phenyl]cyclopropyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(=N2)C3C(C3)C=3C=CC(=CC=3)C(F)(F)F)C2=C1 SMULEHKLKQBAGG-UHFFFAOYSA-N 0.000 claims description 2
- DLDOFEOUZNRQDQ-RMKNXTFCSA-N 3-[6-fluoro-2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1h-benzimidazol-5-yl]phenol Chemical compound OC1=CC=CC(C=2C(=CC=3NC(\C=C\C=4C=CC(=CC=4)C(F)(F)F)=NC=3C=2)F)=C1 DLDOFEOUZNRQDQ-RMKNXTFCSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- 244000025254 Cannabis sativa Species 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- 241000289690 Xenarthra Species 0.000 claims description 2
- CVPOQHFKYVQWJH-KPKJPENVSA-N [2-[2-[(e)-2-[4-(trifluoromethylsulfanyl)phenyl]ethenyl]-3h-benzimidazol-5-yl]phenyl]methanol Chemical compound OCC1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(SC(F)(F)F)=CC=2)=N2)C2=C1 CVPOQHFKYVQWJH-KPKJPENVSA-N 0.000 claims description 2
- RHAVIAZRBUILNB-UHFFFAOYSA-N [2-[2-[2-[4-(trifluoromethyl)phenyl]ethyl]-3h-benzimidazol-5-yl]phenyl]methanamine Chemical compound NCC1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(=CC=2)C(F)(F)F)=N2)C2=C1 RHAVIAZRBUILNB-UHFFFAOYSA-N 0.000 claims description 2
- NENRRCWWLTXRQU-JXMROGBWSA-N [2-[6-(trifluoromethyl)-2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1h-benzimidazol-5-yl]phenyl]methanol Chemical compound OCC1=CC=CC=C1C(C(=C1)C(F)(F)F)=CC2=C1NC(\C=C\C=1C=CC(=CC=1)C(F)(F)F)=N2 NENRRCWWLTXRQU-JXMROGBWSA-N 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 239000003833 bile salt Substances 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 229940090805 clavulanate Drugs 0.000 claims description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229940050410 gluconate Drugs 0.000 claims description 2
- 229930195712 glutamate Natural products 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical class C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- GJJAHNVOKULWAV-MDWZMJQESA-N n-methyl-2-[2-[(e)-2-[4-(trifluoromethyl)phenyl]ethenyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(\C=C\C=2C=CC(=CC=2)C(F)(F)F)=N2)C2=C1 GJJAHNVOKULWAV-MDWZMJQESA-N 0.000 claims description 2
- SFWZAUWDLUETGP-UHFFFAOYSA-N n-methyl-2-[2-[2-[3-(trifluoromethyl)phenyl]ethyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=C(C=CC=2)C(F)(F)F)=N2)C2=C1 SFWZAUWDLUETGP-UHFFFAOYSA-N 0.000 claims description 2
- WCQYCOTVGSVNSU-UHFFFAOYSA-N n-methyl-2-[2-[2-[4-(trifluoromethyl)phenyl]ethyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(=CC=2)C(F)(F)F)=N2)C2=C1 WCQYCOTVGSVNSU-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- 229940049964 oleate Drugs 0.000 claims description 2
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- RPKYGMDQYFEIDP-UHFFFAOYSA-N 2-[2-[2-(4-methylsulfonylphenyl)ethynyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C#CC1=NC2=CC(C=3C(=CC=CC=3)S(N)(=O)=O)=CC=C2N1 RPKYGMDQYFEIDP-UHFFFAOYSA-N 0.000 claims 1
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- CWSNBNRBBOOWDE-PMACEKPBSA-N 2-[2-[2-[(1s,2r)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(=N2)[C@@H]3[C@@H](C3)C=3C=CC(=CC=3)C(F)(F)F)C2=C1 CWSNBNRBBOOWDE-PMACEKPBSA-N 0.000 claims 1
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- IPECOUYCECUHLV-UHFFFAOYSA-N 2-[2-[2-[2-(4-chlorophenyl)ethyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(Cl)=CC=2)=N2)C2=C1 IPECOUYCECUHLV-UHFFFAOYSA-N 0.000 claims 1
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- NVSPGVPXZYGPDB-UHFFFAOYSA-N 2-[2-[2-[2-(4-methylsulfonylphenyl)cyclopropyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(=N2)C3C(C3)C=3C=CC(=CC=3)S(C)(=O)=O)C2=C1 NVSPGVPXZYGPDB-UHFFFAOYSA-N 0.000 claims 1
- GEKWETXATUFBHL-UHFFFAOYSA-N 2-[2-[2-[2-(4-methylsulfonylphenyl)ethyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(=CC=2)S(C)(=O)=O)=N2)C2=C1 GEKWETXATUFBHL-UHFFFAOYSA-N 0.000 claims 1
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- DGNFUOFORGAZPZ-UHFFFAOYSA-N 2-[2-[2-[2-[3-(trifluoromethyl)phenyl]ethynyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(=N2)C#CC=3C=C(C=CC=3)C(F)(F)F)C2=C1 DGNFUOFORGAZPZ-UHFFFAOYSA-N 0.000 claims 1
- DJUOGYKXVSKOCM-UHFFFAOYSA-N 2-[2-[2-[2-[4-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)phenyl]cyclopropyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(=N2)C3C(C3)C=3C=CC(OC(C(F)(F)F)C(F)(F)F)=CC=3)C2=C1 DJUOGYKXVSKOCM-UHFFFAOYSA-N 0.000 claims 1
- QPVJPYOXHGOESR-UHFFFAOYSA-N 2-[2-[2-[2-[4-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)phenyl]ethyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(OC(C(F)(F)F)C(F)(F)F)=CC=2)=N2)C2=C1 QPVJPYOXHGOESR-UHFFFAOYSA-N 0.000 claims 1
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- HOEDHHAUKCMGQD-UHFFFAOYSA-N 2-[2-[2-[2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]ethyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(OCC(F)(F)C(F)(F)F)=CC=2)=N2)C2=C1 HOEDHHAUKCMGQD-UHFFFAOYSA-N 0.000 claims 1
- XJZZJOTXFDATQC-UHFFFAOYSA-N 2-[2-[2-[2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]ethynyl]-3h-benzimidazol-5-yl]phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC=CC=C1C1=CC=C(NC(=N2)C#CC=3C=CC(OCC(F)(F)C(F)(F)F)=CC=3)C2=C1 XJZZJOTXFDATQC-UHFFFAOYSA-N 0.000 claims 1
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- SGMXTGCRHFEUOM-UHFFFAOYSA-N 2-[2-[2-[4-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)phenyl]ethynyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(=N2)C#CC=3C=CC(OC(C(F)(F)F)C(F)(F)F)=CC=3)C2=C1 SGMXTGCRHFEUOM-UHFFFAOYSA-N 0.000 claims 1
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- FAZOEZNUKOGCAX-UHFFFAOYSA-N 2-[2-[2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]cyclopropyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(=N2)C3C(C3)C=3C=CC(OCC(F)(F)C(F)(F)F)=CC=3)C2=C1 FAZOEZNUKOGCAX-UHFFFAOYSA-N 0.000 claims 1
- FQPORUABNKGWOR-UHFFFAOYSA-N 2-[2-[2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]ethyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C1=CC=C(NC(CCC=2C=CC(OCC(F)(F)C(F)(F)F)=CC=2)=N2)C2=C1 FQPORUABNKGWOR-UHFFFAOYSA-N 0.000 claims 1
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- AEXADWOLKALVTC-UHFFFAOYSA-N 2-[2-[2-[4-(methanesulfonamido)phenyl]ethyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1CCC1=NC2=CC(C=3C(=CC=CC=3)S(N)(=O)=O)=CC=C2N1 AEXADWOLKALVTC-UHFFFAOYSA-N 0.000 claims 1
- CAAZEDOEHGENLB-UHFFFAOYSA-N 2-[2-[2-[4-(methanesulfonamido)phenyl]ethynyl]-3h-benzimidazol-5-yl]benzenesulfonamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C#CC1=NC2=CC(C=3C(=CC=CC=3)S(N)(=O)=O)=CC=C2N1 CAAZEDOEHGENLB-UHFFFAOYSA-N 0.000 claims 1
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Description
本申請案係申請2006年5月3日申請之美國臨時專利申請案序號60/797504之權利,其全文及全面係以引用之方式併入本文中。
本發明係關於式(I)化合物:
含有此等化合物之醫藥組合物及使用彼等治療之方法。
有害的化學、熱及機械刺激激發了衍生自感覺神經節(例如背根、節狀及三叉神經節)小直徑感覺神經元(傷害性受器)之周圍神經末端及引發感覺為疼痛之訊號。此等傷害受容性神經元(即傷害性受器)對偵測有害或潛在有害的刺激(例如有害的熱、化學及/或機械性)是很重要的,而該刺激係因胞外環境在發炎、缺血或其他創傷狀況期間之改變所引起並造成或潛在地造成組織傷害(Wall,P.D.,及Melzack,R.,Textbook of Pain,1994,New York:Churchill Livingstone)。
傷害性受器將有害的刺激轉導成造成潛在作用之神經膜去極化,其隨後傳入CNS及最後感覺到疼痛、不適等,以及其某些反應。在分子層次,傷害收受係藉由離子通道及/或受器來進行。植物衍生性類香草素化合物(例如辣椒素(capsaicin)及resiniferatoxin)已知能選擇性去極化傷害性受器及引發灼熱疼痛之感覺:典型由含辣椒素之辣椒所引起之感覺。因此,辣椒素模擬活化「傷害收受路徑」生理/內生性刺激之作用。在疼痛學上新近的進展已辨識出一類香草素、質子及有害熱之受體,稱為VR1(又稱為辣椒素受體或TRPV1)。因為傷害性受器為人類及動物不欲的疼痛及發炎症狀之衍生物,因此調節其功能為減輕及其他止痛治療之有效的措施。
如於動物之疾病模式中,已上市、VR1-標的醫藥劑之臨床效用或VR1調節劑之效用所證實的,在VR1作為調節劑(競爭及非競爭促進劑或拮抗劑[有關辣椒素及/或其辨識部位]及異位調節劑)之化合物具有廣效的治療潛力。再者,請了解,VR1之促進調節劑可具有衍生自其促進劑特性本身,及/或衍生自其產生促進劑介導去敏化作用能力之臨床用途,其可間接的表現功能拮抗作用。同樣的,經由前面所提之去敏化機制,拮抗調節劑可具有直接的拮抗(競爭或非競爭)特性及/或間接的拮抗特性。另外請了解,正性及負性異位調節劑可產生任何或所有前面所提之功能結果,且據此亦可具有臨床上之用途。因此,本發明係關於各個此等類型之調節劑。
VR1促進劑已在發炎性、神經源性及內臟疼痛症狀證明其有效用途。在實驗人類疼痛模式中,皮膚經辣椒素預處理降低了皮下注射酸溶液所造成之疼痛(Bianco,E.D.;Geppetti,P.;Zippi,P.;Isolani,D.;Magini,B.;Cappugi,P.Brit J of Clin Pharmacol 1996,41,1-6),其暗示VR1促進劑在治療發炎性疼痛上之利益。VR1促進劑已在發炎及發炎性疼痛上顯示其特別之角色:例如,resiniferatoxin預防了發炎性過敏及角叉菜膠引起的水腫(Kissin,I.;Bright,C.A.;Bradley,E.L.,Jr.Anesth Analg 2002,94,1253-1258)。
此外,市售含辣椒素之乳霜(例如Axcain及Lidocare)係用於減輕糖尿病神經病變及後遺神經痛有關之疼痛,其指出VR1促進劑於治療神經源性疼痛症狀之用途。再者,此等乳霜已顯示可降低術後之神經源性疼痛(Ellison,N.,Loprinzi,C.L.,Kugler,J.,Hatfield,A.K.,Miser,A.,Sloan,J.A.,Wender,D.B.,Rowland,K.M.,Molina,R.,Cascino,T.L.,Vukov,A.M.,Dhaliwal,H.S.及Ghosh,C.J.Clin.Oncol.15:2974-2980,1997)。就癌症病患,辣椒素係包含在太妃糖媒劑中,已顯示實質上降低了由化療及放射線治療所造成的口腔黏膜炎之疼痛(Berger,A.,Henderson,M.,Naadoolman,W.,Duffy,V.,Cooper,D.,Saberski,L.及Bartoshuk,L.J.Pain Sympt.Mgmt10:243-248,
1995)。
VR1亦在膀胱排空之生理上扮演著一個角色。VR1係藉由膀胱感覺神經原表現,其中其調節了膀胱對液體填注之反應。VR1促進劑resiniferatoxin以劑量依賴的方式將膀胱感覺之傳入去敏化(Avelino,A.;Cruz,F.;Coimbra,A.Eur.J Pharmacol.1999,378,17-22),而支持了其在治療膀胱過動上之用途(Chancellor,M.B.;De Groat,W.C.J.Urol.(Baltimore)1999,162,3-11)。事實上,於正常及脊髓受傷之大鼠二者的內胞膜中給予辣椒素或resiniferatoxin皆抑制了膀胱收縮(Komiyama,I.;Igawa,Y.;Ishizuka,O.;Nishizawa,O.;Andersson,K.-E.J.Urol.(Baltimore)1999,161,314-319),其指出了VR1促進劑對神經受傷尿失禁的病患之效用。辣椒素或resiniferatoxin於治療脊髓受傷病患之尿失禁之效用已在臨床研究上獲得驗證(de Seze,M.;Wiart,L.;de Seze,M.-P.;Soyeur,L.;Dosque,J.-P.;Blajezewski,S.;Moore,N.;Brochet,B.;Mazaux,J.-M.;Barat,M.;Joseph,P.-A.Journal of Urology(Hagerstown,MD,United States)2003,171,251-255)。
辣椒素降低了SHR及WKY大鼠之血壓暗示著VR1促進劑降低升高的血壓之效用(Li,J.;Kaminski,N.E.;Wang,D.H.Hypertension 2003,41,757-762.)。辣椒素亦具與胃竇潰瘍有關之胃保護性(Yamamoto,H.;Horie,S.;Uchida,M.;Tsuchiya,S.;Murayama,T.;Watanabe,K.Eur.J.Pharmacol.2001,432,203-210)。
VR1拮抗劑亦可用於治療發炎性、神經源性及內臟疼痛。例如,VR1拮抗劑於內臟發炎症狀之治療用途已經驗證。VR1在發炎性腸道疾病病患之大腸神經纖維中會升高,且VR1拮抗劑能減輕疼痛及蠕動異常(Yiangou,Y.;Facer,P.;Dyer,N.H.;Chan,C.L.;Knowles,C.;Williams,N.S.;Anand,P.Lancet 2001,357,1338-1339)。在囓齒類中由毒素A或葡聚醣硫酸鈉所引起的腸道發炎可藉由VR1拮抗劑來減輕(McVey,D.C.;Schmid,P.C.;Schmid,H.H.O.;Vigna,S.R.J.Pharmacol.Exp.Ther.2003,304,713-722)。此外,合成的VR1拮抗劑在數個重要的終點藥效評估項目,包括宏觀的損傷、微觀的上皮損傷、骨髓過氧化酶量及腹瀉評分上能降低結腸炎疾病級分,其強烈地支持VR1拮抗劑於發炎性腸道疾病之治療用途(Kimball,E.S.;Wallace,N.H.;Schneider,C.R.;D’ Andrea,M.R.;Hornby,P.J.Neurogasteroenterology 2004,16,811-818)。在天竺鼠(Walker,K.M.;Urban,L.;Medhurst,S.J.;Patel,S.;Panesar,M.;Fox,A.J.;McIntyre,P.J.Pharmacol.Exp.Ther.2003,304,56-62)及大鼠(Pomonis,J.D.;Harrison,J.E.;Mark,L.;Bristol,D.R.;Valenzano,K.J.;Walker,K.J.Pharmacol.Exp.Ther.2003,306,387-393)之發炎性及神經源性疼痛模式中,VR1拮抗劑capsazepine及BCTC反轉了機械性痛覺過敏。
在VR1剔除小鼠中LPS-引起之發燒減輕(Lida,T.;Shimizu,Nealen,M.L.;Campbell,A.;Caterina,M.Neurosci.Lett.2005,378,28-33)。藉由capsazepine來抑制VR1促進劑引起之中心體溫升高,其顯示VR1拮抗劑於治療發熱之用途(Ohnluki,K.;Haramizu,S.;Watanabe,T.;Yazawa,S.;Fushiki,T.J.Nutr.Sci.Vitaminol.(Tokyo)2001,47,295-298)。
VR1促進劑亦可調節體溫及發燒。在雪貂、大鼠及小鼠中給予resiniferatoxin引起體溫過低(Woods,A.J.;Stock,M.J.;Gupta,A.N.;Wong,T.T.L.;Andrews,P.L.R.Eur.J.Pharmacol.1994,264,125-133)。此外,LPS(脂多醣)-引起發燒之第I階段在腹腔內給予低劑量辣椒素之動物中並未發生(Romanovsky,A.A.Frontiers in Bioscience 2004,9,494-504)。
VR1拮抗劑對發炎性支氣管症狀之治療潛力已在發現其拮抗辣椒素及酸引起的支氣管痙攣中得到驗證(Nault,M.A.;Vincent,S.G.;Fisher,J.T.J.Physiol.1999,515,567-578)。相關的發現證明VR1拮抗劑capsazepine在天竺鼠中減輕了安南得邁(anandamide)引起的咳嗽(Jia,Y.;McLeod,R.L.;Wang,x.;Parra,L.E.;Egan,R.W.;Hey,J.A.Brit.J.Pharmacol.2002,137,831-836)。
使用高架十字迷宮,VR1拮抗劑capsazepine已證實能顯著地降低大鼠類焦慮行為(Kasckow,J.W.;Mulchahey,J.J.;Geracioti,T.D.Jr.Progress in Neuro-Psychopharmacol.及Biological Psychiatry 2004,28,291-295)。因此,VR1拮抗劑可具有治療焦慮症、疼痛病症、恐懼症或其他非適應性壓力反應之用途。
美國專利6,299,796B1揭示包含下式單位之電發光元件:
因此,需要有效的VR1調節劑,特別是對人類及大鼠VR1離子通道具強力結合親和力之新穎的苯并咪唑化合物。亦需要作為人類及大鼠VR1離子通道之強力功能拮抗劑及/或促劑之新穎的苯并咪唑化合物。最後,需要以高親和力與VR1結合及作為人類及大鼠VR1離子通道之強力功能拮抗劑之新穎的苯并咪唑化合物。
本發明係關於式(I)化合物:
及其形式,其中R1
、R2
、R3a
、R3b
、R4
、p、q、r、L及A1
係如文中之定義,及彼等作為有效的VR1調節劑之用途。
本發明亦關於供有此需要之對象治療VR1離子通道介導之疾病之方法,其包括於該對象投予一有效量之式(I)化合物。本發明進一步係關於製造式(I)化合物及其鹽類之方法。
本發明係關於式(I)化合物(I):
及其形式,其中:式(I)中位置1、2及3間之虛線係指互變異構雙鍵之位置,當雙鍵係在位置1及2間形成時,則有R3b
存在,當雙鍵係在位置2及3間形成時,則有R3a
存在;p為1或2;q為0或1;r為0、1、2或3;L為C1-3
烷基、C2-3
烯基、C2-3
炔基或環丙基;A1
係由下列組成之群中選出:苯基、聯苯、萘基、吡啶基、喹啉基及吲哚;R1
各係由下列組成之群中選出:羥基、氰基、鹵素、甲醯基、羧基、C1-6
烷基、鹵基C1-6
烷基、C1-6
烷氧基、鹵基C1-6
烷氧基、C1-6
烷基羰基、C1-6
烷氧基羰基、C1-6
烷基硫基、C1-6
烷基磺醯基、C3-8
環烷基、C3-8
環烷基-C1-4
烷基、C3-8
環烷基-C1-4
烷氧基、C3-8
環烷基-氧基、胺基、(C1-6
烷基)1-2
胺基、(C3-6
環烷基)1-2
胺基、(C3-8
環烷基-C1-4
烷基)1-2
胺基、胺基羰基、(C1-6
烷基)1-2
胺基羰基、C1-6
烷基羰基胺基、C1-6
烷氧基羰基胺基、胺基羰基胺基、(C1-6
烷基)1-2
胺基羰基胺基、C1-6
烷基磺醯基胺基、C1-6
烷基亞磺醯基胺基、胺基磺醯基、(C1-4
烷基)1-2
胺基磺醯基、胺基磺醯基胺基及(C1-6
烷基)1-2
胺基磺醯基胺基,其中烷基係視需要經C1-8
烷氧基、胺基、(C1-4
烷基)1-2
胺基、C1-6
烷基羰基胺基、C1-6
烷氧基羰基胺基、胺基羰基胺基、(C1-6
烷基)1-2
胺基羰基胺基、C1-6
烷基磺醯基胺基、胺基磺醯基胺基、(C1-6
烷基)1-2
胺基磺醯基胺基羥基及苯基,其中苯基係視需要經一、二或三個獨立地由下列組成之群中選出之取代基代:鹵素、氰基、硝基、C1-6
烷基、C1-6
烷氧基、C1-6
烷基硫基及C1-6
烷基磺醯基,及其中各烷基及烷氧基之實例可視需要全氟化;R2
係由下列組成之群中選出:鹵素、C1-4
烷基、C1-4
烷氧基、C1-4
烷基磺醯基、硝基、胺基、(C1-4
烷基)1-2
胺基及氰基,其中各烷基及烷氧基之實例可視需要全氟化;R3a
及R3b
各係由氫及視需要全氟化之C1-4
烷基組成之群中選出;及R4
各係由下列組成之群中選出:鹵素、硝基、氰基、羧基、C1-6
烷基、C1-6
烷氧基、鹵基C1-6
烷基、鹵基C1-6
烷氧基、C1-6
烷氧基-C1-6
烷基、C1-6
烷基羰基、C1-6
烷基硫基、鹵基C1-6
烷基硫基、C1-6
烷基磺醯基、鹵基C1-6
烷基磺醯基、C3-8
環烷基、C3-8
環烷基-C1-4
烷基、C3-8
環烷基-C1-4
烷氧基、C3-8
環烷基-氧基、胺基、(C1-6
烷基)1-2
胺基、(C3-8
環烷基)1-2
胺基、(C3-8
環烷基-C1-4
烷基)1-2
胺基、胺基羰基、(C1-6
烷基)1-2
胺基羰基、C1-6
烷基羰基胺基、C1-6
烷氧基羰基胺基、胺基羰基胺基、(C1-6
烷基)1-2
胺基羰基胺基、C1-6
烷基磺醯基胺基、鹵基C1-6
烷基磺醯基胺基、C1-6
烷基亞磺醯基胺基、胺基磺醯基及(C1-4
烷基)1-2
胺基磺醯基,其中各烷基之實例係視需要經一、二或三個獨立地由下列組成之群中選出之取代基代:C1-8
烷氧基、胺基、(C1-4
烷基)1-2
胺基、C1-6
烷基羰基胺基、C1-6
烷氧基羰基胺基、胺基羰基胺基、(C1-6
烷基)1-2
胺基羰基胺基、C1-6
烷基磺醯基胺基、氧基及羥基,及其中各烷基及烷氧基之實例可視需要全氟化。
本發明之實例包括式(I)化合物或其形式,其中q為0。
本發明之實例包括式(I)化合物或其形式,其中A1
係由下列組成之群中選出:苯基、聯苯、萘基、喹啉基及吲哚。
本發明之實例包括式(I)化合物或其形式,其中R1
各係由下列組成之群中選出:羥基、鹵素、甲醯基、C1-6
烷基、鹵基C1-6
烷基、鹵基C1-6
烷氧基、C1-6
烷基羰基、C1-6
烷氧基羰基、C1-6
烷基硫基、C1-6
烷基磺醯基、胺基、胺基羰基、C1-6
烷基羰基胺基、C1-6
烷氧基羰基胺基、C1-6
烷基磺醯基胺基、胺基磺醯基、(C1-4
烷基)1-2
胺基磺醯基及胺基磺醯基胺基,其中烷基係視需要經胺基、(C1-4
烷基)1-2
胺基、胺基磺醯基胺基或羥基取代,且其中烷基係視需要全氟化。
本發明之實例包括式(I)化合物或其形式,其中R2
係由鹵素及C1-4
烷基組成之群中選出,其中烷基係視需要全氟化。
本發明之實例包括式(I)化合物或其形式,其中R3a
及R3b
各係由氫及C1-4
烷基組成之群中選出。
本發明之實例包括式(I)化合物或其形式,其中R4
各係由下列組成之群中選出:鹵素、羧基、C1-6
烷基、C1-6
烷氧基、鹵基C1-6
烷基、鹵基C1-6
烷氧基、C1-6
烷基羰基、鹵基C1-6
烷基硫基、C1-6
烷基磺醯基、鹵基C1-6
烷基磺醯基、(C1-6
烷基)1-2
胺基、(C1-6
烷基)1-2
胺基羰基、C1-6
烷基羰基胺基、C1-6
烷基磺醯基胺基及鹵基C1-6
烷基磺醯基胺基,其中烷基及烷氧基係視需要全氟化。
本發明之實例包括式(I)化合物或其形式,其中p為1或2;q為0;r為0、1、2或3;L為C1-3
烷基、C2-3
烯基、C2-3
炔基或環丙基;A1
係由下列組成之群中選出:苯基、聯苯、萘基、喹啉基及吲哚;R1
各係由下列組成之群中選出:羥基、鹵素、甲醯基、C1-6
烷基、鹵基C1-6
烷基、鹵基C1-6
烷氧基、C1-6
烷基羰基、C1-6
烷氧基羰基、C1-6
烷基硫基、C1-6
烷基磺醯基、胺基、胺基羰基、C1-6
烷基羰基胺基、C1-6
烷氧基羰基胺基、C1-6
烷基磺醯基胺基、胺基磺醯基、(C1-4
烷基)1-2
胺基磺醯基及胺基磺醯基胺基,其中烷基係視需要經胺基、(C1-4
烷基)1-2
胺基、胺基磺醯基胺基或羥基取代,且其中烷基係視需要全氟化;R2
係由鹵素及C1-4
烷基組成之群中選出,其中烷基係視需要全氟化;R3a
及R3b
各係由氫及C1-4
烷基組成之群中選出;及R4
各係由下列組成之群中選出:鹵素、羧基、C1-6
烷基、C1-6
烷氧基、鹵基C1-6
烷基、鹵基C1-6
烷氧基、C1-6
烷基羰基、鹵基C1-6
烷基硫基、C1-6
烷基磺醯基、鹵基C1-6
烷基磺醯基、(C1-6
烷基)1-2
胺基、(C1-6
烷基)1-2
胺基羰基、C1-6
烷基羰基胺基、C1-6
烷基磺醯基胺基及鹵基C1-6
烷基磺醯基胺基,其中烷基及烷氧基可視需要全氟化。
本發明進一步係關於式Ia或式Ib化合物:
其中:R1
獨立地為羥基、鹵素、C1-6
烷基、經氟化之C1-6
烷基、C1-6
烷基氧基、經氟化之C1-6
烷基氧基、C1-6
烷基硫基、經氟化之C1-6
烷基硫基、C1-6
烷基磺醯基、經氟化之C1-6
烷基磺醯基、C3-8
環烷基、C3-8
環烷基、C1-4
烷基、C3-8
環烷基氧基、C3-8
環烷基、C1-4
烷基氧基、胺基、(C1-6
烷基)1-2
胺基、(C3-8
環烷基)1-2
胺基、(C3-8
環烷基、C1-4
烷基)1-2
胺基、氰基、胺基羰基、(C1-6
烷基)1-2
胺基羰基、C1-6
烷基羰基胺基、經氟化之C1-6
烷基羰基胺基、C1-6
烷基氧基羰基胺基、C0-6
烷基胺基羰基胺基、C1-6
烷基磺醯基胺基、經氟化之C1-6
烷基磺醯基胺基、胺基磺醯基、(C1-8
烷基)1-2
胺基磺醯基、經氟化之(C1-8
烷基)1-2
胺基磺醯基;其中在任何含烷基取代基之R1
中的烷基視需要經1至3個獨立由下列組成之群中選出之取代基取代:胺基、(C1-8
烷基)1-2
胺基、C1-6
烷基羰基胺基、經氟化之C1-6
烷基羰基胺基、C1-6
烷基氧基羰基胺基、C0-6
烷基胺基羰基胺基、C1-6
烷基磺醯基胺基、經氟化之C1-6
烷基磺醯基胺基、鹵素、氧基、羥基、經氟化之烷基及C1-8
烷基氧基;p為1或2;R2
獨立地係由下列組成之群中選出:鹵素、C1-4
烷基、經氟化之C1-4
烷基、C1-4
烷基氧基、經氟化之C1-6
烷基氧基、C1-4
烷基磺醯基、經氟化之C1-4
烷基磺醯基、硝基、(C1-4
烷基)1-2
胺基、氰基;n為0或1;R3
係獨立地由下列組成之群中選出:氫、C1-4
烷基及經氟化之C1-4
烷基;L為C2-3
烷基二基,A1
係由苯基及萘基組成之群中選出;R4
獨立地為鹵素、C1-6
烷基、經氟化之C1-6
烷基、C1-6
烷基氧基、經氟化之C1-6
烷基氧基、C1-6
烷基硫基、經氟化之C1-6
烷基硫基、C1-6
烷基磺醯基、經氟化之C1-6
烷基磺醯基、C3-8
環烷基、C3-8
環烷基、C1-4
烷基、C3-8
環烷基氧基、C3-8
環烷基、C1-4
烷基氧基、胺基、(C1-6
烷基)1-2
胺基、(C3-8
環烷基)1-2
胺基、(C3-8
環烷基、C1-4
烷基)1-2
胺基、氰基、胺基羰基、(C1-6
烷基)1-2
胺基羰基、C0-6
烷基羰基胺基、經氟化之C1-6
烷基羰基胺基、C1-6
烷基氧基羰基胺基、C0-6
烷基胺基羰基胺基、C1-6
烷基磺醯基胺基、經氟化之C1-6
烷基磺醯基胺基、胺基磺醯基、(C1-8
烷基)1-2
胺基磺醯基、經氟化之(C1-8
烷基)1-2
胺基磺醯基;其中在任何含烷基取代基之R1
中的烷基視需要經1至3個獨立由下列組成之群中選出之取代基取代:鹵素、氧基、羥基、經氟化之烷基及C1-8
烷基氧基、視需要經1至3個獨立由鹵素組成之群中選出之取代基取代之苯基、C1-4
烷基、經氟化之C1-4
烷基、C1-4
烷基氧基、經氟化之C1-4
烷基氧基、C1-4
烷基磺醯基、經氟化之C1-4
烷基磺醯基、硝基、氰基;r為0、1或2;及其鏡像異構物、非對應異構物、互變異構物、溶劑化物及醫藥上可接受鹽類。
本發明之實例包括由下列組成之群中選出之化合物、其鏡像異構物、非對應異構物、互變異構物、溶劑化物及醫藥上可接受鹽類:
化合物9 化合物10 化合物11 化合物12
作為類香草素VR1離子通道之調節劑,式(I)化合物可用於供對象治療VR1離子通道所介導之疾病之方法,而該疾病可藉由調節一或多種類香草素受體來影響。
因此,本發明係關於供有此需要之對象治療VR1離子通道介導之疾病之方法,其包括於該對象投予一有效量之式(I)化合物或其鹽類或溶劑化物。
有關本發明化合物之術語「形式」係指該等可以(不限於)鹽、立體異構物、互變異構物、晶體、同質異形物、非晶、溶劑化物、水合物、酯、前藥或代謝物形式存在者。本發明涵蓋所有此等化合物形式及其混合物。
有關本發明化合物之術語「單離形式」係指該等可以(不限於)基本純狀態存在者,例如鏡像異構物、外消旋混合物、區域異構物(例如順式或反式立體異構物)、區域異構物之混合物及其類似物。本發明涵蓋所有此等單離形式及其混合物。
某些式(I)化合物可以各種立體異構物或互變異構物形式及其混合物存在。本發明涵蓋所有此等化合物及其混合物。
本發明化合物可以醫藥上可接受鹽類之形式存在。就醫藥用途而言,本發明化合物之「醫藥上可接受鹽類」係指無毒酸性/陰離子或鹼性/陽離子鹽形式。
本發明化合物之適合的醫藥上可接受鹽類包括酸加成鹽,其可例如藉由將本發明化合物之溶液與醫藥上可接受酸(例如鹽酸、硫酸、延胡索酸、馬來酸、琥珀酸、醋酸、苯甲酸、檸檬酸、酒石酸、碳酸或磷酸)之溶液混合來形成。
再者,當本發明化合物帶有一酸性基團時,其適合的醫藥上可接受鹽類可包括鹼金屬鹽類(例如鈉或鉀鹽)、鹼土金屬鹽類(例如鈣或鎂鹽)及與適合的有機配體所形成的鹽類(例如四級銨鹽)。
因此,代表性的醫藥上可接受鹽類包括下列:醋酸鹽、己二酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、鈣鹽、樟腦磺酸鹽(camsylate或camphosulphonate)、碳酸鹽、氯化物、膽鹽、克拉維酸鹽(clavulanate)、檸檬酸鹽、二鹽酸鹽、二鈉鹽、依地酸鹽(edentate)、延胡索酸鹽、葡萄糖酸鹽、麩胺酸鹽、哈胺鹽、氫溴酸鹽、鹽酸鹽、碘化物、異硫代羥酸鹽、乳酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、硝酸鹽、油酸鹽、帕莫酸鹽、棕櫚酸鹽、磷酸鹽/磷酸氫鹽、水楊酸鹽、鈉鹽、硬脂酸鹽、硫酸鹽、琥珀酸鹽、酒石酸鹽、三羥甲基胺基甲烷鹽、甲苯磺酸鹽、三氯醋酸鹽、三氟醋酸鹽及其類似物。
本發明之實例包括式(I)化合物及其鹽形式,其中該鹽係由二鈉鹽、鹽酸鹽及萘鹽組成之群中選出。
本發明包括各種異構物之化合物及其混合物。術語「異構物」係指具有相同組成及分子量但物理及/或化學性質不同之化合物。此等物質具有相同數目及種類之原子但結構不同。結構不同可為建構上(區域異構物)或旋轉偏極光平面之能力(立體異構物)。
術語「光學異構物」係指相同建構之異構物其僅在基團的空間排列不同。光學異構物以不同的方向旋轉偏極光平面。術語「光學活性」係指光學異構物旋轉偏極光平面之角度。
術語「外消旋物」或「外消旋混合物」係指二種鏡像異構物之等莫耳混合物,其中各獨立之異構物係以相反方向旋轉偏極光平面,而使得該混合物無光學活性。
術語「鏡像異構物」係指具有非重疊鏡像之異構物。術語「非對映異構物」係指非鏡像異構物之立體異構物。
術語「對掌性」係指一分子所給予之構形無法與其鏡像重疊。其係與可與其鏡像重疊之非對掌性分子相反。
本發明應視為包括所有式(I)化合物之互變異構物形式。此外,就本發明之掌性實施例,本發明應視為包括純鏡像異構物、外消旋以及具有0.001%至99.99%鏡像異構物超度比之鏡像異構物混合物。此外,某些已式(I)表示之化合物可為前藥,亦即相較於活性藥劑其具有較優良的傳遞能力及治療價值之藥劑衍生物。前藥可藉由活體中之酵素或化學處理轉變為活性藥劑。
依照偏極光旋轉之方式,對掌分子之二種不同的鏡像亦稱為左(左手)縮寫L,或右(右手)縮寫D。符號「R」及「S」代表立體碳原子周圍基團之構形。
由外消旋混合物分離出之富含鏡像異構物形式右旋鏡像異構物,其中該混合物大體上並無左旋異構物。在本文中,根據下式,大體上無係指左旋異構物可含有低於25%之混合物範圍、低於10%、低於5%、低於2%或低於1%之混合物:
同樣地,由外消旋混合物分離出之富含鏡像異構物形式左旋鏡像異構物,其中該混合物大體上並無右旋異構物。在本文中,根據下式,大體上無係指右旋異構物可含有低於25%之混合物範圍、低於10%、低於5%、低於2%或低於1%之混合物
「區域異構物」係指與碳-碳雙鍵、環烷基環或橋聯雙環系相連結之取代基原子其方位不同之異構物。在碳-碳雙鍵二側之取代基原子(氫以外)可為E或Z構形。在「E」構形中,其取代基係在相連結碳-碳雙鍵之相反側。在「Z」構形中,其取代基係在相連結碳-碳雙鍵之同側。本發明化合物之範圍係希望包括所有此等「E」及「Z」異構物。
與環系相連結之取代基原子(氫以外)可為順式或反式構形。在「順式」構形中,其取代基係在相連結環平面之同側;在「反式」構形中,其取代基係在相連結環平面之相反側。具有「順式」及「反式」之混合物係稱為「順式/反式」。本發明化合物之範圍係希望包括所有此等「順式」及「反式」異構物。
異構物之描述符號(「R」、「S」、「E」及「Z」)係指相對於中心分子之原子構形並希望用於定義本文獻。
再者,本發明化合物可具有至少一種晶體、同質異形物或非晶形式。數種此形式係包含在本發明範圍內。此外,某些化合物可與水(即,水合物)或常見的有機溶劑(例如有機酯,如乙醇化物)形成溶劑化物。亦希望數種此溶劑化物涵蓋在本發明範圍內。
由可變的取代基劃至環系之鍵結線係指取代基可連結至任何可經取代之環原子上。
如文中所使用,希望下列術語具有下列意義(整個說明書在預言處提供額外定義)。本文之定義可詳細說明化學術語具有所指之化學式。所提供之特別的化學式不希望限制本發明之範圍,而是提供術語之說明並希望包括數個熟習本項技術者所預期包括之變化。
術語「C1-6
烷基」或「烷基」係指包含從1至6個碳原子之直鏈或支鏈烴烷基。非限定之實例包括甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基、第三丁基(tertiary butyl,亦稱為t-butyl或tert-butyl)、1-戊基、2-戊基、3-戊基、1-己基、2-己基、3-己基及其類似物。此術語進一步係包括其任何組合之烷基基團(例如C1-2
、C1-3
、C1-4
及其類似物)。烷基可以容許之可用價數與中心分子相連接。
術語「C2-3
烯基」及「C2-3
炔基」係指具有2至3個碳原子之直鏈或支鏈碳鏈,其中C2-3
烯基鏈在鏈上具有至少一個雙鍵,而C2-3
炔基鏈在鏈上具有至少一個叁鍵。烯基及炔基可以容許之可用價數與中心分子相連接。
術語「C1-6
烷氧基」或「烷氧基」係指包含從1至6個碳原子之直鏈或支鏈烴烷基或式-O-C1-6
烷基之烷基二基連結基團。實例包括甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基及其類似物。此術語進一步係包括其任何組合之烷氧基基團(例如C1-2
、C1-3
、C1-4
及其類似物)。烷氧基可以容許之可用價數與中心分子相連接。
術語「環烷基」係指由3至14個碳原子組成之飽和或部分不飽和、單環、多環或苯并稠合烴環系。除非另有說明,否則此術語係包括C3-8
環烷基、C3-10
環烷基、C5-6
環烷基、C5-8
環烷基、C5-12
環烷基、C8-10
環烷基、C9-13
環烷基、C3-14
環烷基或苯并稠合C3-14
環烷基環系。實例包括環丙基、環丁基、環戊基、環己基、、環己烯基、環庚基、環辛基、1H-茚基、氫茚基、金剛烷基、9H-茀基、1,2,3,4-四氫-萘基、苊萘基、二環[2.2.1]庚烯基及其類似物。C3-4
環烷基可與中心分子相連接並進一步以容許之可用價數於任何原子上經取代。
術語「苯并稠合」用作環系之字首時係指由任何環系基與苯環稠合所形成之基。苯并稠合基可經由任一雙環系之環與中心分子相連接並進一步以容許之可用價數於任何原子上經取代。
術語「芳基」係指環中含有6至12個碳原子之單環或雙環芳香環系。實例包括苯基、聯苯、萘、薁基、蒽及其類似物。芳基可與中心分子相連接並進一步以容許之可用價數於任何原子上經取代。
術語「芳香」係指具有不飽和、共軛π電子系之環烷基烴環系。
用於環系字首之術語「雜」係指至少一個環上碳原子經一或多個獨立地由氮、氧或硫原子選出之雜原子取代,其中氮及硫原子可以任何容許的氧化態存在。實例包括其中1、2、3或4個環成員為氮原子,或0、1、2或3個環成員為氮原子而1個環成員為氧或硫原子之環。當可用的價數容許時,至高二個相鄰之環成員可為雜原子,其中一個雜原子為氮而另一個雜原子係選自N、S或O。
術語「雜環基」係指非芳香(亦即飽和或部分不飽和)單環、多環或苯并環系基。雜環成員係由至少一個N、O、S、S(O)或SO2
中選出,其中氮及硫原子可以任何容許的氧化態存在。實例包括2H-吡咯、2-吡咯啉基、3-吡咯啉基、吡咯啶基、2-咪唑啉基(亦指4,5-二氫-1H-咪唑基)、咪唑啶基、2-吡唑啉基、吡唑啶基、唑啶基、四唑啉基、四唑啶基、哌啶基、嗎啉基、1,4-二噻烷基、噻嗎啉基、哌基、氮呾基、氮基、二氫-哌喃基、四氫-呋喃基、四氫-噻吩基、四氫-哌喃基、四氫-嗒基、六氫-1,4-二氮呯基、六氫-1,4-氮基、1,3-二烷基、1,4-二烷基、1,3-苯并間二氧雜戊烯基(亦指苯并[1,3]間二氧雜戊烯基)、2,3-二氫-1,4-苯并二氧己環基(亦指2,3-二氫-苯并[1,4]二氧己環基)及其類似物。雜環基可與中心分子相連接並進一步以容許之可用價數於任何原子上經取代。
術語「雜芳基」係指芳香、單環、多環或苯并稠合環系基。雜原子環成員係由至少一個N、O、S、S(O)或SO2
中選出,其中氮及硫原子可以任何容許的氧化態存在。實例包括呋喃基基、噻吩基、吡咯基、吡唑基、1H-咪唑基、異噻唑基、異唑基、唑基、噻唑基、二唑基、三唑基、噻二唑基、1H-四唑基、2H-四唑基、1H-[1,2,3]三唑基、2H-[1,2,3]三唑基、4H-[I,2,4]三唑基、吡啶基、吡基、嘧啶基、嗒基、吲基、吲哚基、氮雜吲哚基、吲唑基、氮雜吲唑基、異吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噻唑基、苯并唑基、苯并異唑基、苯并噻二唑基、苯并三唑基、嘌呤基、4H-喹基、喹啉基、異喹啉基、啈啉基、呔基、喹唑啉基、喹喏啉基、1,8-啶基、喋啶基及其類似物。雜芳基雜環基可與中心分子相連接並進一步以容許之可用價數於任何原子上經取代。
術語「C1-6
烷氧基-C1-6
基」係指下式之基:-C1-6
烷基-O-C1-6
烷基。
術語「C1-6
烷氧基羰基」係指下式之基:-C(0)-O-C1-6
烷基。實例包括C1-4
烷氧基羰基。
術語「C1-6
烷氧基羰基胺基」係指下式之基:-NH-C(O)-O-C1-6
烷基。實例包括C1-4
烷基羰基胺基。
術語「(C1-6
烷基)1-2
胺基」係指下式之基:-NH-C1-6
烷基或-N(C1-6
烷基)2
。實例包括(C14
烷基)12
胺基.
術語「(C1-6
烷基)1-2
胺基-C1-6
烷基」係指下式之基:-C1-6
烷基-NH-C1-6
烷基或-C1-6
烷基-N(C1-6
烷基)2
。實例包括(C14
烷基)1-2
胺基-C1-6
烷基。
術語「(C1-6
烷基)1-2
胺基羰基」係指下式之基:-C(O)-NH-C16
烷基或-C(O)-N(C1-6
烷基)2
。實例包括(C1-4
烷基)1-2
胺基羰基。
術語「(C1-6
烷基)1-2
胺基羰基胺基」係指下式之基:-NH-C(O)-NH-C1-6
烷基或-NH-C(0)-N(C1-6
烷基)2
。實例包括(C1-4
烷基)1-2
胺基羰基胺基。
術語「(C1-4
烷基)1-2
胺基磺醯基」係指下式之基:-SO2
-NH-C1-4
烷基或SO2
-N(C14
烷基)2
。
術語「C1-6
烷基羰基」係指下式之基:-C(O)-C1-6
烷基。實例包括C1-4
烷基羰基。
術語「C1-6
烷基羰基胺基」係指下式之基:-NH-C(O)-C1-6
烷基。實例包括C1-4
烷基羰基胺基。
術語「C1-6
烷基磺醯基」係指下式之基:-SO2
-C1-6
烷基。實例包括C1-4
烷基磺醯基。
術語「C1-6
烷基亞磺醯基胺基」係指下式之基:-NH-S(O)-C1-6
烷基。
術語「C1-6
烷基磺醯基胺基」係指下式之基:-NH-SO2
-C1-6
烷基。
術語「C1-6
烷基硫基」係指下式之基:-S-C1-6
烷基。實例包括C1-4
烷基硫基。
術語「胺基」係指下式之基:-NH2
。
術語「胺基-C1-6
烷基」係指下式之基:-C1-6
烷基-NH2
。
術語「胺基羰基」係指下式之基:-C(0)-NH2
。
術語「胺基羰基胺基」係指下式之基:-NH-C(0)-NH2
。
術語「胺基磺醯基」係指下式之基:-SO2
-NH2
。
術語「胺基磺醯基胺基」係指下式之基:-NH-SO2
-NH2
。
術語「(C1-6
烷基)1-2
胺基磺醯基胺基"」係指下式之基:-NH-SO2
-NH-C1-6
烷基或NH-SO2
-N(C1-6
烷基)2
。實例包括(C1-4
烷基)12
胺基磺醯基胺基。
術語「胺基磺醯基胺基-C1-6
烷基」係指下式之基:-C1-6
烷基-NH-SO2
-NH2
。
術語「(C1-6
烷基)1-2
胺基磺醯基胺基-C1-6
烷基」係指下式之基:-C1-6
烷基-NH-SO2
-NH-C1-6
烷基或-C1-6
烷基-NH-SO2
-N(C1-6
烷基)2
。
術語「羰基」係指下式之基:-C(O)OH。
術語「C3-8
環烷基-C1-6
烷基」係指下式之基:-C1-6
烷基-C3-8
環烷基。實例包括C3-8
環烷基-C1-4
烷基。
術語「C3-8
環烷基-C1-6
烷氧基」係指下式之基:-O-C1-6
烷基-C3-8
環烷基。實例包括C3-8
環烷基-C1-4
烷氧基。
術語「C3-8
環烷基-氧基」係指下式之基:-O-C3-8
環烷基。
術語「(C3-8
環烷基)1-2
胺基」係指下式之基:-NH-(C3-8
環烷基)或-N(C3-8
環烷基)2
。
術語「(C3-8
環烷基-C1-4
烷基)12
胺基」係指下式之基:-NH-C1-4
烷基-C3-8
環烷基或-N(C1-4
烷基-C3-8
環烷基)2
。
術語「甲醯基」係指下式之基:-C(O)H。
術語「氧基」係指下式之基:=O。
術語「鹵素」或「鹵基」係指氯、溴、氟或碘基。
術語「鹵基C1-6
烷基」係指下式之基:-C1-6
烷基(鹵基)n
,其中「n」係代表C1-6
烷基中可用之價數,其可經一或多個鹵素原子取代同時保持穩定。實例包括二氟甲基、三氟甲基、三氟乙基、氯甲基及其類似物。
術語「鹵基C1-6
烷氧基」係指下式之基:-O-C1-6
烷基(鹵基)n
,其中「n」係代表C1-6
烷氧基中可用之價數,其可經一或多個鹵素原子取代同時保持穩定。實例包括二氟甲氧基、三氟甲氧基、三氟乙氧基、氯甲氧基及其類似物。
術語「鹵基C1-6
烷基磺醯基」係指下式之基:-SO2
-C1-6
烷基(鹵基)n
,其中「n」係代表C1-6
烷基中可用之價數,其可經一或多個鹵素原子取代同時保持穩定。實例包括三氟甲基磺醯基及其類似物。
術語「鹵基C1-6
烷基磺醯基胺基」係指下式之基:-NH-SO2
-C1-6
烷基(鹵基)n,其中「n」係代表C1-6
烷基中可用之價數,其可經一或多個鹵素原子取代同時保持穩定。實例包括三氟甲基磺醯基及其類似物。
術語「鹵基C1-6
烷基硫基」係指下式之基:-S-C1-6
烷基(鹵基)n
,其中「n」係代表C1-6
烷基中可用之價數,其可經一或多個鹵素原子取代同時保持穩定。實例包括三氟甲基磺醯基及其類似物。
術語「全氟化」係指以容許之可用價數之程度經氟原子取代而同時保持穩定。
術語「經取代」係指中心分子上一或多個氫原子經一或多個功能基團取代。可用價數所容許之數目限制了取代基之量。取代作用並不限於中心分子,亦可發生在去取代基上,據此取代基變成一連結基團。
作為類香草素VR1離子通道之調節劑,式(I)化合物可用於供對象治療VR1離子通道所介導之疾病之方法,而該疾病可藉由調節一或多種類香草素受體來影響。
因此,本發明係關於供有此需要之對象治療VR1離子通道介導之疾病之方法,其包括於該對象投予一有效量之式(I)化合物或其鹽類或溶劑化物。
術語「VR1離子通道介導之疾病」係指造成發炎疼痛、灼熱疼痛或術後疼痛之疾病所引起之慢性或急性疼痛。
式(I)化合物或其鹽類或溶劑化物之用途之實例包括用於製造供治療離子通道介導疾病之醫藥品,其中該離子通道介導之疾病為造成發炎疼痛、灼熱疼痛或術後疼痛之疾病所引起之慢性或急性疼痛。
式(I)化合物或其鹽類或溶劑化物之用途之實例包括用作治療離子通道介導疾病之醫藥,其中該離子通道介導之疾病為造成發炎疼痛、灼熱疼痛或術後疼痛之疾病所引起之慢性或急性疼痛。
術語「前藥」係指式(I)化合物或其形式其在活體中轉變成可提供治療生物活性之功能性衍生物形式,該轉變之形式可為:1)相對活化形式;2)相對非活化形式;3)相對低活性活化形式;或4)直接或間接由此活體轉化所產生之任何形式。
當該化合物對全身性給藥可能太毒、消化道吸收差或在其到達標的前受到破壞時,可使用前藥。選擇及製備適合的前藥衍生物之習用製程係如,例如"Design of Prodrugs",
ed.H.Bundgaard,Elsevier,1985中所述。
術語「代謝物」係指藉由活體中之代謝作用或代謝處理轉變為該化合物衍生物之式(I)化合物形式或其形式。
本文所用之術語「對象」係指病患,例如動物、哺乳動物或人類,其為治療、觀察或實驗對象且處於(或易處於)發展(會或將會)造成離子通道介導慢性或急性疼痛之疾病之風險者,其中該疾病所造成的疼痛為發炎疼痛、灼熱疼痛或術後疼痛。
術語「有效量」係指式(I)化合物或其形式、醫藥組合物、醫藥、醫藥品之量能引起研究者、獸醫、醫師或其他臨床醫師所欲尋求之組織系統、動物或人類之生物或醫藥反應(例如抑制、預防或改善VR1離子通道介導之慢性或急性疼痛),其包括減輕所欲治療之發炎疼痛、灼熱疼痛或術後疼痛之症狀。
式(I)化合物或其形式之有效治療量係從約0.001 mg/kg/天至約300 mg/kg/天。
術語「醫藥組合物」係指含有式(I)化合物或其形式之產品,例如包含特定成份特定量之產品,以及任何直接或間接由此等定成份特定量之組合所產生之產品。
術語「醫藥品」或「醫藥」係指含有式(I)化合物或其形式之產品。本發明包括此等醫藥品用於治療VR1離子通道介導之慢性或急性疼痛之用途。
術語「醫藥上可接受」係指分子實體及組合物其具足夠的純度及品質供用於調配本發明之醫藥組合物、醫藥或醫藥品。因為人類用途(臨床或非處方)及獸醫用途同樣地包含在本發明範圍內,所以醫藥上可接受之調配物應包括供人類或獸醫使用之藥組合物物、醫藥或醫藥品。
術語「治療」係指(不限於)抑制、減輕、輔助根除、抑制VR1離子通道介導之慢性或急性疼痛之惡化或促進其停止。
就口服給藥,醫藥組合物、醫藥或醫藥品較佳地係為含有,例如0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100、150、200、250及500毫克之式(I)化合物或其形式之錠劑形式,供所欲治療之病患作劑量之症狀調整。最適劑量將依與所欲治療的特定病患有關之因素(例如年齡、體重、飲食及給藥時間)、所欲治療症狀之嚴重性、所欲使用之特定化合物、給藥模式及製備藥強度而不同。可應用每日給藥或限期給劑。
代表性的式(I)化合物或其形式包括由下列組成之群中選出之化合物:
代表性的式(I)化合物或其形式包括由下列組成之群中選出之化合物:
代表性的式(I)化合物或其形式包括由下列組成之群中選出之化合物:
代表性的式(I)化合物或其形式包括由下列組成之群中選出之化合物:
代表性預期之式(I)化合物或其形式包括由下列組成之群中選出之化合物:
代表性預期之式(I)化合物或其形式包括由下列組成之群中選出之化合物:
本發明代表性的化合物可根據下列所述之通用合成方法來合成並於下列流程中說明。因為流程僅作說明,不應視為受到所示之化學反應及條件限制。各種用於流程中之起始物質已完全為熟習本項技術者所了解。
本發明化合物可使用下列流程所述之方法來合成。
用於描述本發明之術語為常用及為熟習本項技術者所知之術語。如文中所用,下列縮寫及化學式具有所指之意義:
流程AA係說明式AA5苯并咪唑,代表性式(I)化合物之通用合成。
典型地,將4-溴苯-1,2-二胺AA1
與適合的羰酸AA2
於氧氯化磷(POCl3
)中加熱回流,得到溴苯并咪唑AA3
。
另外,酸可使用草醯氯及催化量之DMF於溶劑(例如二甲烷)中轉變為氯酸。
將氯酸AA2
與4-溴苯-1,2-二胺AA1於醋酸中加熱得到AA3
。可藉由各種偶合反應(Suzuki,Stille)將一適合之經取代苯基基團加附至AA3
上,其已為熟習本項技術者所熟知。特別有用的取代方法係應用鈀催化交叉偶合Suzuki反應(Huff,B.等人,Org.Syn.1997,75:53-60;及Goodson,F.E.等人,Org.Synth.1997,75:61-68)。
如一實例,係將溴苯并咪唑AA3
與適合的苯基硼酸AA4
於例如碳酸銫試劑及催化量之鈀催化劑(例如PdCl2
dppf)之存在下,於溶劑中(例如二噁烷及乙醇混合物)並於升高的溫度下反應,得到AA5
。可藉由於微波合成器中以類似(約100℃)或較低的溫度進行此製程,來降低反應時間。其他適合此類反應之鈀催化劑包括Pd(PPh3
)4
。
肉桂酸,若需要,可經由反應流程BB中所述之製程來合成。
將芳基醛BB1
及(乙氧羰基伸甲基)三苯基磷烷之溶液於溶劑(例如甲苯或苯)中,於鹼(例如NaOH)之存在下,通常在升高的溫度下攪拌,得到對應的肉桂酸酯。基該酯於標準的條件下水解,得到對應的肉桂酸BB2
。
苯基丙酸BB3
,若需要,可由肉桂酸BB2
藉由氫化使用各種標準製程來合成。如上所示,將BB2
之乙醇混合物與催化量之鈀碳(10%)於氫氣壓(50 psi)及室溫下攪拌,得到酸BB3
。
反應流程BB’為反應流程BB之變化。
將醛BB1
與丙二酸及催化量之哌啶於吡啶中在升高的溫度下反應,產生高產率之肉桂酸BB2
。
藉由與草醯氯及催化量之DMF於溶劑(例如二氯甲烷)中反應,將酸BB2
轉變為氯酸。然後將該氯酸與AA1
於醋酸中加熱,得到BB’1
,將其如反應流程AA所述取代AA3
進一步作用。
反應流程CC係提供製備經取代4-溴苯-1,2-二胺中間物之方法。
如一實例,於適合的經取代4-溴苯胺CC1
之三氟醋酸酐之溶液中於適合的溫度逐滴加入KNO3
。然後將反應混合物升溫製室溫以適於轉變為硝基醯胺CC2
。
隨後,使用標準製程將醯胺水解並將硝基基團還原,得到溴二胺CC3
。將中間物CC3
如反應流程AA所述進一步作用。
另一種製造本發明化合物之合成順序係如反應流程DD所述。
將經取代溴苯并咪唑DD1
(流程AA中AA3
之代表)加保護(使用保護基團例如Boc),然後於標準的Suzuki偶合條件下轉變為硼酸頻哪醇酯DD2(Prieto,M.等人,J.Org.Chem.2004,69:
6812-6820;McDonald,D.等人,Bioorg.Med.Chem.Lett.2005,
15:5241-5246;及Poon,S.F.等人,Bioorg.Med.Chem.Lett.2004,
14,5477-5480)。
在典型的製程中,係將溴-苯并咪唑DD1、雙(頻哪醇)二硼、碳酸鉀及催化量之鈀催化劑(例如PdCl2
dppf)之混合物於DMF中於升高的溫度下加熱,得到硼酸酯DD2。通常,可藉由微波照射裝置以類似或較低的溫度進行此製程,來降低反應時間。
硼酸酯DD2
可藉由與苯基鹵化物、甲磺酸鹽或三氟甲磺酸鹽(R1
)pPh-X進行Suzuki偶合,轉變為本發明化合物(Bo保護DD3
)。在此實例中,硼烷DD2係與適合的芳基鹵化物、肆(三苯基膦)鈀(0)及三第三-丁基六氟硼酸鏻之2M的碳酸鉀水溶液,於的甲苯中及100℃下反應,得到保護形式之DD3
。與酸(例如TFA)去保護,得到DD3
。
反應流程EE係描述製備本發明代表化合物之方法。
苯胺EE1
可利用任何數種熟習本項技術者常用之醯化方法轉變為各種醯胺、胺甲酸酯或尿素EE2
。如一實例,將EE1
於溶劑(例如THF)中與經取代之氯酸及鹼(例如三乙胺)反應,得到對應的EE2
之醯胺。如另一實例,將EE1
於THF中與經取代之氯甲酸酯及三乙胺反應,得到EE2
之胺甲酸酯。
EE1
can可利用各種磺醯化條件轉變為磺醯胺。例如,將EE1
於溶劑(例如THF)中與烷基磺醯氯及三乙胺反應,得到烷基磺醯胺EE3
。EE1
可選擇性或連續地經取代得到EE3。
一有效達到此目標之方法係以醛或酮經由還原性烷化反應(參見Mattson,R.J.等人,J.Org.Chem.
1990,55,2552-2554)及文中所引述之參考文獻]。於此製程中,將等量的EE1及醛或酮於異丙醇鈦(IV)攪拌,接著加入氰基硼氫化鈉於溶劑(例如乙醇)中,得到經取代胺EE3。
製造本發明化合物(其中L為環丙基)之合成順序係如反應流程FF中所述。
肉桂酸酯FF1
之反應,在此案例中,將甲酯與三甲基碘化鋶業立德,於溶劑(例如DMSO)及氫化鈉中(如Burger,A.等人,J.Med.Chem.
1970,13,33-35)
,得到環丙酯FF2
。將FF2
水解得到酸FF3
,將其如反應流程AA所述進一步作用成苯并咪唑。
反應流程GG係描述另一種製備環丙基酸中間物之方法。
藉由如反應流程AA及BB’轉變成氯酸之描述,將肉桂酸轉變為對應的Weinreb醯胺。將氯酸與N,N-二甲基羥基胺鹽酸鹽及鹼(例如三乙胺)於二氯甲烷中反應,得到醯胺GG2
。
如流程FF所述將醯胺GG2
轉變成環丙基醯胺GG3
。然後將醯胺GG3
水解得到酸GG4
,典型地係與第三丁醇鉀於THF中反應。
製造本發明化合物(其中R1
Ar為苯磺醯胺)之合成順序係如反應流程HH中所述。
以Suzuki反應將反應流程DD得來之硼酸酯DD2
及溴苯-第三丁基磺醯胺HH1
偶合,接著以TFA去保護,得到產物HH2
。
製造本發明化合物(其中R為醚基團)之合成順序係如反應流程II中所述。
市售4
-羥基肉桂酸II1
之酯可藉由數種路徑(包括Williamson反應)轉變為醚類似物。在此熟知之製程中,將II1
及烷基鹵化物與鹼(例如碳酸銫)於溶劑(例如乙腈)中反應,得到產物112
。
更有效的親電子劑可為醇類衍生物,例如甲磺酸酯、對甲苯磺酸酯或三氟甲磺酸酯。另一種有效之方法係經由Mitsunobu反應將II1
轉變為醚類似物112
(請參見Mitsunobu,O.,Synthesis,
1981,1-28)。
醚類似物112
可使用標準技術進一步還原成酸113
。
反應流程JJ係描述製備含有經取代胺基基團之肉桂酸之方法。
肉桂酸酯JJ1
可利用任何數種熟習本項技術者常用之醯化方法轉變為各種醯胺、胺甲酸酯或尿素。如一實例,將JJ1
於溶劑(例如THF)中與經取代之氯酸及鹼(例如三乙胺)反應,得到對應的JJ2
之醯胺。如另一實例,將JJ1
於THF中與經取代之氯甲酸酯及三乙胺反應,得到JJ2
之胺甲酸酯。JJ1
可利用各種磺醯化條件轉變為磺醯胺。
例如,將JJ1
於溶劑(例如THF)中與烷基磺醯氯及三乙胺反應,得到烷基磺醯胺JJ3
。JJ1
可選擇性或連續地經取代得到JJ4
。一有效達到此目標之方法係以醛或酮經由還原性烷化反應(參見Mattson,R.J.等人,J.Org.Chem.
1990,55,2552-2554及文中所引述之參考文獻)。於此製程中,將等量的JJ1
及醛或酮與異丙醇鈦(IV)攪拌,接著加入氰基硼氫化鈉於溶劑(例如乙醇)中,得到經取代胺JJ4
。
製造本發明化合物(其中L為乙炔)之合成順序係如反應流程KK中所述。
當無法從市面上購得時,丙炔酸KK2
可藉由乙炔KK1與正丁基鋰於THE中及-78℃下反應,升溫至0℃歷時30分鐘來製備。將混合物冷卻至-78℃,並於-78℃轉置於二氧化碳之THE飽和溶液中。將反應緩慢地升溫至rt,得到對應的丙炔酸KK2
。
經丙炔酸KK2
與4-溴苯-1,2-二胺二鹽酸KK3
於回流的乙二醇中反應,得到氯乙烯基苯并咪唑KK4
。
將KK3
與苯基硼酸於Suzuki條件下於微波合成器中及如反應流程AA中所述之熱條件下,得到乙炔化合物KK4
。
製造本發明化合物之另一種合成順序係如反應流程LL中所述。
將保護的溴二胺LL1
與適合的硼酸經由如前述反應流程所述之Suzuki偶合,得到二胺LL2
。
然後將LL2
與酸或氯酸反應,得到LL3
(如反應流程AA或BB’所述)。
製造本發明化合物(其中L為乙烯基或乙基)之合成順序,其可作為流程BB’之另一種選擇,係如反應流程MM中所述。
將AA1
及二氯亞胺MM1(如McEIvain,S.M.等人,J.Am.Chem.Soc.
1942,64,1825中所述)之乙醇溶液加熱,得到氯甲基苯并咪唑MM2
(如Komoriya等人,Bioorg.Med.Chem.,
2004,12,2099-2114中所述)。
與三苯基膦於二氯乙烷中加熱,將MM2
轉變為鏻鹽MM3
。
將MM3
與各種醛或酮於無水THE及EtOH之溶液中與鹼(例如DBU(1,8-二氮雜雙環[4.5.0]十一-7-烯))反應,得到溴苯并咪唑BB’1
,將其如反應流程AA所述進一步作用。
製造本發明化合物之另一種合成順序係如反應流程NN中所述。
將二芳基二胺LL2與二氯亞胺MM1
如反應流程MM所述反應,得到NN1
。
如反應流程MM
中所述,將NN1
繼續進行反應得到NN2
。
本發明化合物(其中L為伸乙基)可由反應流程OO中所述之另一路徑來製備。
將本發明化合物例如NN3
,其中L為乙烯基,溶於溶劑(例如甲醇中並使用催化劑(例如10%鈀(Pd)碳)氫化,得到OO1
。
製造本發明化合物(其中L為環丙基)之合成順序,係如反應流程PP中所述。
烯烴PP1
與烷基二偶氮醋酸酯,例如二偶氮醋酸乙酯,再催化劑(例如三氟甲磺酸銅(I)三氟及Evans’對掌配體(Evans,D.A.;Woerpel,K.A.;Hinman,M.M.;Faul,M.M.J.Am.Chem.Soc. 1991,
113,726-728)之存下,於溶劑(例如氯仿)中,得到環丙酯鏡像異構物PP2
。
當使用對掌配體例如2,2-雙-[2-((4S)-(1,1-二甲基乙基)-1,3-唑啉)]丙烷化合物38b
時,得到(R,R)-環丙酯PP2
鏡像異構物。當使用對掌配體2,2-雙-[2-((4R)-(1,1-二甲基乙基)-1,3-唑啉)]丙烷化合物38a
時,得到(S,S)-環丙酯鏡像異構物。環丙基基團之構形係以Evans’J.Am.Chem.
Soc.1991
報告為基準所作之預測。將酯PP2
水解得到PP3
,將其進一步作用成流程AA之苯并咪唑。
測定不對稱性環丙烷化產物PP2
之鏡像異構物超度,係將酸PP3
與N,O-二甲基羥基胺在鹼(例如二異丙基乙基胺)及醯胺偶合試劑(例如BOP)之存在下,於溶劑(例如DMF)中反應,產生甲氧基甲基醯胺PP4
。
所生成的醯胺PP4
之1
H NMR在適當量的掌性位移劑(例如(R)-(-)-2,2,2-三氟-1-(9-蒽基)乙醇)之存在下,得到所生成的甲氧基單峰之基線解析度。整合甲氧基單峰之比例得到ee值。因此,NMR顯示甲氧基單峰約3.47及3.45 ppm。整合單峰分別為1及99;因此得到99%之ee值。
製造本發明化合物(其中R1
為醇)之合成順序,係如反應流程QQ中所述。
如流程BB’
之作用,將醛QQ1
與丙二酸及催化量之哌啶於吡啶中及升高的溫度下反應,得到酸QQ2
。將酸QQ2
藉由與草醯氯及催化量之DMF於溶劑(例如二氯甲烷)中反應,轉變為氯酸QQ3
。
如流程AA
之作用,將氯酸QQ3
與4
-溴苯-1,2-二胺AA1
於醋酸中加熱,得到溴苯并咪唑QQ4
。
如流程AA
之作用,將適合經取代之苯基硼酸與苯并咪唑QQ4
在試劑及催化量之鈀催化劑之存在下於溶劑中反應,得到經醇取代之苯并咪唑QQ5
,一式(I)化合物之代表。
(E)-1-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮(化合物1
)步驟A. (E)-5-溴-2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑於3-(4-第三-丁基-苯基)-丙烯酸(12 g,58.7 mmol)之POCI3
(200 mL)溶液中,緩慢地加入4-溴-苯-1,2-二胺(10g,53.4 mmol)。將溶液加熱回流18小時。將溶液濃縮並與甲苯共沸將殘餘的POCI3
移除。將殘餘置於EtOAc及10% Na2
CO3
間分溶。以鹽水清洗有機層,以Na2
SO4
乾燥,過濾並將濾液濃縮。以層析法純化殘餘物(矽膠,EtOAc:己烷,3:7)得到標題化合物1a
(7.1 g,31%產率)。1
H-NMR(400 MHz,CDCl3
)δ(ppm):7.64(d,1H,J=13.9 Hz)7.62(s,1H)7.41(d,2H,J=8.4 Hz)7.36(d,1H,J=8.5 Hz)7.33(d,2H,J=8.4 Hz)7.28(s,1H)7.22(dd,1H,J=1.8 Hz,J=8.5 Hz)7.02(d,1H,J=16.5 Hz)1.25(s,9H).
步驟B. (E)-1-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮將化合物1a(0.106 g,0.30 mmol)、2-乙醯基苯硼酸(136 mg;0.76 mmol)、PdCl2
dppf(0.06 mmol)及Cs2
CO3
(0.244 g,0.75 mmol)之1,4-二噁烷:EtOH 5:1溶液加熱至115℃。18小時後,將溶液冷卻並濃縮。使用製備式TLC板純化殘餘物(矽膠,20 X 20 cm,2000微米,EtOAc:己烷3:7)得到標題化合物1(0.0146 g)。1
H-NMR(400 MHz,CD3
OD)δ(ppm):7.54(m,11H)7.23(dd,1H,J=1.6 Hz,J=8.3 Hz)7.15(d,1H,J=16.5 Hz)2.02(s,3H)1.36(s,9H)。MS(ESI,正電離子)m/z:395.3(M+1)。
使用實例1中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-1-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇(化合物2
)將(E)-1-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮化合物1
(0.005 g,0.01 mmol)之乙醇(0.5 mL)溶液以NaBH4
(0.003 g,0.08 mmol)處理。3小時後,將反應混合物置於製備式TLC板(2000微米,矽膠,20 x 20)並使用1:1之EtOAc:己烷展開。將所欲的條帶萃取出並濃縮,得到標題化合物(0.002 g)。1
H-NMR(400 MHz,CD3
OD)δ(ppm)7.69(m,1H)7.62(m,3H)7.50(m,3H)7.41(ddd,2H,J=2.5 Hz,J=10.1Hz,J=14.1Hz)7.32(dt,1H,J=1.4 Hz,J=7.5 Hz)7.23(m,2H)7.17(d,1H,J=16.5 Hz)4.99(q,1H,J=6.3Hz)1.38(s,9H)1.35(d,1.5H,J=6.1Hz)1.33(d,1.5H,J=6.1Hz).MS(ESI,正電離子)m/z:397.2(M+1)。
(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺(化合物13
)步驟A. (E)-5-溴-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑使用實例1步驟A之製程,由3-(4-三氟甲基-苯基)-丙烯酸化合物10a
(1.5 g,6.9 mmol)及4-溴-苯-1,2-二胺(1.3 g,6.9 mmol)製備標題化合物10c
(0.910 g)。1
H-NMR(400 MHz,CDCl3
+DMSO(d6))δ(ppm)7.78(d,1H,J=16.5 Hz)7.73(d,1H,J=1.7 Hz)7.66(m,4H)7.48(d,2H,J=8.0 Hz)7.33(dd,1H,J=1.8 Hz,J=8.5 Hz)7.23(d,1H,J=16.5 Hz)。
步驟B. (E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺使用實例1步驟B之製程,由2-甲醯胺基苯基苯硼酸(0.120 g,0.76 mmol)及化合物10c(0.110 g,0.30 mmol)製備標題化合物(0.001 g)。1
H-NMR(400 MHz,CD3
OD)6(ppm)7.74(d,2H,J=8.2 Hz)7.63(m,3H)7.57(s,1H)7.40(m,6H)7.22(d,1H,J=16.5 Hz).MS(ESI,正電離子)m/z:408.1(M+1)。
使用實例3中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺(化合物19
)步驟A. 3-(4-三氟甲氧基-苯基)-丙烯酸將4-三氟甲氧基苯甲醛(26.3 mmol)、丙二酸(5.6 g,53.8 mmol)及哌啶(0.265 mL,2.7 mmol)之吡啶(15 mL)溶液加熱至70℃歷時18 h。將水(200 mL)加到反應溶液中。使用濃鹽酸將混合物酸化至pH 4。將溶液過濾。以水清洗固體。將固體真空乾燥得到標題化合物4a
(1.2 g)。1
H-NMR(d6-DMSO)(ppm):6.80(d,J=16.02 Hz,1H),6.72(m,2H),6.38(m,2H),5.55(d,J=16.00 Hz,1H)。
步驟B. 3-(4-三氟甲氧基-苯基)-丙烯醯氯將化合物4a
(1.2 g,5.2 mmol)之二氯甲烷(20 mL)溶液已草醯氯(7.8 mL,3.6 mmol)處理。於溶液中加入DMF(0.02 mL)。將反應溶液於室溫下攪拌2 h。將反應溶液濃縮。將殘餘物真空乾燥得到標題化合物4b
,不需進一步純化將其用於下個步驟。
步驟C. (E)-5-溴-2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑將化合物4b
(1g,4 mmol)之醋酸(10 mL)溶液緩慢地加到4-溴-苯-1,2-二胺(0.744g,4 mmol)之醋酸(10 mL)溶液中。將溶液加熱至100℃歷時18 h。將溶液冷卻至室溫。於溶液中加到3:7之醋酸乙酯:己烷(100 mL)中。將溶液過濾。將固體真空乾燥得到標題化合物4c(1.1 g)。1
H-NMR(400 MHz,DMSO d6)ppm 8.12(d,J=16.60 Hz,1H),7.98(m,1H),7.87(m,2H),7.82-7.68(m,1H),7.67-7.37(m,4H),7.34(d,J=16.58 Hz,1H).MS(ESI正電離子)m/z:383.2及385.2。
步驟D. (E)-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺使用實例1步驟B之製程,由2-甲醯胺基-苯基苯硼酸及化合物4c
製備標題化合物19。
使用實例4中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
2-{2-[3-(4-第三-丁基-苯基)-丙基]-1H-苯并咪唑-5-基}-酚(化合物29
)步驟A. 5-溴-2-[3-(4-第三-丁基-苯基)-丙基]-1H-苯并咪唑使用實例1步驟A之製程,由4-(4-第三-丁基-苯基)-丁酸(2.0 g,10.7 mmol)及4-溴-苯-1,2-二胺(2.0 g,10.7 mmol)製備標題化合物5a
(0.512 g)。1
H-NMR(400 MHz,CDCl3
)δ(ppm)7.73(d,1H,J=1.6 Hz)7.45(d,1H,J=8.5 Hz)7.38(dd,1H,J=1.8Hz,J=8.5Hz)7.32(m,3H)7.12(d,2H,J=8.3 Hz)2.97(m,2H)2.73(t,2H,J=7.4 Hz)2.23(m,2H)1.33(s,9H).
步驟B. 2-{2-[3-(4-第三-丁基-苯基)-丙基]-1H-苯并咪唑-5-基}-酚使用實例1步驟B之製程,由2-羥基苯硼酸(0.07 g,0.5 mmol)及化合物5a
(0.074 g,0.2 mmol)製備標題化合物29
(0.0083 g)。1
H-NMR(400 MHz,CDCl3
)δ(ppm)7.51(s,1H)7.39(d,1H,J=8.1Hz)7.16(m,6H)6.95(d,3H,J=8.2 Hz)6.88(t,1H,J=7.4 Hz)2.73(t,2H,J=7.5 Hz)2.52(t,2H,J=7.3 Hz)2.00(m,2H)1.20(s,9H).MS(ESI,正電離子)m/z:385.3(M+1)。
2-{2-[2-(4-第三-丁基-苯基)-乙基]-1H-苯并咪唑-5-基}-酚(化合物32
)步驟A. 3-(4-第三-丁基-苯基)-丙酸將3-(4-第三-丁基-苯基)-丙烯酸(12.28 g,60.1 mmol)及10%鈀碳(0.6 g)之乙醇混合物於50 psi氫氣壓下氫化2小時。將反應混合物以矽藻土墊、尼龍閘板過濾,並真空移除溶劑得到化合物6a
(12.36 g,59.9 mmol)之白色結晶粉末。1
H-NMR(d6-DMSO)δ(ppm):12.10(s,1H),7.29(d,2H),7.12(d,2H),2.88(t,2H),2.50(t,2H),1.25(s,9H).MS(ESI正電離子)m/z:228.9(M+Na+
)。
步驟B. 5-溴-2-[2-(4-第三-丁基-苯基)-乙基]-1H-苯并咪唑於化合物6a
(1.04 g,5.04 mmol)之25 mL的POCl3
溶液中加入4-溴-苯-1,2-二胺(0.946 g,5.06 mmol)。將反應混合物於氮氣壓下回流2.5小時,然後真空濃縮。將殘餘物以25 mL的苯處理並真空蒸發。將殘餘物置於50 mL EtOAc及50 mL飽和NaHCO3
中分溶。將有機分溶液以50 mL的飽和NaHCO3
及以50 mL食鹽水清洗。將有機分溶液以Na2
SO4
乾燥,並將濾液真空濃縮。以層析純化殘餘物(矽膠,EtOAc:庚烷,2:8-4:6))產生標題化合物6b
(0.726 g,2.03 mmol)之褐色粉末。1
H-NMR(d6-DMSO)δ(ppm):12.48-12.32(m,1H),7.74-7.58(m,1H),7.51-7.38(m,1H),7.33-7.22(m,3H),7.17(d,2H),3.10(m,4H),1.27(s,9H).MS(ESI正電離子)m/z:357.1/359.1(M+H+
).
步驟C. 2-{2-[2-(4-第三-丁基-苯基)-乙基]-1H-苯并咪唑-5-基}-酚將化合物6b
(0.036 g,0.10 mmol)、2-羥基苯基硼酸(0.022 g,0.16 mmol)、Cs2
CO3
(0.074 g,0.23 mmol)及PdCl2
(dppf)(0.008 g,0.01 mmol)之2 mL 5:1二噁烷/EtOH混合物置於密封試管中於微波合成器中以100℃加熱15分鐘。加入更多的2-羥基苯基硼酸(0.024 g,0.17 mmol)及更多的PdCl2
(dppf)(0.010 g,0.01 mmol)及將反應於120℃加熱20分鐘。將反應混合物置於20 mL EtOAc、20 mL水及2 mL水間分溶。蒸發有機分溶液,並以層析純化殘餘物。(逆相,乙腈:水+0.1% TFA,25:75-95:5)。將適切的分溶液冷凍及冷凍乾燥,得到產物化合物32
(0.013 g,0.04 mmol)之褐色粉末。1
H-NMR(d6-DMSO)δ(ppm):14.55(br s,1H),9.69(s,1H),7.87(s,1H),7.77(d,1H),7.65(d,1H),7.36-7.30(m,3H),7.24-7.15(m,3H),6.98(d,1H),6.92(t,1H),3.40(t,2H),3.17(t,2H),1.25(s,9H).MS(ESI正電離子)m/z:371.2(M+H+
).
使用實例6中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-(2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇(化合物35
)步驟A. (E)-3-(4-三氟甲基硫基-苯基)-丙烯酸乙酯於4-三氟甲基硫基-苯甲醛(15.46 g,75.0 mmol)之350 mL的苯溶液中加入(乙氧羰基伸甲基)三苯基磷烷(26.14 g,75.0 mmol)。將反應混合物於氮氣壓下回流6小時。真空移除溶劑並將生成的物質以350 mL的乙醚濕磨並過濾。將濾液真空濃縮並以50 mL乙醚再濕磨一次並過濾。將濾液真空濃縮並以層析純化(矽膠,EtOAc:庚烷,0:10-1:9)得到標題化合物7a
(15.8 g,57.3 mmol)之白色固體。1
H-NMR(400MHz,d6-DMSO)δ(ppm):7.89(d,2H),7.75(d,2H),7.70(d,1H),6.77(d,1H),4.21(q,2H),1.27(t,3H).MS(ESI正電離子)m/z:277.0(M+H+
).
步驟B. (E)-3-(4-三氟甲基硫基-苯基)-丙烯酸於化合物7a
(10.31 g,37.3 mmol)之300 mL的乙醇溶液中加入3N NaOH水溶液(13.0 mL,39.0 mmol)。將反應混合物攪拌21小時,然後真空蒸發。將殘餘物溶於250 mL水中並於其中加入1N HCl水溶液(45 mL,45 mmol)。將生成的沉澱過濾,以水清洗及蒸氣下風亁,產生標題化合物7b
(8.967 g,36.1 mmol)之白色粉末。1
HNMR(400M Hz,d6-DMSO)δ(ppm):12.58(s,1H),7.85(d,2H),7.74(d,2H),7.63(d,1H),6.66(d,1H)。
步驟C. (E)-5-溴-2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑於化合物7b
(1.240 g,5.00 mmol)之100 mL的CH3
CN懸浮液中加入POCl3
(2.3 mL,25.1 mmol)及4-溴-苯-1,2-二胺(0.938 g,5.01 mmol)。將反應混合物於氮氣壓下回流18小時,稍微冷卻然後加入4-溴-苯-1,2-二胺(0.468 g,2.50 mmol)。持續回流6小時,然後加入最後量之4-溴-苯-1,2-二胺(0.468 g,2.50 mmol)。另再加熱15小時後,將反應混合物真空濃縮。以層析純化殘餘物(矽膠,NH3
之MeOH溶液(2M):CH2
Cl2
,1:99-5:95),然後進行第二次層析(EtOAc:庚烷,1:9-1:1))得到標題化合物7c(1.255 g,3.14 mmol)之棕色粉末。1
H-NMR(400 MHz,d6-DMSO)δ(ppm):12.96-12.83(br d,1H),7.87-7.68(m,6H),7.60-7.45(m,1H),7.39-7.29(m,2H).MS(ESI正電離子)m/z:398.9/400.9(M+H+
)。
步驟D. (E)-2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇將化合物7c
(0.040 g,0.10 mmol)及2-羥基甲基苯基硼酸(0.029 g,0.19 mmol)之3 mL二噁烷溶液置於小壓力管中加入Na2
CO3
水溶液(0.13 mL,2M,0.26 mmol),接著加入PdCl2
(dppf)(0.008 g,0.01 mmol)。於容器中充入氬氣,加蓋並於120℃的油浴中加熱1小時。將反應混合物置於20 mL EtOAc、20 mL水及2 mL鹽水中分溶。將有機分溶液以Na2
SO4
乾燥,過濾並蒸發濾液。以層析純化殘餘物(逆相,乙腈:水+0.1% TFA,1:3-95:5)。將適切的分溶液與聚(乙烯基吡啶)混合,過濾、冷凍並冷凍乾燥,得到標題化合物35
(0.027 g,0.063 mmol)之黃色粉末。1
H-NMR(400 MHz,d6-DMSO)δ(ppm):7.89-7.78(m,5H),7.71-7.57(m,3H),7.44-7.28(m,5H),4.44(s,2H).MS(ESI正電離子)m/z:426.7(M+H+
).
使用實例7中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮(化合物40
)步驟A. (E)-3-(4-三氟甲磺醯基-苯基)-丙烯酸於化合物7b
(2.483 g,10.01 mmol)之50 mL的TFA懸浮液中加入30% H2
O2
溶液(8 mL,83 mmol)。將反應混合物攪拌21小時,然後倒入250 mL冰水中。將生成的沉澱濾出,以水清洗並於50℃真空下乾燥,產生標題化合物8a
(2.281 g,8.14 mmol)之白色粉末。1
H-NMR(400MHz,d6-DMSO)δ(ppm):12.80(s,1H),8.15(s,4H),7.73(d,1H),6.83(d,1H).MS(ESI正電離子)m/z:278.9(M-H+
).
步驟B. (E)-5-溴-2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑於化合物8a
(1.405 g,5.01 mmol)之100 mL的乙腈懸浮液中加入POCl3
(2.3 mL,25.1 mmol)。將反應混合物於氮氣壓下回流30分鐘,然後稍微冷卻。於反應混合物中加入4-溴-苯-1,2-二胺(0.946 g,5.06 mmol)並將反應混合物回流2小時,之後再加入4-溴-苯-1,2-二胺(0.942 g,5.04 mmol)。加熱1小時後,將反應混合物冷卻並以矽藻土墊過濾。以乙腈、醋酸乙酯及甲醇清洗濾餅。將濾液與NaHCO3
/EtOAc水溶液共同攪拌。將有機分溶液蒸發置於100 mL EtOAc及100 mL飽和的NaHCO3
間分溶。將有機分溶液以Na2
SO4
乾燥,過濾並蒸發濾液。以層析純化殘餘物(矽膠,EtOAc:庚烷,1:4-1:1)),產生標題化合物8b
(1.595 g,3.70 mmol)之棕色粉末。1
H-NMR(400 MHz,d6-DMSO)δ(ppm):13.00(d,1H),8.14(q,4H),7.87-7.73(m,2H),7.63-7.50(m,2H),7.40-7.33(m,1H).MS(ESI正電離子)m/z:430.8/432.8(M+H+
).
步驟C. (E)-1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮將化合物8b
(0.043 g,0.10 mmol)及2-乙醯基苯基硼酸(0.035 g,0.21 mmol)之3 mL二噁烷溶液置於小壓力管中攪拌。加入Na2
CO3
溶液(0.13 mL,2M,0.26 mmol)接著加入PdCl2
(dppf)(0.007 g,0.01 mmol)。於容器中充入氬氣,加蓋並於120℃的油浴中加熱1小時。將反應混合物置於20 mL EtOAc、20 mL水及2 mL鹽水中分溶。將有機分溶液以Na2
SO4
乾燥,過濾並蒸發濾液。將殘餘物於矽膠塞上以100% EtOAc溶離然後蒸發。層析純化粗物質(逆相,乙腈/水+0.1% TFA,1:3-95:5)。將適切的分溶液與聚(乙烯基吡啶)混合,過濾、冷凍並冷凍乾燥,得標題化合物40
(0.022 g,0.047 mmol)之黃色粉末。1
H-NMR(400 MHz,d6-DMSO)δ(ppm):8.16(q,4H),7.87(d,1H),7.70(d,1H),7.64-7.56(m,3H),7.55-7.47(m,3H),7.21(d,1H),2.09(s,3H).MS(ESI正電離子):471.0(M+H+
)。
使用實例8中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇(化合物45
)1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醇(化合物46)於化合物40
(0.047 g,0.10 mmol)之5 mL EtOH溶液中加入NaBH4
(0.028 g,0.74 mmol)。1 h後,加入另量之NaBH4
(0.024 g,0.63 mmol)。又4.5 h後,將反應以25 mL EtOAc稀釋並以25 mL水/鹽水清洗二次。將有機分溶液以Na2
SO4
乾燥,過濾並蒸發濾液。以層析純化殘餘物(逆相(乙腈/水帶有0.1% TFA,1:3-95:5)。將二種產物分離,冷凍並冷凍乾燥,得到產物化合物45(0.024 g,0.051 mmol)之黃色粉末及化合物46
(0.020 g,0.042 mmol)之白色粉末。
化合物45: 1
H-NMR(400MHz,d6-DMSO)δ(ppm):8.18(dd,4H),7.93(d,1H),7.74(d,1H),7.67(d,1H),7.64-7.57(m,2H),7.43(dt,1H),7.35-7.27(m,2H),7.21(dd,1H),4.80(q,1H),1.22(d,3H).MS(ESI正電離子)m/z:472.8(M+H+
).
化合物46
:1
H-NMR(400 MHz,d6-DMSO)δ(ppm):8.12(d,2H),7.82-7.74(m,3H),7.70-7.63(m,2H),7.47-7.37(m,2H),7.32(dt,1H),7.18(dd,1H),4.72(q,1H),3.47(t,2H),3.40(t,2H),1.19(d,3H).MS(ESI正電離子)m/z:474.8(M+H+
).
(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇(化合物18
)
步驟A. 3-(4-三氟甲基-苯基)-丙烯酸將4-三氟甲基苯甲醛(7.7 mL,57.7 mmol)、丙二酸(12.0 g,115.4 mmol),0.5674 μ L哌啶(5.75 mmol)之30 mL的吡啶溶液於70℃攪拌18 h。將反應混合物冷卻至室溫。加入水(300 mL)並將生成的混合物使用濃鹽酸酸化至pH 4(石蕊試紙),得到沉澱。將固體過濾並以水清洗直到濾液為中性。將固體產物乾燥得到標題化合物10a之白色粉末(11.2 g,90%)。1
HNMR(400MHz,DMSO-d6
)δ(ppm):12.60(bs,1H),7.92(d,2H,J=8.2 Hz),7.77(d,2H,J=8.2 Hz),7.66(d,1H,J=16.0 Hz),6.70(d,1H,J=16.0 Hz).
步驟B. (E)-5-溴-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑將化合物10a
(20.6g,95.4 mmol)之無水二氯甲烷(200 mL)以草醯氯(16.6 mL,190 mmol)及"3滴"之無水二甲基甲醯胺處理。將生成的溶液於室溫及氬氣壓下攪拌18小時。濃縮溶劑得到3-(4-三氟甲基-苯基)-丙烯醯氯化合物10b
之固體,將其用於下個步驟不需進一步純化。
於4-溴-苯-1,2-二胺(16.1 g,86.7 mmol)之醋酸(100 mL)溶液中逐滴加入化合物10b
(assumed 95.4 mmol)之醋酸(100 mL)溶液。將反應混合物於100℃攪拌18小時。將反應混合物冷卻至室溫並加入3:7醋酸乙酯及己烷之混合物(500 mL)。將混合物於室溫下濕磨3 h,得到沉澱。將固體濾出並真空乾燥,得到標題化合物10c
(23.2 g,73%)。1
H NMR(400MHz,DMSO-d6
/CDCI3
)δ(ppm):8.45(d,1H,J=16.7 Hz),7.84-7.90(m,1H),7.74(d,2H,J=8.3 Hz),7.56-7.62(m,3H),7.50-7.52(m,1H),7.34(d,1H,16.7 Hz).
步驟C. 2-(2-溴-苯基)-丙-2-醇於2-溴苯甲酸甲酯(20.76 g,96 mmol)之120 mL無水乙醚溶液中於氬氣壓0℃下,以使混合物內部溫度低於20℃之速度,緩慢地加入甲基溴化鎂(77 mL,3.26 M)。生成一白色懸浮液並將混合物於室溫下攪拌2小時。將混合物置於冰浴中冷卻。非常緩慢地將鹽酸(400 mL,0.5 M)加到反應混合物中。以數滴2M鹽酸將混合物最終的pH調整至低於約6。進行分層,以乙醚萃取水層二次。將有機層組合並以硫酸鎂乾燥。將有機分溶液過濾並濃縮濾液產生標題化合物之黃色液體,將其於真空下蒸餾得到標題化合物10d
之無色液體(16.9 g,82%,b.p.約65-70℃/0.3 mmHg)。1
H NMR(400MHz,CDCl3
)(ppm):7.67(dd,1H,J=1.7,7.9 Hz),7.58(dd,1H,J=1.3,7.9 Hz),7.30(ddd,1H,J=1.4,7.4,7.9 Hz),7.10(ddd,1H,J=1.7,7.4,7.8 Hz),2.77(br s,1H),1.76(s,6H).
步驟D. 3,3-二甲基-3H-苯并[c][1,2]氧雜戊硼烷-1-醇於n-BuLi(166 mL,2.6 M,432 mmol)之200 mL的THE溶液中於-78℃氬氣壓下,以維持內部溫度低於-70℃之速度緩慢地加入化合物10d
(42.2 g,196 mmol)之60 mL的THE溶液。將混合物於-75℃攪拌2小時。然後於反應混合物中分三次加入三異丙基硼酸酯(59 mL,255 mmol)。讓混合物緩慢地升溫至室溫至隔夜。然後將混合物冷卻至0℃並小心地以稀鹽酸(250 mL,2N)進行驟冷。然後將混合物於室溫下攪拌1小時。然後檢測混合物之pH並(若可能)使用額外的2N HCl調整。將二層分離,以乙醚萃取水層二次。將有機層組合並以硫酸鎂乾燥及過濾。將濾液減壓濃縮濾液產生淡黃色油狀物。然後以醋酸乙酯(400 mL)稀釋殘餘物及以1N氫氧化鈉溶液(150 mL x 3)清洗。將鹼性水層組合並以2N HCl酸化。當酸增加時澄清的溶液轉為渾濁。以乙醚(150 mL x 3)萃取混合物。將有機層組合並以硫酸鎂乾燥。將溶液過濾並減壓濃縮濾液產生標題化合物10e
之無色油狀物(26.2 g,82%),將其用於下個步驟需進一步純化。1
H NMR(400MHz,DMSO-d6
)δ(ppm):9.00(s,1H),7.66(dm,1H,J=7.3 Hz),7.45(dt,1H,J=1.1,7.7 Hz),7.40(dm,1H,J=7.6 Hz),7.31(dt,1H,J=1.2,7.1Hz),1.44(s,6H).
步驟E. (E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇將化合物10e
(11.7 g,71 mmol)、化合物10c
(19.9 g,54 mmol)、碳酸鈉(46 g,435 mmol)及PdCl2
(dppf).CH2
Cl2
(8.9 g,11 mmol)之混合物置於裝有水冷凝器之1 L圓底燒瓶中,加入400 mL的無水DME及200 mL水。將混合物撤出通入氬氣三次。將混合物加熱至100℃歷時20 h。然後將反應混合物冷卻至室溫。將此雙向系統轉置於1 L分液漏斗中並將二層分離。以鹽水(2 x 300 mL)清洗有機層。將水層組合並以醋酸乙酯萃取一次(約300 mL)。將有機層組合並以硫酸鎂乾燥並過濾。將濾液體積於減壓下減至約170 mL。然後將混合物經由矽膠墊過濾,並以醋酸乙酯清洗此墊直到濾液不含任何產物。濃縮後,得到淡粉紅色/米色固體。將此固體以50 mL醋酸乙酯濕磨並將混合物加熱至85℃歷時5分鐘。將混合物緩慢地冷卻至r.t.,然後於0℃冷卻0.5 h。將混合物過濾並以冷的醋酸乙酯清洗固體二次,及於40℃真空下產生標題化合物18
之淡米色固體(7.58 g,33%)。RP-HPLC 95%純度。1
H NMR(400MHz,DMSO-d6
)δ(ppm):12.73(m,1H,),7.90(d,2H,J=8.2 Hz),7.85(dd,1H,J=8.0,0.6 Hz),7.78(d,2H,.J=8.4 Hz),7.74(d,1H,J=16.8 Hz),7.59-7.47(m,1H),7.41(s,1H),7.37-7.32(m,2H),7.21(dt,1H,J=1.2,7.4 Hz),7.06(s,1H),7.02(d,1H,J=7.4 Hz),4.85(s,1H),1.21(s,6H).質譜(LCMS,APCI正電)C25
H21
F3
N2
O之理論值423.2(M+H),實測值423.3。m.p.(不正確)250-251℃。
使用實例10中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
大量製備(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇(化合物18
)步驟A. 3-(4-三氟甲基-苯基)-丙烯酸於裝有空氣冷凝器/氬氣入口、機器攪拌器、熱電偶及停止器之2-L的4-頸圓底燒瓶中裝入4-(三氟甲基)苯甲醛(250 g,196.2 mL,1.44 mol)、丙二酸(302.6 g,2.87 mol)及吡啶(750 mL)。有放熱產生(約38-40℃),將其維持30分鐘。然後將哌啶(14.202 mL,143.58 mmol)加到反應中並有第二次放熱產生(約10分鐘後最高溫(Tmax
)約42℃)。將反應攪拌30分鐘並加熱至60℃歷時18 h(至隔夜)。TLC顯示反應完成並將其冷卻至約40℃,以水稀釋(2 L;用以預防反應結凍),冷卻至室溫並進一步以水稀釋(4 L,總計6L)。將漿液以濃鹽酸(約675-700 mL)酸化至pH=2.0-3.0。將物質攪拌30分鐘,並過濾收集白色固體。以水清洗濾餅直到濾液為中性(pH約5.5-6,2.5 L),於布氏漏斗中風亁2小時,然後進一步於60℃真空烘箱中乾燥至隔夜,得到300.5 g(96%)標題化合物10a
之白色固體。
步驟B. (E)-5-溴-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑於裝有磁性攪拌器、排除碳酸之氬氣入口-氬氣出口、二個停止器及室溫水浴之5-L的4-頸圓底燒瓶中裝入4-(三氟甲基)肉桂酸(315 g,1.46 mol)及二氯甲烷(3.15 L),得到一漿液。於漿液中加入草醯氯(151.71 mL,1.75 mol)及DMF(1.13 mL,14.57 mmol)。加入DMF後氣體開始產出,讓反應持續約3 h,在此期間產生一溶液。當反應完成(LC-MS),將其濃縮至亁得到342.4 g之3-(4-三氟甲基-苯基)-丙烯醯氯化合物10b
(>100%)之黃色油狀固體。
於裝有機器攪拌器、熱電偶、帶有氬氣入口之空氣冷凝器及停止器之2-L的4-頸圓底燒瓶中裝入4-溴-苯-1,2-二胺(244 g,1.27 mol)及醋酸(2.13 L)。於此溶液中加入化合物10b
(327 g,1.39 mol)之甲苯(237 mL)溶液。添加後,溫度定在45℃約30秒,然後消退。然後將反應加熱至90℃歷時16 h(隔夜)。將反應冷卻至40℃,並倒入混合的EtOAc及庚烷溶液中(約1:3,5.75 L)並有沉澱發生。將生成的漿液攪拌3 h並過濾收集固體,以EtOAc:庚烷(1:3,3 L)清洗,然後於真空烘箱中乾燥(60℃)得到324.3 g(65%)標題化合物10c
之部分醋酸鹽。
步驟C. 2-(2-溴-苯基)-丙-2-醇於裝有熱電偶、冷凝器、隔片、添加漏斗及上方機器攪拌器之12-L的4-頸燒瓶中於氬氣壓下裝入甲基-2-溴苯甲酸酯(226.5 g,1.05 mol)及THE(1.6 L,19.66 mol)。攪拌下將混合物冷卻至2至5℃溫度間並保持30分鐘。以維持反應溫度低於15℃之速度,經由添加漏斗於溶液中緩慢地加入甲基溴化鎂之乙醚(3M,1.05 L;3.15 mol)溶液。在添加期間觀察到放熱,反應溫度由3升至15℃。於4 h完成1.05 L格林那(Grignard)溶液之添加(加入速度約4.17 mL/min)。反應混合物顯示為灰白/黃色漿液。讓反應升至室溫並攪拌至隔夜(15 h)。以HPLC/TLC由反應中取樣,顯示無起始物質存在。再次於反應燒瓶使用冰浴並於2 h期間緩慢地加入0.5 M HCl溶液(4.5 L;2.25 mol)。溫度由0快速地增加至15℃。驟冷完成後,將反應於室溫下攪拌30分鐘。另再緩慢添加2 N HCl(500 mL;1.00 mol)以將pH維持低於6。加入MTBE(1 L)以幫助相分離。將反應於室溫下攪拌1至2 h將固體物質溶解成水相(最可能為Mg(OH)2
其鹼性非常強)。必須檢測pH並(若需要)以額外的酸調整pH。進行相分離並另外以1 L MTBE(2 x 500 mL)清洗水層。將有機層組合並以NaHCO3
溶液(2 x 300 mL)清洗,以MgSO4
乾燥,過濾並真空下濃縮濾液,產生標題化合物10d
(220.83 g,97.48%產率)之澄清黃色油狀物。
步驟D. 3,3-二甲基-3H-苯并[c][1,2]氧雜戊硼烷-1-醇於裝有熱電偶、冷凝器、添加漏斗及上方機器攪拌器之12-公升的4-頸圓底燒瓶中於氬氣壓下裝入無水THF(3 L)並經由乾冰/丙酮浴冷卻至-70至-78℃。經由添加漏斗緩慢地加入正丁基鋰(2.5N之己烷溶液,860 mL,2.15 mol)。觀察到放熱反應因溫度由-78升至-70℃。於添加漏斗中加入化合物10d
(220 g,979.97 mmol)之無水THF(1 L)溶液。緩慢地將2-(2-溴苯基)丙-2-醇溶液加到n-BuLi溶液中。添加費時90分鐘以便將反應溫度維持在以下-70℃。添加完成後,將反應於-70至-75℃間攪拌30分鐘。於-70℃分三次可快速地加入三乙基硼酸酯(230 mL,1.35 mol)。觀察到放熱反應,批式溫度由-70上升至-64℃。將反應於-70℃攪拌並升溫至室溫至隔夜。將反應冷卻至0-5℃後,將反應緩慢地由添加漏斗添加2M HCl(1 L,2.00 mol)進行驟冷同時將批式溫度維持在0-5℃。將反應混合物攪拌1h。水層之pH為9-10。然後以2M HCl(200 mL)調整pH至酸性(4-5)。將二層分離並以MTBE(2 x 500 mL)萃取水層。將組合的有機層以硫酸鎂乾燥。將溶液過濾並濃縮,產生黃色油狀物。將此黃色油狀物以MTBE(1.5 L)稀釋並以1M NaOH(3 x 500 mL)清洗。將含有產物之鹼性水層組合以2M HCl(800 mL)酸化(因添加酸,澄清溶液轉為渾濁)。攪拌此渾濁溶液15分鐘後(pH=4-5)(註解1),以MTBE(2 x 500 mL)萃取。將有機層組合並以MgSO4
乾燥。將溶液過濾並將濾液濃縮,產生標題化合物10e
之澄清黃色油狀物(121.78克,77%產率)。
步驟E. (E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇於裝有熱電偶控制器、冷凝器、上方機器攪拌器、Firestone valve及氮氣入口/出口之5-L的4-頸燒瓶中裝入二甲氧基乙烷(2 L)、DI水(1 L)及碳酸鈉(230.9 g,2.18 mol)。將溶液脫氣並充入N2
三次。將化合物10e
(71.7 g,0.35 mol)及化合物10c
(100.0 g,0.27 mol)加到脫氣的溶液中。將溶液脫氣並充入N2
三次。將PdCl2
(dppf)(44.48 g,54.4 mmol)加到溶液中,並將溶液脫氣及充入N2
三次。將生成的二相懸浮液加熱回流18 h,然後冷卻至室溫。將反應混合物轉置於12-L的分液漏斗中,進行分層。將有機層以鹽水(1L)清洗。將二水層組合並以EtOAc(1L)萃取。將組合的有機層乾燥(Na2
SO4
),過濾並將濾液濃縮成油狀物。將二個分別的100 g偶合反應組合並於ISCO製備式層析系統上(10 x 1.5 Kg SiO2,5倍管柱體積之EtOAc,250 mL/min流速)進行10次連續層析純化。將組合的分溶液轉置於22-L的4-頸圓底燒瓶,並於各溶液中加入Silicycle Si-硫醇功能化矽膠(2 g)。讓溶液升至40℃並放置1 h。將溶液以中型玻璃漏斗過濾並以EtOAc(4L)清洗及組合。將濾液蒸發成半固體,將其轉置於2 L圓底燒瓶中,於其中EtOAc(0.4L)。將生成的白色沉澱漿液冷卻至-5℃並攪拌1小時。將漿液過濾並以冷的EtOAc(100 mL)清洗二次。將固體置於40℃真空烘箱烘乾40 h,得到84.0 g(36.5%產率,98.8區域%純度)標題化合物18
之白色固體。分析C25
H21
N20
F3
之理論值0.04% H2
O 0.15 mol MeOH:C,70.48;H,5.14:N,6.42;F,13.06實測值:C,70.54;H,4.83:N,6.18;F,13.33
(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇單鈉鹽(化合物18
)於裝有熱電偶控制器、上方機器攪拌器及氮氣入口/出口之5-L的4-頸燒瓶中裝入(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇、化合物18
(125.0 g,0.510 mol)及MeOH(1.25 L)。加入甲醇鈉之甲醇(0.5 M,592 mL,0.3 mol)溶液。將反應加熱至65℃歷時30 min並溶解所有固體。將溶液冷卻並蒸發至亁。擦抹燒瓶收集泡沫。將固體置於40℃真空烘箱烘乾24 h,得到139 g(約100%分開產率)標題化合物18
單鈉鹽之淡黃色固體。1
H NMR(400MHz,DMSO-d5
)δ 7.80-7.84(m,3H),7.74(d,2H,J=8.59 Hz),7.65(d,1H,J=16.4 Hz),7.40-7.44(m,2H),7.25-7.37(m,2H),7.16-7.20(m,1H),7.01-7.05(m,1H),6.84-6.87(m,1H),1.23(s,6H).質譜(LCMS,APCI正電)C25
H21
F3
N2
O之理論值:423.2(M+H),實測值423.3。m.p.(不正確)258-259℃。
(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇鹽酸鹽(化合物18
)於250-mL分液漏斗中裝入(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇、化合物18
(1.0 g,2.4 mmol)及EtOAc(20 mL)。將HCl水溶液(1M,20 mL)加到此白色漿液中並震盪此分液漏斗。固體產物快速溶解並有白色沉澱開始形成。將有機層轉置於裝有磁性攪拌棒之100 mL的圓底燒瓶中,並攪拌2 h。將濃漿液過濾,以EtOAc(2 x 5 mL)清洗及置於40℃真空烘箱乾燥36 h,得到0.95 g(87.5%)標題化合物18
鹽酸鹽。
(E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-酚(化合物48
)步驟A. N-(4-溴-2-硝基-5-三氟甲基-苯基)-2,2,2-三氟-乙醯胺將4-溴-3-三氟甲基苯胺(4.8 g,0.02 mol)分次加到經攪拌冰冷的三氟醋酸酐(50 mL)中。於生成的溶液中分次加入KNO3
(2.22 g,0.022 mol,1.1 eq)。將反應混合物於0℃攪拌1h,然後升至室溫至隔夜。以冰水(150 mL)稀釋反應混合物並真空過濾收集固體。以水(50 mL)清洗固體並真空乾燥,得到標題化合物11a
之淡黃色固體(6.4 g)。1
H-NMR(400MHz,CDCl3
)δ(ppm):9.19(s,1H)8.64(s,1H)MS(ESI,正電離子)m/z:381.4(M+1)。
步驟B. 4-溴-2-硝基-5-三氟甲基-苯基胺將化合物11a
(5.7 g,0.015 mol)溶於甲醇(25 mL)及飽和的K2
CO3
水溶液(15 mL)之混合物中。然後將反應混合物於室溫下攪拌10 h。以水(25 mL)稀釋反應混合物並真空過濾收集固體,得到標題化合物11b
之黃色固體(2.99 g)。1
H-NMR(400MHz,CDCl3
)δ(ppm):8.44(s,1H)7.21(s,1H),6.21(bs,2H).MS(ESI,正電離子)m/z:285.0(M+1)。
步驟C. 4-溴-5-三氟甲基-苯-1,2-二胺將化合物11 b
(2.85 g,0.01 mol)溶於30 mL乙醇。分次加入鋅粉(5.9 g,0.09 mol)接著加入氯化銨(1.07 g,0.02 mol,2 eq)。將反應混合物於室溫下攪拌至隔夜(16 h)。將反應混合物以矽藻土墊過濾並真空蒸發溶劑。將殘餘物置於醋酸乙酯(40 mL)中處理,以35 mL鹽水清洗,以Na2
SO4
乾燥並真空蒸發。以層析純化殘餘物(矽膠,CH2
Cl2
:MeOH,96:4-94:6)),得到標題化合物11 c
之黃色固體(1.53 g),將其用於下個步驟不需進一步純化。1
H-NMR(400MHz,CD3
OD)δ(ppm):6.99(s,1H)6.92(s,1H)MS(ESI,正電離子)m/z:254.7(M+1)。
步驟D. (E)-5-溴-2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑將4-第三丁基丙烯酸(1.02 g,0.0055,1.1 eq)溶於30 mL的POCl3
。於其中加入化合物11 c
(1.27 g,0.005 mol)並將反應混合物加熱回流6小時。(反應混合物顏色相當深)。將反應混合物冷卻至室溫並真空濃縮。將殘餘物置於50 mL醋酸乙酯中處理,以50 mL鹽水清洗,以Na2
SO4
乾燥,過濾並真空蒸發濾液。以層析純化殘餘物(矽膠,己烷:EtOAc,1:3-2:3),得到標題化合物11d
之淡棕色固體(0.84 g)。1
H-NMR(400MHz,CDCI3
)δ(ppm):7.91(d,2H,J=18.5 Hz)7.69(d,1H,J=16.4 Hz),7.32(m,4H)7.09(d,1H,J=16.5 Hz)1.28(s,9H).MS(ESI,正電離子)m/z:423.7(M+1).
步驟E. (E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-酚將化合物11d
(0.00026 mol,0.10 g)溶於5 mL的二噁烷中。加入2-羥基苯基硼酸(0.00052 mol,0.072 g,2.0當量)接著加入Na2
CO3
水溶液(0.00055 mol,0.28 mL的2M溶液)及二氯雙(三環己基膦)-鈀(11)(0.011 g,6 mol %)。將反應混合物置於110℃微波反應器中加熱20分鐘。將反應混合物冷卻並真空濃縮,將殘餘物置於10 mL的CH2
Cl2
處理,隨後以10 mL飽和NaHCO3
水溶液及10 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並將濾液真空濃縮。以層析純化殘餘物(矽膠,CH2
Cl2
:MeOH,98:2-95:5),得到標題化合物48
之白色固體。1
H-NMR(400 MHz,CDCl3
)δ(ppm):7.29-7.56(m,8H)7.15(d,1H,J=6.7 Hz)6.89-7.05(m,3H))1.34(s,9H).MS(ESI,正電離子)m/z:437.1(M+1).
使用實例11中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-N-(2-{6-三氟甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺(化合物56
)步驟A. (E)-5-溴-6-三氟甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑使用實例11步驟D之製程,將4-三氟甲基丙烯酸(1.19 g,0.0055,1.1 eq)溶於30 mL的POCl3
中。於此溶液中加入化合物11c
(1.27 g,0.005 mol)並將反應混合物加熱回流6 h(反應混合物顏色相當深)。將反應混合物冷卻至室溫然後真空濃縮。將殘餘物置於50 mL醋酸乙酯中處理,以50 mL鹽水清洗,以Na2
SO4
乾燥,過濾並將濾液真空濃縮。以層析純化殘餘物(矽膠,己烷:EtOAc,3:1-3:2),得到標題化合物12a
之淡黃色固體(1.02 g)。1
H-NMR(400 MHz,CDCl3
)δ(ppm):7.92(d,2H,J=14.1Hz)6.67-7.76(m,5H)7.21(d,1H,J=16.5 Hz)MS(ESI,正電離子)m/z:368.3(M+1).
步驟B. (E)-N-(2-{6-三氟甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺將化合物12a
(0.00025 mol,0.10 g)溶於5 mL二噁烷中。加入2-乙醯胺基苯基硼酸(0.0005 mol,0.089 g,2.0當量)接著加入Na2
CO3
水溶液(0.00055 mol,0.28 mL of 2M溶液)及二氯雙(三環己基膦)-鈀(11)(0.011 g,6 mol %)。將反應混合物置於110℃微波反應器中加熱20分鐘。將反應混合物冷卻並真空濃縮,將殘餘物置於10 mL的CH2
Cl2
處理,隨後以10 mL飽和NaHCO3
水溶液及10 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並將濾液真空濃縮。以層析純化殘餘物(矽膠CH2
Cl2
:MeOH,98:2-95:5),得到標題化合物56
之白色固體。1
H-NMR(400M Hz,DMSO-d6)δ(ppm):8.68(s,1H)8.03(s,1H)7.80-7.96(m,6H)7.35-7.50(m,3H)7.20(d,2H,J=4.1Hz)1.8(s,3H)MS(ESI,正電離子)m/z:490.0(M+1).
使用實例12中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚(化合物59)步驟A. N-(4-溴-5-氟-2-硝基-苯基)-2,2,2-三氟-乙醯胺將4-溴-3-氟甲基苯胺(3.8 g,0.02 mol)分次加到經攪拌冰冷的三氟醋酸酐(50 mL)中。於溶液中分次加入KNO3
(2.22 g,0.022 mol,1.1 eq)。將反應混合物於0℃攪拌1h,然後升至室溫至隔夜。以冰水(150 mL)稀釋反應混合物並真空過濾收集固體。以水(50 mL)清洗固體並真空乾燥,得到標題化合物13a
之淡黃色固體(5.42 g)。1
H-NMR(400MHz,CDCl3
)δ(ppm):8.66(d,1H,J=10.0 Hz)8.60(d,1H,J=11.3 Hz).MS(ESI,正電離子)m/z:402.0(M+Na).
步驟B. 4-溴-5-氟-2-硝基-苯基胺將化合物13a
(5.0 g,0.015 mol)溶於甲醇(25 mL)及飽和的K2
CO3
(15 mL)水溶液並將反應混合物於室溫下攪拌10 h。將反應混合物以水(25 mL)稀釋並真空過濾收集固體,得到標題化合物13b
之黃色固體(2.5 g)。1
H-NMR(400 MHz,CDCl3
)δ(ppm):8.39(d,1H,J=7.1Hz)6.75(d,1H,J=9.6 Hz)6.19(bs,2H).MS(ESI,正電離子)m/z:236.9(M+1).
步驟C. 4-溴-5-氟-苯-1,2-二胺將化合物13b
(1.88’g,0.008 mol)溶於20 mL的乙醇中。分次加入鋅粉(4.71 g,0.072 mol)接著加入氯化銨(0.86 g,0.016 mol)。將反應混合物於室溫下攪拌至隔夜(16 h)。將反應混合物以矽藻土墊過濾並真空蒸發溶劑。將殘餘物置於醋酸乙酯(30 mL)中處理,以25 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並真空濃縮濾液。以快速層析純化殘餘物(矽膠,CH2
Cl2
:MeOH,96:4-94:6)),得到標題化合物13c
之深黃色固體(1.02 g),將其立即用於下個反應。MS(ESI,正電離子)m/z:235.7(M+1)。
步驟D. (E)-5-溴-6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑將4-三氟甲基肉桂酸(1.2 g,0.0055,1.1 eq)溶於30 mL的POCl3
中。於溶液中加入化合物13c
(1.02 g,0.005 mol),並將反應混合物加熱回流6 h。將反應混合物冷卻至室溫然後真空蒸發。將殘餘物置於50 mL醋酸乙酯中處理,以50 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥並真空濃縮。以層析純化殘餘物(矽膠,己烷:EtOAc,3:1-3:2),得到標題化合物13d
之淡棕色固體(0.80 g)。1
H-NMR(400 MHz,DMSO-d6)δ(ppm):7.63-8.09(m,4H)7.4(d,1H,J=20.7 Hz)6.69(d,1H,J=20.7 Hz)MS(ESI,正電離子)m/z:386.0(M+1).
步驟E. (E)-2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚將化合物13d
(0.00025 mol,0.096 g)溶於5 mL的二噁烷。加入2-羥基苯基硼酸(0.0005 mol,0.069 g)接著加入Na2
CO3
水溶液(0.00055 mol,0.28 mL之2M溶液)及二氯雙(三環己基膦)-鈀(11)(0.011 g,6 mol %)。將反應混合物置於110℃微波反應器中加熱20分鐘。將反應混合物冷卻並真空蒸發溶劑,將殘餘物置於10 mL的CH2
Cl2
處理,隨後以10 mL飽和NaHCO3
水溶液及10 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並將濾液真空濃縮。以層析純化殘餘物(矽膠(CH2
Cl2
:MeOH,98:2-95:5),得到標題化合物59之褐色固體。1
H-NMR(400 MHz,DMSO-d6)δ(ppm):7.90(d,2H,J=8.0 Hz)7.79(d,2H,J=7.8 Hz)7.22-7.53(m,4H)6.88-6.96(m,4H)MS(ESI,正電離子)m/z:399.1(M+1).
使用實例13中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-(2-{6-氯-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇(化合物66
)步驟A. N-(4-溴-5-氯-2-硝基-苯基)-2,2,2-三氟-乙醯胺將4-溴-3-氯甲基苯胺(4.1 g,0.02 mol)分次加到經攪拌冰冷的三氟醋酸酐(50 mL)中。於生成的溶液中分次加入KNO3
(2.22 g,0.022 mol,1.1 eq)。將反應混合物於0℃攪拌1h,然後升至室溫至隔夜。以冰水(150 mL)稀釋反應混合物並真空過濾收集固體。以水(50 mL)清洗固體並真空乾燥,得到標題化合物14a
之淡黃色固體(5.55 g)。
步驟B. 4-溴-5-氯-2-硝基-苯基胺將化合物14a
(5.2 g,0.015 mol)溶於甲醇(25 mL)及飽和的K2
CO3
水溶液(15 mL)之混合物中。將反應混合物於室溫下攪拌10小時。以水(25 mL)稀釋反應混合物並真空過濾收集固體,得到標題化合物14b
之黃色固體(2.71 g)。1
H-NMR(400 MHz,CDCl3
)δ(ppm):8.39(s,1H)6.98(s,1H)6.08(bs,2H).MS(ESI,正電離子)m/z:250.9(Br,Cl模式).
步驟C. 4-溴-5-氯-苯-1,2-二胺將化合物14b
(2.0 g,0.008 mol)溶於20 mL的乙醇中。分次加入鋅粉(4.7 g,0.072 mol)接著加入氯化銨(0.88 g,0.016 mol,2 eq)。將反應混合物於室溫下攪拌至隔夜(16 h)。將反應混合物以矽藻土墊過濾並真空蒸發溶劑。將殘餘物置於醋酸乙酯(30 mL)中處理,以25 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並真空濃縮。以快速層析純化殘餘物(矽膠,CH2
Cl2
:MeOH,96:4-94:6),得到標題化合物14c
之暗黃棕色固體(1.08 g)將其立即用於下個反應。MS(ESI,正電離子)m/z:220.9(Br,Cl模式)。
步驟D. (E)-5-溴-6-氯-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑將4-三氟甲基肉桂酸(1.2 g,0.0055,1.1 eq)溶於30 mL的POCl3
。於溶液中加入化合物14c
(1.08 g,0.005 mol)並將反應混合物加熱回流6小時(反應混合物顏色相當深)。將反應混合物冷卻至室溫並真空蒸發。將殘餘物置於50 mL醋酸乙酯中處理,以50 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並真空蒸發濾液。以層析純化殘餘物(矽膠,己烷s:EtOAc,3:1-3:2),得到標題合物14d
之淡棕色固體(0.80 g)。1
H-NMR(400 MHz,DMSO-d6)δ(ppm):7.57-8.21(m,4H)7.35(d,1H,J=19 Hz)6.72(d,1H,J=18.5 Hz).MS(ESI,正電離子)m/z:401.0.
步驟E. (E)-(2-{6-氯-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇將化合物14d
(0.00025 mol,0.100 g)溶於5 mL的二噁烷中。加入2-羥基甲基苯基硼酸(0.0005 mol,0.067 g,2.0當量)接著加入Na2
CO3
(0.00055 mol,0.28 mL之2M溶液)及二氯雙(三環己基膦)-鈀(11)(0.011 g,6 mol %)。將反應混合物置於110℃微波反應器中加熱20分鐘。將反應混合物冷卻並真空蒸發濃劑,將殘餘物置於10 mL的CH2
Cl2
處理,隨後以10 mL飽和NaHCO3
水溶液及10 mL鹽水清洗。將有機分溶液以Na2
SO4
乾燥,過濾並真空蒸發濃劑。以層析純化殘餘物(矽膠,CH2
Cl2
:MeOH,98:2-95:5),得到標題化合物66
之黏稠黃色固體。1
H-NMR(400 MHz,CD3
OD)δ(ppm):7.82-7.85(d,2H,J=8.4 Hz)7.72-7.74(d,2H,J=8.3 Hz)7.56-7.66(m,3H)7.26-7.43(m,5H)5.05(s,1H)4.58(s,2H).MS(ESI,正電離子)m/z:395.3(-CH2
OH).
使用實例14中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物70
)(E)-N-第三-丁基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物309)步驟A. (E)-N-第三-丁基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺將2-(第三-丁基胺基)磺醯基苯基硼酸(12.4 g,0.048 mol)、化合物10c(13.6 g,0.037 mol)、Pd(dppf)Cl2
CH2
Cl2
(3.00 g,3.70 mmol)、TBAB(11.9 g,0.037 mmol)及Na2
CO3
(31.4,0.296 mol)溶於750 mL混合溶劑(DME:水,4:1)之混合物於90℃加熱12小時。將反應混合物濃縮,以層析純化殘餘物(矽膠,己烷:EtOAc,1:1),得到標題化合物309
之黃色油狀物。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.14(dd,1H,J=1.6及7.6 Hz)7.84(d,2H,J=8.4 Hz)7.73(d,2H,J=8.4 Hz)7.70-7.62(m,4H)7.54(dt,1H,J=1.6及8.6 Hz)7.41(dd,1H,J=1.2及7.6 Hz)7.37-7.31(m,2H)1.00(s,9H)MS(ESI,正電離子)m/z:490.3(M+1).
步驟B. (E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺將化合物309
之60 mL TFA溶液中於70℃加熱2小時。將反應濃縮,將殘餘物溶於EtOAc並以飽和的NaHCO3
清洗。將有機層以Na2
SO4
乾燥,過濾並將殘餘物濃縮。以快速層析純化殘餘物(矽膠,己烷:EtOAc,1:2),得到標題化合物70
之淡棕色固體。M.p.168-170℃。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.16(dd,1H,J=1.2及8.0 Hz)7.95-7.91(m,3H)7.82-7.76(m,4H).7.70-7.56(m,3H)7.44(s,1H)7.16(d,1H,J=9.6 Hz)MS(ESI,正電離子)m/z:444.3(M+1).
使用實例15中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物69
)步驟A. (5-溴-2-第三-丁氧基羰基胺基-苯基)-胺甲酸第三丁酯將4-溴-苯二胺(25 g,0.134 mol)於25℃逐滴加到二碳酸二第三丁酯(175 g,0.802 mol),並將反應混合物攪拌10小時。以層析純化混合物(矽膠,己烷對己烷:EtOAc,1:1)得到標題化合物16a
之淡棕色固體。1
H-NMR(400 MHz,CDCI3
)δ(ppm):7.76(brs,1H)7.32(brs,1H)7.22(dd,1H,J=2.0及8.8 Hz)6.72(brs,1H)6.53(brs,1H).
步驟B. (3-第三-丁氧基羰基胺基-2’-第三-丁基胺磺醯基-聯苯-4-基)-胺甲酸第三-丁酯將2-(t-丁基胺基)磺醯基苯基硼酸(4.7 g,0.018 mmol)、化合物16a
(4.7 g,0.012 mmol)、Pd(dppf)Cl2
.CH2
Cl2
(0.99 g,0.0012 mmol)、TBAB(3.90 g,0.012 mmol)及20 mL 1M Na2
CO3
(aq)之100 mL DME混合物中於100℃加熱12小時。將反應混合物濃縮,並以層析純化殘餘物(矽膠,己烷:EtOAc,2:1)得到標題化合物16b
之棕色油狀物。
步驟C. 3’,4’-二胺基-聯苯-2-磺酸第三-丁基醯胺將溶於20 mL的4M HCl化合物16b
之二噁烷混合物攪拌3小時。將反應混合物濃縮,以EtOAc稀釋並以飽和的NaHCO3
(aq)清洗,然後以Na2
SO4
乾燥並過濾。將濾液濃縮得到標題化合物16c
之棕色油狀物。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.04(dd,1H,J=1.2及7.6 Hz)7.56(dt,1H,J=1.2及8.2 Hz)7.44(dt,1H,J=1.2及8.4 Hz)7.33(dd,1H,J=1.2及7.6 Hz)6.86(d,1H,J=1.6 Hz)6.77(d,1H,J=7.6 Hz)6.73(dd,1H,J=2.0及8.0 Hz)0.97(s,9H).MS(ESI,正電離子)m/z:319.9(M+1).
步驟D. (E)-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺將化合物16c
(0.120 g,0.376 mmol)、反式4-(三氟甲氧基)-肉桂酸(0.105 g,0.451 mmol)及0.4 mL的4N HCl(aq)之4 mL的乙二醇混合物於180℃加熱1小時。將反應混合物直接以HPLC純化殘餘物(YMC ODS-A,H2
O:MeCN,90:10至40:60,10 min內)得到標題化合物69
之灰白色固體。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.14(dd,1H,J=1.2及8.0 Hz)7.75(d,2H,J=8.4 Hz)7.68-7.53(m,5H)7.41(dd,1H,J=1.2及7.6 Hz)7.37-7.33(m,3H)7.19(d,1H,J=16.8 Hz)MS(ESI,正電離子)m/z:460.3(M+1).
使用實例16中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
使用實例15或16中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,可製備下列預測之本發明代表化合物:
(E)-N-甲基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基)-苯磺醯胺(化合物310
)步驟A. N-甲基苯磺醯胺-2-硼酸於N-甲基苯磺醯胺(2.00 g,0.0117 mmol)之20 mL THE溶液中於0℃逐滴加入正丁基鋰(1.6 M之己烷溶液,14.6 mL,0.0234 mmol)。30分鐘後,加入硼酸三異丙酯(3.1 mL,0.0164 mmol),並將混合物於0℃攪拌2小時。加入20 mL的1M HCl(aq)讓反應驟冷。以EtOAc萃取混合物,將有機分溶液以鹽水清洗,以Na2
SO4
乾燥,過濾並將濾液濃縮,得到標題化合物18a
之黃色油狀物。1
H-NMR(400 MHz,CD3
OD)δ(ppm):7.81(d,1H)7.62-7.56(m,2H)2.52(s,3H).
步驟B. (3-第三-丁氧基羰基胺基-2’-甲基胺磺醯基-聯苯-4-基)-胺甲酸第三-丁酯將新鮮製備的化合物18a
(9.3 g,0.0434 mol)、化合物16a
(11.2 g,0.289 mol)、Pd(dppf)Cl2
CH2
Cl2
(4.7 g,6.42 mmol)、TBAB(9.3 g,0.0289 mol)之120 mL 1M Na2
CO3
(aq)及600 mL DME混合物中於85℃加熱10小時。將反應混合物冷卻並濃縮。以層析純化殘餘物(矽膠,己烷:EtOAc,2:1)得到標題化合物18b
之黃色油狀物。1
H-NMR(400 MHz,CDCl3
)δ(ppm):8.12(d,1H)7.86(d,1H)7.62-7.46(m,3H)7.22(d,1H)7.14(d,1H)2.62(d,3H)1.55(s,9H)1.44(s,9H).
步驟C. 3’,4’-二胺基-聯苯-2-s磺酸甲基醯胺將溶於210 mL 4M HCl的化合物18b
(21.4 g,0.0995 mol)之二噁烷溶液攪拌4小時。將反應混合物濃縮,以1M NaOH(aq)使其成鹼性,及以EtOAc萃取。將有機分溶液以Na2
SO4
乾燥,過濾並將濾液濃縮,得到標題化合物18c
之棕色油狀物。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.00(dd,1H,J=1.6及8.0 Hz)7.59(dt,1H,J=1.6及8.4 Hz)7.48(dt,1H,J=1.2及8.4 Hz)7.33(dd,1H,J=1.2及8.0 Hz)6.79(d,1H,J=2.0 Hz)6.75(d,1H,J=8.4 Hz)6.68(d,1H,J=2.0及7.6 Hz)2.93(s,3H)MS(ESI,正電離子)m/z:277.9(M+1).
步驟D. (E)-N-甲基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺將化合物18c
(0.100 g,0.361 mmol)及4-三氟甲基肉桂酸(0.324 mmol)之2 mL的POCl3
混合物加熱至100℃歷時14小時。蒸發反應混合物得到一殘餘物,然後將其以HPLC純化(H2
O:MeCN,90:10至30:70,15分鐘內)得到標題化合物310
之白色固體。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.07(dd,1H,J=1.2及8.4 Hz)7.85(d,2H,J=8.4 Hz)7.73(d,2H,J=8 Hz)7.69-7.63(m,3H)7.58(dt,2H,J=1.6及7.2 Hz)7.44(dd,1H,J=1.2及7.2 Hz)7.34(d,J=16.4 Hz)2.37(s,3H)MS(ESI,正電離子)m/z:499.2(M+MeCN+1).
使用實例18中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
(E)-N-(2-{2-[2-(4-乙氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺(化合物414
)步驟A. (3-第三-丁氧基羰基胺基-2’-甲磺醯基胺基-聯苯-4-基)-胺甲酸第三-丁酯於化合物16a
(2.0 g,5.1 mmol)、2-甲基磺醯基苯基硼酸(1.1 g,5.1 mmol)及K2
CO3
(2.1g,15.3 mmol)之1,4-二噁烷:水(4:1,120 mL)之溶液中於氬氣壓下加入Pd(dppf)Cl2
CH2
Cl2
(0.42 g,0.51 mmol)。將混合物於95℃加熱12小時。將反應混合物冷卻至室溫並減壓濃縮。以層析純化殘餘物(矽膠,EtOAc:己烷s,3:7)得到標題化合物19a
之黃色固體(1.7 g,70%產率)。1
H NMR(400MHz,CDCI3
)δ(ppm):7.64(d,J=8.4 Hz,1H),7.57(d,J=14.4 Hz,1H),7.34(t,J=8.4 Hz,1H),7.26-7.15(m,3H),7.07(s,1H),7.04(d,J=8 Hz,1H),6.87(s,1H),6.63(s,1H),2.90(s,3H),1.51(s,9H),1.49(s,9H).質譜(LCMS,ESI正電)C23
H31
N3
06
S之理論值:478.19(M+H),實測值478.0。
步驟B. N-(3’,4’-二胺基-聯苯-2-基)-甲磺醯胺將化合物19a
(1.0 g,2.1 mmol)溶於4M HCl之1,4-二噁烷(10 mL)混合物於70℃加熱2 h。將反應濃縮後,將殘餘物溶於二氯甲烷(20 mL),及於溶液中加入K2
CO3
(0.5 g)並將混合物於室溫攪拌20分鐘。過濾及移除溶劑後,將殘餘物乾燥得到標題化合物19b
之棕色固體(0.58 g,定量產率)。1
H NMR(400MHz,CD3
OD)δ(ppm):7.47(d,J=8.4 Hz,1H),7.40-7.35(m,1H),7.32-7.29(m,2H),7.16-7.09(m,3H),2.80(s,3H).質譜(LCMS,ESI正電)C13
H15
N3
02
S之理論值:278.09(M+H),實測值278.1。
步驟C. (E)-N-(2-{2-[2-(4-乙氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺將化合物19b
(50 mg,0.18 mmol)及市售3-(4-乙氧基-苯基)-丙烯酸(34.6 mg,0.18 mmol)之POCl3
(1.5 mL)溶液加熱至100℃歷時12 h。將反應冷卻,減壓下移除過量的POCl3
及以HPLC純化殘餘物HPLC(Gilson,C-18管柱,CH3
CN:H2
O(CH3
CN之梯度:5%-80%))得到標題化合物414
之灰白色固體(25 mg,32%產率)。1
H NMR(400 MHz,CD3
OD)δ(ppm):7.62-7.59(m,4H),7.54-7.52.(m,1H),7.41-7.37(m,2H),7.35-7.30(m,2H),7.03(d,J=16.8 Hz,2H),6.97(d,J=12 Hz,2H),4.09(q,J=7.2 Hz,2H),2.72(s,3H),1.41(t,J=7.2 Hz,3H).質譜(LCMS,ESI正電)C24
H23
N3
O3
S之理論值:434.1(M+H),實測值434.1.
使用實例19中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
使用實例19中所述之製程或使用實例1之製程及對應的溴苯并咪唑和硼酸或硼酸酯,以及熟習本項技術者熟知之試劑、起始物質及條件,可製備下列預測之本發明代表化合物:
使用實例1或實例19中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,可製備下列預測之本發明代表化合物:
2-{2-[2-(2-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物401
)將(E)-2-{2-[2-(2-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺化合物364
(0.020 g,0.045 mmol)及10%鈀碳(0.005 g,0.0045 mmol)之2 mL MeOH混合物於H2
氣壓下(1 atm)氫化1小時。過濾移除催化劑,將濾液濃縮至亁及以層析純化殘餘物(矽膠,MeOH:CH2
Cl2
=10:1)得到標題化合物之白色固體。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.14(dd,1H,J=1.2及7.6 Hz)7.74-7.53(m,4H)7.60-7.56(m,2H)7.51-7.40(m,4H)3.41(m,4H)MS(ESI,正電離子)m/z:446.5(M+1)
使用實例22中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
N-甲基-2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物400
)使用實例18之製程,由化合物18c
及4-三氟甲基苯基丙酸製備標題化合物。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.04(dd,1 H,J=1.2及8.0 Hz)7.66-7.53(m,6H)7.42-7.38(m,3H)7.29(dd,1H,J=1.6及8.4 Hz)3.27(m,4H)MS(ESI,正電離子)m/z:460.4(M+1).
N-甲基-2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物350
)使用實例18之製程,由化合物18c
及3-三氟甲基苯基丙酸製備標題化合物。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.05(dd,1H,J=1.2及7.6 Hz)7.64(td,1H,1.2及8.2 Hz)7.58-7.53(m,4H)7.50-7.44(m,3H)7.40(dd,1H,J=1.2及7.2 Hz)7.25(dd,1H,J=1.6及8.0 Hz)3.26-3.22(m,4H)MS(ESI,正電離子)m/z:460.4(M+1).
2-(2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇(化合物464
)使用實例10之製程,由5-溴-2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑化合物25a
(0.048 g,0.13 mmol)及化合物10e
(0.032g,0.20 mmol)製備標題化合物464
(0.013 g)。1
H-NMR(400 MHz,DMSO d6)δ(ppm)7.71(dd,J=1.26,8.08Hz,1H)7.45(d,J=7.8Hz,2H)7.37(d,J=8.34Hz,1H)7.31(d,J=8.08Hz,2H)7.20-7.26(m,2H)7.10(ddd,J=1.51,7.33,7.58Hz,1H)6.93-7.20(m,2H)3.14(m,4H)1.21(s,6H).MS(ESI,正電離子)m/z:425.1(M+1).
使用實例25所述之製程和化合物25a
以及熟習本項技術者熟知之試劑、起始物質及條件,下列代表本發明之化合物係由對應的乙烯基衍生物所製備:
使用實例22、23、24或25之製程及熟習本項技術者熟知之試劑、起始物質及條件,可製備下列預測之本發明代表化合物:
2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺(化合物190
)步驟A. 2-(4-三氟甲基-苯基)-環丙羧酸甲酯於三甲基碘化鋶(0.53 g,2.39 mmol)之8 mL的DMSO溶液中於25℃加入氫化鈉(0.06 g,2.39 mmol)。攪拌一小時後,加入4-三氟甲基肉桂酸甲酯(0.50 g,2.17 mmol)之4 mL DMSO溶液。以飽和的NH4
Cl溶液進行驟冷時,將反應混合物攪拌六小時。將生成的混合物以CH2
Cl2
萃取,將有機層以Na2
SO4
乾燥,過濾並將濾液濃縮。以層析純化殘餘物(矽膠,己烷:EtOAc,2:1)得標題化合物27a
之固體。
步驟B. 2-(4-三氟甲基-苯基)-環丙羧酸將化合物27a
之10 mL MeOH及4 mL of 1N LiOH(aq)溶液於70℃加熱4 h。然後將混合物以4N HCl(aq)酸化及以EtOAc萃取。將有機層以鹽水清洗,以Na2
SO4
乾燥,過濾並將濾液濃縮得到標題化合物27b
。1
H-NMR(400 MHz,CD3
OD)δ(ppm):7.56(d,2H)7.25(d,2H)2.39(m,1H)1.80(m,1H)1.47(m,1H)1.18(m,1H).
步驟C. 2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺於化合物16c
(0.140 g,0.438 mmol)及N-(3-二甲基胺基丙基)-N’-乙基碳二亞胺鹽酸鹽化合物27c
(0.060 g,0.313 mmol)之4 mL乙腈溶液中於rt緩慢加入化合物27b
(0.072 g,0.313 mmol)之2 mL 乙腈溶液。攪拌2小時後,將混合物通過一短管柱(矽膠,己烷:EtOAc,2:1)。收集溶離液並將殘餘物溶於AcOH中。將反應於80℃加熱3 h。將反應濃縮及以層析純化殘餘物(矽膠,己烷:EtOAc,2:1)。將此物質溶於TFA及將混合物於60℃加熱2 h。將反應濃縮及以層析純化殘餘物(矽膠,己烷:EtOAc,1:1)得到標題化合物190
之固體。1
H-NMR(400 MHz,CD3
OD)δ(ppm):8.14(dd,1H,J=1.2及7.6 Hz)7.74-7.63(m,6H)7.60-7.47(m,5H)7.40(dd,1H,J=1.6及7.2 Hz)2.97-2.92(m,1H)2.76-2.71(m,1H)2.12-2.00(m,2H)MS(ESI,正電離子)m/z:458.3(M+1).
2-(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇(化合物471
)步驟A. N-甲氧基-N-甲基-3-(4-三氟甲基-苯基)-丙烯醯胺於4-三氟甲基肉桂酸(3.6 g,16.7 mmol)之無水二氯甲烷(40 mL)溶液中緩慢加入草醯氯(1.7 mL,19.5 mmol)。與此溶液中加入無水二甲基甲醯胺(10 μL)及將反應於室溫及氬氣壓下攪拌。18 h後,將反應濃縮。將殘餘化合物10b(16.7 mmol)之二氯申烷(40 mL)於0℃逐滴加到N,N-二甲基羥基胺鹽酸鹽(1.6 g,16.7 mmol)及三乙胺(5.8 mL,41.7 mmol)之二氯甲烷(40 mL)溶液中。將反應混合物於0℃攪拌30分鐘,然後升溫至室溫。6 h後,將反應連續以碳酸鈉(10%水溶液)、水及鹽水清洗。將有機分溶液以硫酸鎂乾燥,過濾並將濾液濃縮。以層析純化化合物(矽膠,EtOAc:己烷s,1:1)得到標題化合物28a(2.2 g,50%於二個步驟)。1
H-NMR(400 MHz,DMSO d6)δ(ppm)7.96(d,J=8.3Hz,2H).7.78(d,J=8.08Hz,2H)7.64(d,J=15.9Hz,1H)7.24(d,J=15.9Hz,1H)3.77(s,3H)3.23(s,3H).
步驟B. 2-(4-三氟甲基-苯基)-環丙羧酸甲氧基-甲基-醯胺將無水的二甲基亞碸(8 mL)於氬氣壓下逐滴加到氫化鈉(60%油懸浮液,0.369 g,9.2 mmol)及三甲基碘化亞碸(2 g,9.1 mmol)之混合物中。於溶液中逐滴加入化合物28a
(1.2g,4.6 mmol)之DMSO(8 mL)溶液。將反應混合物於室溫下攪拌18小時。將反應倒入乙醚:水(1:1,50 mL)中。將有機層分離並連續以水和鹽水清洗。將有機分溶液以釐酸鎂乾燥,過濾並將濾液濃縮得到標題化合物28b
(1.9 g,90%)。1
H-NMR(400 MHz,CDCl3
)δ(ppm)7.55(d,J=8.08Hz,2H)7.25(d,J=8.3Hz,2H)3.72(s,3H)3.26(s,3H)2.54-2.59(m,1H)2.43-2.52(m,1H)1.68-1.74(m,1H)1.33-1.38(m,1H).
步驟C. 2-(4-三氟甲基-苯基)-環丙羧酸於化合物28b
(3.6g,13.2 mmol)之四氫呋喃(45 mL)溶液中加入第三丁醇鉀溶液(1 M之四氫呋喃溶液,50 mL,50 mmol)。於反應中加入水(1.5 mL,83.3 mmol)及將反應於室溫及氬氣壓下攪拌。18 h後,將冰加到反應中直到變成均質。於溶液中加入乙醚及進行分層。將水層冷卻並以1 M HCl酸化直到pH為4。以醋酸乙酯萃取水層。連續以水和鹽水清洗醋酸乙酯層。將有機層以硫酸鎂乾燥,過濾並將濾液濃縮得到標題化合物28c
(2.2 g,73%)。1
H-NMR(400 MHz,DMSO d6)δ(ppm)12.4(s,1H)7.62(d,J=8.08Hz,2H)7.40(d,J=8.08Hz,2H)2.46-2.54(m,1H)1.88-1.96(m,1H)1.46-1.52(m,1H)1.38-1.44(m,1H).
步驟D. 5-溴-2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑使用實例1之製程,由化合物28c及4-溴苯-1,2-二胺製備標題化合物28d
。1
H-NMR(400 MHz,DMSO d6)δ(ppm)7.96(s,1H)7.68-7.75(m,3H)7.60-7.64(dd,J=1.5,8.6Hz,1H)7.46-7.56(m,4H)7.10-7.14(d,J=8.4Hz,2H)2.96-3.02(m,1H)2.70-2.78(m,1H)2.10-2.16(m,1H)2.00-2.08(m,1H).
步驟E. 2-(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇使用實例10之製程,由化合物28d
及化合物10e
製備標題化合物471
。1
H-NMR(400 MHz,CD3
OD)δ(ppm)12.4(s,0.5H)12.32(s,0.5H)7.88(m,1H)7.65(d,2H,J=8.084 Hz)7.46(m,2H)7.35(m,2H)7.20(m,1H)6.95(m,2H)4.85(s,1H)2.70(m,1H)2.46(m,1H)1.90(m,1H)1.70(m,1H)1.20(d,6H).MS(ESI,正電離子)m/z:437.2(M+1).
使用實例28所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,下列代表本發明之化合物係由對應的乙烯基衍生物所製備:
使用實例27或28之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列本發明之預測化合物代表:
2-[2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯基]-丙-2-醇(化合物489
)步驟A. (E)-5-溴-2-(2-氯-2-苯基-乙烯基)-1H-苯并咪唑將4-溴-苯-1,2-二胺二鹽酸鹽(1.3 g,5 mmol)、苯基丙炔酸(0.73 g,5 mmol)之4 mL乙二醇混合物加熱回流5 h。將混合物冷卻至rt及倒入水中。將混合物以2N氫氧化鈉中和並過濾。將固體懸浮於水中並以醋酸乙酯萃取。將有機層組合以無水硫酸鈉乾燥並過濾。將濾液濃縮產生紅色油狀物。使用製備式TLC板純化殘餘物二次(矽膠,20 X 20 cm,2000微米,EtOAc:己烷3:7及矽膠,20 X 20 cm,2000微米,EtOAc二氯甲烷3:97)得到標題化合物30a(0.345 g)之順式和反式異構物之混合物。1
H NMR(400 MHz,DMSO-d6
)δ(ppm):12.59(m,1H),7.86-7.78(m,3H),7.64-7.56(m,1H),7.54-7.49(m,3H),7.46(s,1H),7.40-7.34(m,1H).質譜(LCMS,APCI正電)C15
H10
BrClN2
之理論值:333.0(M+H),實測值333.1.
步驟B. 2-[2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯基]-丙-2-醇將化合物30a
(25 mg,0.075 mmol)、化合物10e
(18 mg,0.113 mmol)及Pd(dppf)Cl2
CH2
Cl2
(12 mg,0.015 mmol)之3 Ml的DME及碳酸鈉溶液(1.0 M,0.6 mL)混合物於Biotage InitiatorTM
微波合成器中以150℃加熱1h。將混合物經由矽膠墊過濾。總計將反應重複三次。將殘餘物組合,使用製備式TLC板純化二次(矽膠,20 X 20 cm,2000微米,EtOAc:己烷3:7,然後矽膠,20 X 20 cm,2000微米,EtOAc:己烷:甲醇2:8:1)得到標題化合物489
(8.4 mg)。1
H NMR(400 MHz,CD3
OD)δ(ppm):7.78(dd,1H,J=8.1,1.1Hz,1H),7.62-7.60(m,2H),7.52(d,1H,J=8.3 Hz),7.46-7.38(m,4H),7.31(dt,1H,J=1.5,8.0 Hz),7.21-7.17(m,2H),7.02(dd,J=7.5,1.3 Hz,1H),1.30(s,6H).質譜(LCMS,APCI正電)C24
H20
N2
O之理論值:353.2(M+H),實測值353.3.
2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯磺醯胺(化合物490
)步驟A. N-第三-丁基-2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯磺醯胺將化合物30a
(25 mg,0.075 mmol)、2-(第三丁基胺基)磺醯基苯基硼酸(29 mg,0.113 mmol)及Pd(dppf)Cl2
.CH2
Cl2
(12 mg,0.015 mmol)之3 mL的DME及碳酸鈉溶液(1.0 M,0.6 mL)混合物於Biotage InitiatorTM
微波合成器中以150℃加熱1h。將混合物經由矽膠墊過濾。將殘餘物以製備式TLC純化(矽膠,20 X 20 cm,2000微米,EtOAc:己烷3:7)得到標題化合物31a
(12.8 mg)。質譜(LCMS,APCI正電)C25
H23
N3
O2
S之理論值:430.2(M+H),實測值430.3.
步驟B. 2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯磺醯胺將化合物31a
(14.9 mg,0.034 mmol)之三氟醋酸及1,2-二氯乙烷(2 mL,1:1)於90℃加熱3 h。將反應冷卻至rt及減壓濃縮。將殘餘物溶於二氯甲烷中及以飽和的碳酸氫鈉溶液清洗。將水層以醋酸乙酯萃取二次。將有機層組合,以無水硫酸鎂乾燥,過濾並減壓移除濾液。使製備式TLC板純化殘餘物(矽膠,20 X 20 cm,2000微米,EtOAc:己烷:甲醇5:5:1)得到標題化合物490
(12.1 mg)。1
H NMR(400 MHz,CD3
OD)δ(ppm):8.11(dd,1H,J=8.0,1.2 Hz),7.67-7.56(m,5H),7.52(ddd,1H,J=7.6,6.4,1.4 Hz),7.48-7.33(m,5H).質譜(LCMS,ESI正電)C21
H15
N3
O2
S之理論值:374.1(M+H),實測值374.2.
使用實例30及31所述之製程以及熟習本項技術者熟知之試劑、起始物質及條件,下列代表本發明之化合物係由對應的乙烯基衍生物所製備:
然後以2N鹽酸酸化。以醋酸乙酯萃取水層。將有機層組合及以無水硫酸鈉和硫酸鎂乾燥。將混合物過濾並將濾液減壓濃縮產生標題化合物31b
之白色固體(5.4 g,87%)。1
H NMR(400MHz,DMSO-d6
)δ(ppm):7.81(s,4H)。使用實例31之製程將化合物31b
繼續作用得到標題化合物492
。
使用實例30或31之製程、對應的溴苯并咪唑及,當無法從市面上購得時,如反應流程KK之描述所製備的芳基炔酸前驅物以及熟習本項技術者熟知之試劑、起始物質及條件,可製備下列本發明之預測化合物代表。另外,下列化合物可由其對應的乙烯基化合物藉由氫化來製備:
(E)-2-{2-[2-(2-喹啉6-基-乙烯基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇(化合物449
)步驟A. 5-溴-2-氯甲基-1H-苯并咪唑將4-溴-苯-1,2-二胺(200 mg,1.07 mmol)及2-氯乙醯亞胺酸乙酯鹽酸鹽(168 mg,1.07 mmol;根據J.Med.Chem. 1986,
29,2280中描述之製程所製備)之無水乙醇(200度,5 mL)溶液於室溫下攪拌4 h。將反應混合物減壓濃縮並以醋酸乙酯及水萃取。將有機層以Na2
SO4
乾燥,過濾並將濾液真空濃縮得到標題化合物33a
之灰白色固體(240 mg,92%產率)。1
H NMR(400MHz,CDCl3
)δ(ppm):7.75(d,1H,J=l.4Hz),7.47(d,1H,J=8.6Hz),7.42(dd,1H,J=8.6Hz,J=1.3Hz),4.84(s,2H).質譜(LCMS,ESI正電)C18
H20
CIN3
O2
S:247.50(M+H),實測值247.0.
步驟B. (5-溴-1H-苯并咪唑-2-基甲基)-三苯基-氯化鏻將化合物33a
(240 mg,0.98 mmol)及三苯基膦(385 mg,1.47 mmol)之1,2-二氯乙烷(10 mL)混合物於140℃加熱1小時。將反應混合物減壓濃縮得到標題化合物33b
,將其用於下個步驟不需進一步純化。
步驟C. (E)-6-[2-(5-溴-1H-苯并咪唑-2-基)-乙烯基]-喹啉將化合物33b
(100 mg,0.204 mmol)、6-喹啉甲醛(32 mg,0.29 mmol)及DBU(39.6 uL,0.265 mmol)之乙醇:四氫呋喃(1:1,2 mL)混合物於室溫下攪拌12 h。將反應混合物減壓濃縮及以逆相製備式TLC純化殘餘物(10-100%梯度乙腈/水,於10 min內)得到標題化合物33c
之灰白色固體(50 mg,72 產率)。C18
H12
BrN3
之理論值:350.21(M+H),實測值350.2。
步驟D. (E)-2-{2-[2-(2-喹啉6-基-乙烯基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇將化合物33c
(50.0 mg,0.143 mmol)、化合物10e
(46 mg,0.29 mmol)、PdCl2
(dppf)(23.4 mg,0.029 mmol)及1M碳酸氫鈉溶液(1.15 mL,1.15 mmol)之1,2-二甲氧基乙烷(1 mL)混合物加熱回流12 h。將反應混合物減壓濃縮。以層析純化殘餘物(矽膠,EtOAc)得到標題化合物449
之灰白色固體(11.8 mg,20%產率)。1
H NMR(400MHz,CD3
OD)δ(ppm):9.01(br s,1H),8.68(d,1H,J=8.1Hz),8.35(m,2H),8.12-8.21(m,2H),7.76(m,3H),7.67(s,1H),7.53(m,2H),7.38-7.43(m,1H),7.28(m,1H),7.09(m,1H),1.42(s,6H).C27
H23
N3
O之理論值:406.5(M+H),實測值406.3.
使用實例33所述之製程以及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯甲基胺(化合物486
)步驟A. (E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲腈將化合物10c
(52 mg,0.14 mmol)、2-氰基苯基硼酸(38 mg,0.26 mmol)、Pd(dppf)Cl2
CH2
Cl2
(36 mg,0.044 mmol)、四丁基溴化銨(55 mg,0.17 mmol)及碳酸鈉(1 mL,1.0 M)之DME(5 mL)混合物於90℃加熱18 h。將混合物冷卻至rt,經由矽藻土過濾及減壓濃縮。使用製備式TLC板純化殘餘物(矽膠,20 X 20 cm,2000微米,EtOAc:己烷1:1及己烷:二氯甲烷:甲醇6:14:1)得到標題化合物34a(20 mg,37%)。1
H NMR(400 MHz,CD3
OD+CDCI3
)δ(ppm):7.72-7.47(m,10H),7.40-7.30(m,3H),7.14(d,1H,J=16.55 Hz).質譜(LCMS,APCI正電)C23
H14
F3
N3
之理論值:390.1(M+H),實測值390.3.
步驟B. 2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯甲基胺將化合物34a
(20 mg,0.051 mmol)、雷尼鎳(Raney-Nickel)、氫氧化銨(0.1 mL)之乙醇混合物於50 psi氫化18 h。經由矽藻土過濾及以乙醇清洗。將濾液減壓濃縮。使用製備式TLC板純化殘餘物(矽膠,20 X 20 cm,2000微米,NH3
溶於甲醇:EtOAc 1:9)得到標題化合物486
(6.3 mg,31%)。1
H NMR(400 MHz,CD3
OD)δ(ppm):7.57-7.52(m,4H),7.46-7.34(m,6H),7.14(dd,J=8.2,1.5 Hz,1H),4.05(s,2H),3.24(s,4H).質譜(LCMS,APCI正電)C23
H20
F3
N3
之理論值:396.2(M+H),實測值396.2.
(Z)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇(化合物469
)將化合物18
(0.030 g,0.07 mmol)之DMSO(5 mL)溶液於60W燈泡下及室溫下攪拌5天。然後將反應使用2000微米之製備式TLC板(20 X 20 cm)及使用醋酸乙酯:己烷4:6展開。將所欲的條帶以MeOH萃取,過濾並濃縮得到標題化合物469
(0.001 g)。1
H-NMR(400 MHz,DMSO d6)δ(ppm)7.71(dd,J=1.01,8.34Hz,1H)7.53(s,4H)7.37-7.41(m,1H)7.21-7.28(m,2H)7.11(dt,J=1.26,7.33Hz,1H)7.05(dd,J=1.52,8.34Hz,1H),6.94-7.10(m,4H)6.67(d,12.6Hz,1H)1.23(s,6H).MS(ESI,正電離子)m/z:423.2(M+1).
(E)-N-(2-{3-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-3H-苯并咪唑-5-基}-苯基)-甲磺醯胺(化合物443
)(E)-N-(2-{1-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺(化合物477
)步驟A. (E)-5-溴-1-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑及(E)-6-溴-1-甲基-2-[2-(4-三氟甲基苯基)-乙烯基]-1H-苯并咪唑於氫化鈉(60%油懸浮液,0.131 g,3.2 mmol)之無水四氫呋喃(10 mL)溶液中加入化合物10c
(1 g,2.7 mmol)。將溶液於室溫及氬氣壓下攪拌。五分鐘後,加入碘甲烷(0.205 mL,3.2 mmol)及並將溶液於室溫下攪拌3 h。將反應混合物置於醋酸乙酯(10 mL)及冰水(20 mL)中分溶。將有機分溶液以鹽水清洗,以硫酸鎂乾燥,然後過濾及濃縮,得到標題化合物36a及36b
(0.38g)之1:1混合物。
步驟B. (E)-N-(2-{3-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-3H-苯并咪唑-5-基}-苯基)-甲磺醯胺及(E)-N-(2-{1-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺使用實例1步驟B之製程,由(E)-5-溴-1-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑和(E)-6-溴-1-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑及2-甲基磺醯基胺基苯基硼酸之混合物製備標題化合物。
化合物443
:1
H-NMR(400 MHz,CD3
OD)δ(ppm)7.82-7.80(m,3H)7.75(d,J=8.1Hz,3H)7.52-7.62(m,3H)7.34-7.42(m,4H)4.00(s,3H)2.76(s,3H).MS(ESI,正電離子)m/z:472.1(M+1).
化合物477
:1
H-NMR(400 MHz,CD3
OD)S(ppm)7.88-7.95(m,3H)7.72-7.77(m,3H)7.56-7.67(m,4H)7.40-7.44(m,3H)4.10(s,3H)2.73(s,3H).MS(ESI,正電離子)m/z:472.1(M+1).
(E)-2-羥基-1-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮(化合物311
)步驟A. (E)-2-[2-(4-三氟甲基-苯基)-乙烯基]-5-[2-(1-三甲基矽烷基氧基-乙烯基)-苯基]-1H-苯并咪唑於化合物15
(0.20 g,0.492 mmol)之16 mL 1,2-二氯乙烷之溶液中於0℃加入TBSOTf(0.19 mL,1.08 mmol)及Et3
N(0.27 mL,1.97 mmol)。5 min後,將混合物升溫至25℃並攪拌8小時。將反應濃縮及以層析純化殘餘物(矽膠,己烷:EtOAc,4:1)得到標題化合物37a
之無色油狀物。
步驟B. (E)-2-[2-(4-三氟甲基-苯基)-乙烯基]-5-[2-(2-三甲基矽烷基氧基-環氧乙烷基)-苯基]-1H-苯并咪唑將化合物37a
(0.124 g,0.238 mmol)及mCPBA(0.053g ,0.238 mmol)之10 mL CH2
Cl2
混合物攪拌二小時。將反應濃縮並以層析純化殘餘物(矽膠,己烷:EtOAc,4:1)得到標題化合物37b
之黃色油狀物。
步驟C. (E)-2-羥基-1-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮將化合物37b
(0.026 g,0.048 mmol)及對甲苯磺酸單水合物(p-TsOHH2
O,0.018 g,0.0968 mmol)之4 mL THE混合物攪拌四小時。將反應濃縮並以層析純化殘餘物(矽膠,己烷:EtOAc,1:2)得到標題化合物311
之棕色固體。1
H-NMR(400 MHz,CD3
OD)δ(ppm):7.85(d,2H,J=8.8 Hz)7.74(d,2H,J=7.6 Hz)7.71(d,1H,J=16.4 Hz)7.63-7.47(m,6H)7.33(d,1H,J=16.0 Hz)7.25(dd,1H,J=1.6及8.4 Hz)4.08(s,2H)MS(ESI,正電離子)m/z:423.3(M+1).
2-(2-{2-[(1R,2R)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇(化合物501
)步驟A. (1 R,2R)-2-(4-三氟甲基-苯基)-環丙羧酸乙酯於三氟甲磺酸銅(I)甲苯複合物(31.0 mg,0.12 mmol)之無水CHCl3
(3.0 mL)懸浮液中加入2,2-雙-[(4S)-(1,1-二甲基乙基)-1,3-唑啉-2-基]丙烷(35 mg,0.12 mmol)之氯仿(1.2 mL)溶液。於周圍溫度攪拌1 h後,將生成的綠色溶液於氬氣壓下經由玻璃棉過濾至預先裝入4-(三氟甲基)-苯乙烯(0.887 mL,6.00 mmol)之氯仿(0.9 mL)溶液的燒瓶中。於周圍溫度下經由滴液漏斗於6 h期間在此溶液中加入二偶氮醋酸乙酯(1.56 mL,15.0 mmol)之氯仿(12.0 mL)溶液。將生成的混合物攪拌24 h,濃縮至乾並以快速層析於矽膠管柱(45 mm X 140 mm矽膠)上,以醋酸乙酯/己烷(1,1.5,2%)溶離純化得到標題化合物38a
(892 mg,58%產率,98% ee)之無色液體及順式異構物(1 R,2S)-2-(4-三氟甲基-基)-環丙羧酸乙酯化合物38b
(128 mg,5%產率,由1 NMR以含有34 wt%之延胡索酸乙酯分析為基準所計算)。如下文步驟E中所述,測定產物鏡像異構物超度。
化合物38a
之1
H-NMR(400 MHz,CDCl3
)δ(ppm):7.53(d,2H,J=8.3 Hz),7.23(d,2 H,J=8.1Hz),4.18(q,2 H,J=7.1Hz),2.55(dd,1H,J=2.6,4.3,& 6.6 Hz),1.94(ddd,1H,J=4.3,5.6,& 9.6 Hz),1.68-1.53(m,1H),1.34(1H,ddd,4.8,6.7,& 1.1Hz),1.29(t,2H,J=7.0 Hz).
化合物38b
之1H-NMR(400 MHz,CDCl3
)δ(ppm):7.51(d,2H,J=7.9 Hz),7.37(d,2H,J=7.8 Hz),3.92-3.86(m,2H),2.62-2.56(m,1H),2.14(ddd,1H,J=5.8,8.1 & 9.3 Hz),1.73(td,1H,J=5.3 & 7.6 Hz),1.39(ddd,1H,J=5.1,7.8 & 8.6 Hz),0.99(t,3H,J=7.1Hz).
步驟B. (1 R,2R)-2-(4-三氟甲基-苯基)-環丙羧酸於化合物38a
(750 mg,2.91 mmol)之乙醇(7.27 mL)溶液中加入1M的NaOH水溶液(7.27 mL)。將生成的混合物於周圍溫度下攪拌16 h,濃縮至約4 g,以2M HCl酸化至pH 3及以醋酸乙酯萃取(15 mL x 2)。將萃取液組合,以鹽水清洗,以Na2
SO4
乾燥,濃縮得到標題化合物38c
(611 mg,91%產率)之白色固體。1
H-NMR(400 MHz,CDCl3
帶有一滴CD3
OD)δ(ppm):7.51(d,2H,J=8.3 Hz),7.18(d,2H,J=8.1Hz),2.57(ddd,1H,J=4.2,6.6,& 10.3 Hz),1.90(ddd,1H,J=4.0,5.3,& 8.3 Hz),1.65(dt,1H,J=4.9 & 9.3 Hz),1.35(ddd,1H,J=4.9,6.4,& 11.1Hz).
步驟C:2-(2-{2-[(1 R,2R)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇使用實例10步驟B及E之製程,由化合物38c
製備標題化合物501。1
H-NMR(400 MHz,DMSO-d6)δ(ppm):12.40(s,0.5 H),12.32(s,0.5 H),7.87-7.84(m,1H),7.66(d,2H,J=8.0 Hz),7.49-7.17(m,6H),7.00-6.96(m,2H),4.84
(s,1H),2.72-2.67(m,1H),2.50-2.46(m,1H),1.92-1.86(m,1H),1.74-1.68(m,1H),1.19(s,3H),1.18(s,3H).質譜(LCMS,ESI正電)C26
H24
F3
N2
O之理論值:437.2.實測值437.3.
步驟D:(1R,2R)-2-(4-三氟甲基-苯基)-環丙羧酸甲氧基-甲基-醯胺於化合物38c
(50 mg,0.216 mmol)、N,O-二甲基羥基胺鹽酸鹽(30 mg,0.30 mmol)、BOP(134 mg,0.30 mmol)及DMF(0.4 mL)之混合物中加入DIEA(0.15 mL)。將生成的混合物於周圍溫度下攪拌48h,濃縮至乾以及置於飽和的NaHCO3
(2 mL)及醋酸乙酯(4 mL)間分溶。將醋酸乙酯層分離出並以醋酸乙酯(5 mL X 2)萃取水層。將所有的醋酸乙酯層組合,以鹽水清洗,以Na2
SO4
乾燥,濃縮並以置備式-TLC純化,以10%醋酸乙酯/DCM展開,得到化合物38d
(46 mg,78%產率)之白色固體。1
H-NMR(400 MHz,CDCl3
)δ(ppm):7.52(d,2H,J=8.4 Hz),7.23(d,2H,J=8.1Hz),3.70(s,3H),3.24(s,3H),2.56-2.52(m,1H),2.45(bs,1H),2.17-1.67(m,1H),1.34(ddd,1H,J=4.6,6.3,& 8.7 Hz).
步驟E:ee之測定:於化合物38d
(0.8 mg)之CDCl3
(0.6 mL)溶液中逐滴加入(R)-(-)-2,2,2-三氟-1-(9-蒽基)乙醇並以1
HNMR監看添加量直到所生成的甲氧基單峰達到基礎解析度。由此,鏡像異構物甲氧基單峰約為3.47及3.45 ppm。整合這些單峰分別為1及99;因此得到99%之ee值。
使用實例38中所述之製程及熟習本項技術者熟知之試劑、起始物質及條件,製備下列代表本發明之化合物:
人類VR1(hVR1)結合分析
於如前述(Zhang,Sui-Po.Improved ligand binding assays for vanilloid receptors.
PCT Int.Appl.(2002),WO 0233411 A1 20020425 AN 2002:315209,及Elfrida G.R.等人,J.Pharmacol.Exp.
Thor.,2002,300(1):9-17.)之[3
H]RTX結合分析試驗本發明化合物其抑制[3
H]RTX與hVR1受體結合之能力。
將HEK293細胞以類香草素受體轉染及以漢克氏(Hank’s)平衡鹽溶液清洗,以細胞解離緩衝液(Sigma)解離,然後以1000 x g離心5 min。將底部細胞置於含有5.8 mM NaCl、320 mM蔗糖、2 mM MgCl2
、0.75 CaCl2
及5 mM KCl之冷的20 mM HEPES緩衝液(pH=7.4)中均質,並以1000 x g離心15 min。然後將產生的上清液以40,000 x g離心15 min。將底部胞膜儲存於-80℃之冷凍庫中。
將來自胞膜之大約120 μ g蛋白/ml以指示[3
H]RTX濃度之0.5 ml的HEPES緩衝液(pH 7.4)(含有0.25 mg/mL無脂肪酸之牛血清白蛋白)於37℃培養60 min。然後將反應混合物冷卻至4℃及並於各樣本中加入0.1 mg的α1
-酸糖蛋白,然後將其於4℃培養15 min。將樣本以18,500 x g離心15 min。將含有底部團塊之微量離心管尖部剪下。以閃爍計數定量結合放射活性。在200 nM未標定RTX之存在下測量非專一性結合。
數據係根據下列方程式所計算:抑制%=100% x[(總結合-結合)/(總結合量-非專一性結合)]
Ki
值係使用Prism程式來計算。
人類VR1(hVR1)功能分析
試驗化合物之功能活性係使用Ca++
-敏感螢光染劑及FLIPRTM
技術藉由測量胞內鈣濃度之變化來測定。因使用辣椒素可容易偵測Ca++
濃度之增加。
將表現hVR1之HEK293細胞培養於塗覆聚-D-離胺酸之384孔黑壁測定盤(BD 354663)中,1天後於37℃及5% CO2
下載入鈣3染劑35 min,然後於室溫下放置25 min,隨後進行使用FLIPRTM
技術進行促進劑引起之胞內Ca2+
量增加。以試驗化合物刺激細胞(各種濃度)以及於所有孔槽中添加辣椒素使最終濃度達到0.030 μM引起約80%最大反應,之後測量胞內Ca2+
5分鐘。由濃度反應研究測定IC50
值,其通常係使用各數據點四重複孔槽之平均所產生。
就該等所試驗之化合物,IC50
(nM)值及抑制百分比之值係如表2所示。除了指出處,該抑制百分比之值係於1 μM之試驗濃度所得到。其他:(1)
試驗濃度為5 μM。在無得到IC50
值處得到該等化合物抑制百分比之值。術語「NA」係指「沒有」該數據,因為沒有得到特定化合物之數據。
化學所引起之發炎疼痛模式
於動物之發炎及發炎疼痛模式中試驗本發明化合物。為了評估試驗化合物消退熱痛覺過敏之能力,係在雄性Sprague-Dawley大鼠腳底注射100 μ L(1 μ g/μ L)CFA(1:1 CFA:鹽水)之前,得到輻射熱(RH)爪刺激物之基礎反應潛伏。僅記錄快速後爪移動之戒斷反應(有或無拍打後爪)。與運動或重量移位有關之爪移動部並不視為戒斷反應。使用產生10-15秒基礎戒斷潛伏期之刺激強度並施以20秒之最大截斷。給予CFA 24小時後評估過敏反應。僅將展現至少降低25%之基礎反應潛伏(亦即痛覺過敏)之大鼠納入進一步分析。
致發炎後潛伏評估之後,口服給予大鼠(2.5 mL/kg)試驗化合物(10 mg/kg)或媒劑(20%羥基丙基β環葡聚糖)。在投予化合物30、60、100、180及300分鐘後在測定潛伏期,以測定高峰效用之時間。
數據係以300分鐘的試驗期間所得到之過敏反應之最大消退百分比來表示,其係根據下列方程式對各動物所計算出:消退%=100% x(治療反應-致發炎後反應)/(致發炎前反應-致發炎後反應)
術後之切口引發模式
如前述(Brennan,T.J.等人,Pain,
1996,64:493-501)以動物之術後模式試驗本發明化合物。以2-3%異氟烷將雄性Sprague-Dawley大鼠麻醉及使用三種交替之優碘及酒精擦拭消毒後爪之足底表面。使用10號解剖刀由足跟底部0.5 cm開始向腳指延伸經由腳底皮膚切開一個1 cm的縱向切口。使用鑷子及縱向切割將足底肌肉切除。然後使用5-0絲線將二處皮膚縫合。然後在受傷部位塗覆上抗生素軟膏並讓動物回到其各自的籠子中。在受術前及受術後24小時評估熱敏感度之變化。口服給予媒劑(20% HP(3CD)或試驗化合物並在30、60、100、180及300分鐘後再次評估熱敏感度。
數據係以300分鐘的試驗期間所得到之過敏反應之最大消退百分比來表示,其係根據下列方程式對各動物所計算出:消退%=100% x(治療反應-致發炎後反應)/(致發炎前反應-致發炎後反應)
在前述說明中以說明為目的提供實例來教導本發明原理之同時,應了解,本發明之施行包含了所有常見的變化,調整及/或修正,如同在下列申請專利範圍及其同等之範圍內。
於上述說明中所揭示之所有的刊物其全文係以引用的方式併入本文中。
Claims (17)
- 一種式(I)化合物,
- 如申請專利範圍第1項之化合物,其中q為0。
- 如申請專利範圍第1項之化合物,其中A1 係由下列組成之群中選出苯基、聯苯、萘基、喹啉基及吲哚。
- 如申請專利範圍第1項之化合物,其中R1 各係由下列組成之群中選出:羥基、鹵素、甲醯基、C1-6 烷基、鹵基C1-6 烷基、鹵基C1-6 烷氧基、C1-6 烷基羰基、C1-6 烷氧基羰基、C1-6 烷基硫基、C1-6 烷基磺醯基、胺基、胺基羰基、C1-6 烷基羰基胺基、C1-6 烷氧基羰基胺基、C1-6 烷基磺醯基胺基、胺基磺醯基、(C1-4 烷基)1-2 胺基磺醯基及胺基磺醯基胺基,其中烷基係視需要經胺基、(C1-4 烷基)1-2 胺基、胺基磺醯基胺基或羥基取代,且其中烷基係視需要全氟化。
- 如申請專利範圍第1項之化合物,其中R2 係由鹵素及C1-4 烷基組成之群中選出,其中烷基係視需要全氟化。
- 如申請專利範圍第1項之化合物,其中R3a 及R3b 各係由氫及C1-4 烷基組成之群中選出。
- 如申請專利範圍第1項之化合物,其中R4 各係由下列組成之群中選出:鹵素、羧基、C1-6 烷基、C1-6 烷氧基、鹵基C1-6 烷基、鹵基C1-6 烷氧基、C1-6 烷基羰基、鹵基C1-6 烷基硫基、C1-6 烷基磺醯基、鹵基C1-6 烷基磺醯基、(C1-6 烷基)1-2 胺基、(C1-6 烷基)1-2 胺基羰基、C1-6 烷基羰基胺基、C1-6 烷基磺醯基胺基及鹵基C1-6 烷基磺醯基胺基,其中烷基及烷氧基係視需要全氟化。
- 如申請專利範圍第1項之化合物,其中p為1或2;q為0;r為0、1、2或3;L為C1-3 烷基、C2-3 烯基、C2-3 炔基或環丙基;A1 係由下列組成之群中選出:苯基、聯苯、萘基、喹啉基及吲哚;R1 各係由下列組成之群中選出:羥基、鹵素、甲醯基、C1-6 烷基、鹵基C1-6 烷基、鹵基C1-6 烷氧基、C1-6 烷基羰基、C1-6 烷氧基羰基、C1-6 烷基硫基、C1-6 烷基磺醯基、胺基、胺基羰基、C1-6 烷基羰基胺基、C1-6 烷氧基羰基胺基、C1-6 烷基磺醯基胺基、胺基磺醯基、(C1-4 烷基)1-2 胺基磺醯基及胺基磺醯基胺基,其中烷基係視需要經胺基、(C1-4 烷基)1-2 胺基、胺基磺醯基胺基或羥基取代,且其中烷基係視需要全氟化;R2 係由鹵素及C1-4 烷基組成之群中選出,其中烷基係視需 要全氟化;R3a 及R3b 各係由氫及C1-4 烷基組成之群中選出;及R4 各係由下列組成之群中選出:鹵素、羧基、C1-6 烷基、C1-6 烷氧基、鹵基C1-6 烷基、鹵基C1-6 烷氧基、C1-6 烷基羰基、鹵基C1-6 烷基硫基、C1-6 烷基磺醯基、鹵基C1-6 烷基磺醯基、(C1-6 烷基)1-2 胺基、(C1-6 烷基)1-2 胺基羰基、C1-6 烷基羰基胺基、C1-6 烷基磺醯基胺基及鹵基C1-6 烷基磺醯基胺基,其中烷基及烷氧基係視需要全氟化。
- 一種由下列組成之群中選出之化合物:(E)-1-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚,(E)-N-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-3-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-4-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-N-(4-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-苯基)-乙醯胺,(E)-N-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-胺甲酸第三-丁酯,(E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基胺,(E)-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚,(E)-1-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-N-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-1-(2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-N-(2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-(2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-N-(2-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-N-(3-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-2-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-1-(2-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-N-(2-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-{2-[3-(4-第三-丁基-苯基)-丙基]-1H-苯并咪唑-5-基}-酚,2-[3-(4-第三-丁基-苯基)-丙基]-5-m-甲苯基-1H-苯并咪唑,N-(2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-{2-[2-(4-第三-丁基-苯基)-乙基]-1H-苯并咪唑-5- 基}-酚,3-{2-[2-(4-第三-丁基-苯基)-乙基]-1H-苯并咪唑-5-基}-酚,4-{2-[2-(4-第三-丁基-苯基)-乙基]-1H-苯并咪唑-5-基}-酚,(E)-(2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚,(E)-N-(2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-1-(2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚,(E)-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-N-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-苯甲醯胺,(E)-1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,1-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-2-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-酚,(E)-3-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-酚,(E)-N-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-2-[2-(4-第三-丁基-苯基)-乙烯基]-5-(2-氟-苯基)-6-三氟甲基-1H-苯并咪唑e,(E)-2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-苯基)-胺甲酸第三-丁酯,(E)-N-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-6-三氟甲基-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{6-三氟甲基-2-[2-(4-三氟甲基-苯基)-乙烯 基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-1-(2-{6-三氟甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-(2-{6-三氟甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚,(E)-3-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-酚,(E)-(2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-1-(2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醯胺,(E)-N-(2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-N-(2-{6-氟-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-(2-{6-氯-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-1-(2-{6-氯-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-2-{6-氯-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯 并咪唑-5-基}-酚,(E)-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-C,C,C-三氟-N-(2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-C,C,C-三氟-N-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-C,C,C-三氟-N-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-1-(2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-N-(2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-(2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-(2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5- 基}-苯基)-C,C,C-三氟-甲磺醯胺,(E)-1-(2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-N-(2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-(2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-C,C,C-三氟-N-(2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-1-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-乙酮,(E)-1-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-乙醇,(E)-N-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,(E)-2-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,(E)-2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯磺醯胺,(E)-C,C,C-三氟-N-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲 基-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,(E)-1-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-乙酮,(E)-1-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-乙醇,(E)-N-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,(E)-2-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,(E)-2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯磺醯胺,(E)-C,C,C-三氟-N-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,(E)-1-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-乙酮,(E)-1-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-乙醇,(E)-N-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,(E)-2-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,(E)-2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯磺醯胺, (E)-C,C,C-三氟-N-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙烯基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,(E)-1-(2-{2-[2-(3-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(3-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-N-(2-{2-[2-(3-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-(2-{2-[2-(3-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(3-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-(2-{2-[2-(3-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-C,C,C-三氟-甲磺醯胺,(E)-1-(2-{2-[2-(3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-1-(2-{2-[2-(3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醇,(E)-N-(2-{2-[2-(3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-(2-{2-[2-(3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑 -5-基}-苯磺醯胺,(E)-C,C,C-三氟-N-(2-{2-[2-(3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(4-{2-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯基)-甲磺醯胺,(E)-N-[4-(2-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙烯基)-苯基]-甲磺醯胺,(E)-N-(2-{2-[2-(4-甲磺醯基胺基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙烯基)-苯基]-甲磺醯胺,(E)-2-{2-[2-(4-甲磺醯基胺基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-C,C,C-三氟-N-(2-{2-[2-(4-甲磺醯基胺基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(4-{2-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯基)-C,C,C-三氟-甲磺醯胺,(E)-C,C,C-三氟-N-[4-(2-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙烯基)-苯基]-甲磺醯胺,(E)-C,C,C-三氟-N-(4-{2-[5-(2-甲磺醯基胺基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯基)-甲磺醯胺,(E)-C,C,C-三氟-N-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙烯基)-苯基]-甲磺醯胺,(E)-2-{2-[2-(4-三氟甲磺醯基胺基-苯基)-乙烯基]-1H- 苯并咪唑-5-基}-苯磺醯胺,(E)-C,C,C-三氟-N-(4-{2-[5-(2-三氟甲磺醯基胺基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯基)-甲磺醯胺,2-{2-[2-(4-三氟甲氧基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-三氟甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲氧基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-(2-{2-[2-(4-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(4-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(4-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(4-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[2-(4-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯 胺,N-(2-{2-[2-(4-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-C,C,C-三氟-甲磺醯胺,1-(2-{2-[2-(4-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(4-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(4-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(4-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[2-(4-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-乙酮,1-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-乙醇,N-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,2-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙 基}-1H-苯并咪唑-5-基)-苯磺醯胺,C,C,C-三氟-N-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,1-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基]-1H-苯并咪唑-5-基)-苯基]-乙酮,1-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-乙醇,N-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,2-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯磺醯胺,C,C,C-三氟-N-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,1-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-乙酮,1-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-乙醇,N-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,2-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇, 2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯磺醯胺,C,C,C-三氟-N-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-乙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,1-(2-{2-[2-(3-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(3-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(3-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(3-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-01,2-{2-[2-(3-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,N-(2-{2-[2-(3-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-C,C,C-三氟-甲磺醯胺,1-(2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇, 2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,N-(4-{2-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基]-乙基}-苯基)-甲磺醯胺,N-[4-(2-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙基)-苯基]-甲磺醯胺,N-(2-{2-[2-(4-甲磺醯基胺基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,N-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙基)-苯基]-甲磺醯胺,2-{2-[2-(4-甲磺醯基胺基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-甲磺醯基胺基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,N-(4-{2-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基]-乙基}-苯基)-C,C,C-三氟-甲磺醯胺,C,C,C-三氟-N-[4-(2-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙基)-苯基]-甲磺醯胺,C,C,C-三氟-N-(4-{2-[5-(2-甲磺醯基胺基-苯基)-1H-苯并咪唑-2-基]-乙基}-苯基)-甲磺醯胺,C,C,C-三氟-N-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙基)-苯基]-甲磺醯胺, 2-{2-[2-(4-三氟甲磺醯基胺基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲磺醯基胺基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-{2-[2-(4-三氟甲氧基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-三氟甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲氧基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-(2-{2-[2-(4-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(4-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(4-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(4-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇, 2-{2-[2-(4-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,N-(2-{2-[2-(4-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-C,C,C-三氟-甲磺醯胺,1-(2-{2-[2-(4-甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(4-甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(4-甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(4-甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[2-(4-甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-甲磺醯基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-乙酮,1-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-乙醇,N-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,2-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇, 2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯磺醯胺,C,C,C-三氟-N-[2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,1-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-乙酮,1-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-乙醇,N-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,2-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯磺醯胺,C,C,C-三氟-N-[2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,1-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-乙酮,1-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-乙醇,N-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,2-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-環丙 基}-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯磺醯胺,C,C,C-三氟-N-[2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基]-環丙基}-1H-苯并咪唑-5-基)-苯基]-甲磺醯胺,1-(2-{2-[2-(3-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[2-(3-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(3-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(3-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[2-(3-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,N-(2-{2-[2-(3-氯-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-C,C,C-三氟-甲磺醯胺,1-(2-{2-[2-(3-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙酮,-(2-{2-[2-(3-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[2-(3-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[2-(3-三氟甲基-苯基)-環丙基]-1H-苯并咪唑 -5-基}-苯基)-丙-2-醇,2-{2-[2-(3-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(3-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,N-(4-{2-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基]-環丙基}-苯基)-甲磺醯胺,N-[4-(2-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基}-環丙基)-苯基]-甲磺醯胺,N-(2-{2-[2-(4-甲磺醯基胺基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,N-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基}-環丙基)-苯基]-甲磺醯胺,2-{2-[2-(4-甲磺醯基胺基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-甲磺醯基胺基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,N-(4-{2-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基]-環丙基}-苯基)-C,C,C-三氟-甲磺醯胺,C,C,C-三氟-N-[4-(2-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基}-環丙基)-苯基]-甲磺醯胺,C,C,C-三氟-N-(4-{2-[5-(2-甲磺醯基胺基-苯基)-1H-苯并咪唑-2-基]-環丙基}-苯基)-甲磺醯胺,C,C,C-三氟-N-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯 基]-1H-苯并咪唑-2-基}-環丙基)-苯基]-甲磺醯胺,2-{2-[2-(4-三氟甲磺醯基胺基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[2-(4-三氟甲磺醯基胺基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-[2-(4-三氟甲氧基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,2-[2-(4-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,2-[2-(4-三氟甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,C,C,C-三氟-N-{2-[2-(4-三氟甲氧基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,C,C,C-三氟-N-{2-[2-(4-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,C,C,C-三氟-N-{2-[2-(4-三氟甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,1-{2-[2-(4-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙酮,1-{2-[2-(4-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙醇,N-{2-[2-(4-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,2-{2-[2-(4-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}- 丙-2-醇,2-[2-(4-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,N-{2-[2-(4-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-C,C,C-三氟-甲磺醯胺,1-{2-[2-(4-甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙酮,1-{2-[2-(4-甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙醇,N-{2-[2-(4-甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,2-{2-[2-(4-甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇,2-[2-(4-甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,C,C,C-三氟-N-{2-[2-(4-甲磺醯基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,1-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇, 2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[4-(2,2,2-三氟-1-三氟甲基-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[4-(2,2,2-三氟-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[4-(2,2,2-三氟-乙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-乙酮,1-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-乙醇,N-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇, 2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯磺醯胺,C,C,C-三氟-N-(2-{2-[4-(2,2,3,3,3-五氟-丙氧基)-苯基乙炔基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,1-{2-[2-(3-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙酮,2-{2-[2-(3-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇,N-{2-[2-(3-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,1-{2-[2-(3-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙醇,2-[2-(3-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,N-{2-[2-(3-氯-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-C,C,C-三氟-甲磺醯胺,1-{2-[2-(3-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙酮,1-{2-[2-(3-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-乙醇,N-{2-[2-(3-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,2-{2-[2-(3-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇,2-[2-(3-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯 磺醯胺,C,C,C-三氟-N-{2-[2-(3-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基)-甲磺醯胺,N-{4-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基-乙炔基]-苯基}-甲磺醯胺,N-(4-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基-乙炔基}-苯基)-甲磺醯胺,N-{2-[2-(4-甲磺醯基胺基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,N-(4-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基-乙炔基}-苯基)-甲磺醯胺,2-[2-(4-甲磺醯基胺基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯磺醯胺,C,C,C-三氟-N-{2-[2-(4-甲磺醯基胺基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,N-{4-[5-(2-乙醯基-苯基)-1H-苯并咪唑-2-基-乙炔基]-苯基}-C,C,C-三氟-甲磺醯胺,C,C,C-三氟-N-(4-{5-[2-(1-羥基-乙基)-苯基]-1H-苯并咪唑-2-基-乙炔基}-苯基)-甲磺醯胺,C,C,C-三氟-N-{4-[5-(2-甲磺醯基胺基-苯基)-1H-苯并咪唑-2-基-乙炔基]-苯基}-甲磺醯胺,C,C,C-三氟-N-(4-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基-乙炔基}-苯基)-甲磺醯胺,2-[2-(4-三氟甲磺醯基胺基-苯基乙炔基)-1H-苯并咪唑 -5-基]-苯磺醯胺,C,C,C-三氟-N-{2-[2-(4-三氟甲磺醯基胺基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,(E)-N-第三-丁基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-甲基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-羥基-1-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙酮,(E)-2-{2-[2-(4-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-N-甲基-2-[2-(2-對甲苯基-乙烯基)-1H-苯并咪唑-5-基]-苯磺醯胺,(E)-2-{2-[2-(4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(3,4-二氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(3-溴-4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(4-二甲基胺基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(3-氟-4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2-氟-4-三氟甲基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(3-氯-4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(3-氟-5-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-N-甲基-2-{2-[2-(2,3,4-三氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-甲基-2-{2-[2-(2,4,5-三氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,3-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2,5-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2,6-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(3,5-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(4-氟-2-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(4-氟-3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2-氟-3-三氟甲基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(3,5-雙-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2,5-雙-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(3-氯-2-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2-氯-6-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2,4-二氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(3-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(4-氯-2-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(4-氯-2-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-N-甲基-2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-甲基-2-{2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-甲基-2-{2-[2-(2-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-甲基-2-{2-[2-(3-三氟甲氧基-苯基)-乙烯基]-1H- 苯并咪唑-5-基}-苯磺醯胺,(E)-N-甲基-2-{2-[2-(4-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(4-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(2-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,(E)-2-{2-[2-(2,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,N-甲基-2-{2-[2-(3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3,4-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,3-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,5-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3,5-二氟-苯基)-乙烯基]-1H-苯并咪唑-5- 基}-苯磺醯胺,(E)-2-{2-[2-(3-三氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-氟-2-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-氟-3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-氟-3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,3,4-三氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,4,5-三氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,6-二氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3,5-雙-三氟甲基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,5-雙-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-氯-2-甲磺醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-氯-3-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(5-溴-2-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-三氟甲基硫基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-氟-3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,3,4-三氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,4,5-三氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,6-二氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(3,5-雙-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,5-雙-三氟甲基-苯基)-乙基]-1H-苯并咪唑 -5-基}-苯磺醯胺,2-{2-[2-(4-氯-2-甲磺醯基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-氯-3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(3-三氟甲氧基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,4-二氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(3,4-二氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,3-二氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2,5-二氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(3,5-二氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-(2-苯乙基-1H-苯并咪唑-5-基)-苯磺醯胺,(E)-N,N-二甲基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,N,N-二甲基-2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,N-甲基-2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺, 2-{2-[2-(2-氯-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-氟-2-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(2-氟-3-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-(2-{2-[2-(4-溴-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(4-異丙基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(3-氯-4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(3-溴-4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(4-二氟甲氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(3-氟-5-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-{2-[2-(2-p-甲苯基-乙烯基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,(E)-N-(2-{2-[2-(4-二甲基胺基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(4-乙氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺, (E)-N-{2-[2-(2-萘-2-基-乙烯基)-1H-苯并咪唑-5-基]-苯基}-甲磺醯胺,(E)-N-(2-{2-[2-(3,4-二氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(3-氟-4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(2-氟-4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,2-{2-[2-(2-氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-氟-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(3-氟-5-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-5-(2-甲磺醯基-苯基)-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑,(E)-2-{2-[2-(3-氟-4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-氟-4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3-乙氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-(2-苯乙烯基-1H-苯并咪唑-5-基)-苯磺醯胺,(E)-2-{2-[2-(3,4-二氯-苯基)-乙烯基]-1H-苯并咪唑-5- 基}-苯磺醯胺,(E)-2-{2-[2-(4-氯-2-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-異丙基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-[2-(2-對甲苯基-乙烯基)-1H-苯并咪唑-5-基]-苯磺醯胺,(E)-2-{2-[2-(3-氯-2-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3-氯-4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-[2-(2-萘-2-基-乙烯基)-1H-苯并咪唑-5-基]-苯磺醯胺,(E)-2-{2-[2-(4-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(4-二氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3-氟-5-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2,4-二氯-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(2-氯-6-氟-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-2-{2-[2-(3-溴-4-氟-苯基)-乙烯基]-1H-苯并咪唑 -5-基}-苯磺醯胺,(E)-2-{2-[2-(4-乙氧基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-4-氟-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-{2-[2-(4-異丙基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-N-(2-{3-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-3H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-4-三氟甲基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,4-三氟甲基-2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-5-三氟甲基-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯磺醯胺,5-三氟甲基-2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯磺醯胺,(E)-1-[4-(2-{5-[2-(1-羥基-1-甲基-乙基)-苯基]-1H-苯并咪唑-2-基}-乙烯基)-苯基]-乙酮,(E)-2-{2-[2-(2-喹啉6-基-乙烯基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇,(E)-N-異丙基-4-{2-[5-(2-甲基胺磺醯基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯甲醯胺,(E)-2-{2-[2-(4-氰基-苯基)-乙烯基]-1H-苯并咪唑-5- 基}-N-甲基苯磺醯胺,(E)-N-(4-{2-[5-(2-甲基胺磺醯基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯基)-乙醯胺,(E)-4-{2-[5-(2-甲基胺磺醯基-苯基)-1H-苯并咪唑-2-基]-乙烯基}-苯甲酸,(E)-2-{2-[2-(1H-吲哚-6-基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(2,4-雙-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基-苯磺醯胺,(E)-2-{2-[2-(4-乙醯基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-N-甲基苯磺醯胺,N-(2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-2,2,2-三氟-N-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-2,2,2-三氟-乙磺酸(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-醯胺,(E)-2,2-二甲基-N-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙醯胺,(E)-乙磺酸(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-醯胺,(E)-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-胺甲酸甲酯,(E)-2-(2-{2-[2-(4-第三-丁基-苯基)-乙烯基]-1H-苯并 咪唑-5-基}-苯基)-丙-2-醇,2-(2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基胺,(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲酸乙酯,N-(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-2-[2-(2-苯乙烯基-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,(Z)-2-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-5-(2-胺基磺醯基胺基-苯基)-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑,2-(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-酚,(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-胺甲酸第三-丁酯,(2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-N-{2-[2-(2-聯苯-4-基-乙烯基)-1H-苯并咪唑-5- 基]-苯基}-甲磺醯胺,(E)-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲醇,(E)-N-(2-{1-甲基-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-甲磺醯胺,(E)-N-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-乙醯胺,(E)-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-胺甲酸第三-丁酯,(E)-5-(2-甲基硫基-苯基)-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑,(E)-2-[2-(4-三氟甲磺醯基-苯基)-乙烯基]-5-(2-三氟甲基苯基)-1H-苯并咪唑,(E)-2-(2-{2-[2-(2-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,(E)-二甲基-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲基)-胺,(E)-2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲醛,(E)-甲基-(2-{2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑-5-基}-苯甲基)-胺,2-{2-[2-(4-三氟甲基-苯基)-乙基]-1H-苯并咪唑-5-基}-苯甲基胺,(E)-5-(2-三氟甲基-苯基)-2-[2-(4-三氟甲基-苯基)-乙 烯基]-1H-苯并咪唑,(E)-5-(2-三氟甲氧基-苯基)-2-[2-(4-三氟甲基-苯基)-乙烯基]-1H-苯并咪唑,2-[2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯基]-丙-2-醇,2-(2-苯基乙炔基-1H-苯并咪唑-5-基)-苯磺醯胺,(E)-5-(2-胺基磺醯基胺基-甲基苯基)-2-[2-(4-三氟甲基苯基)-乙烯基]-1H-苯并咪唑,2-{2-[2-(4-三氟甲基-苯基乙炔基)-1H-苯并咪唑-5-基]-苯基}-丙-2-醇,2-(2-{2-[2-(4-甲氧基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-(2-{2-[2-(4-三氟甲氧基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯甲醯胺,N-第三-丁基-2-{2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,5-(2-甲磺醯基-苯基)-2-[2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑,2-(2-{2-[(1R,2R)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[(1R,2R)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-(2-{2-[(1S,2S)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯 并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[(1S,2S)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-(2-{2-[(1S,2R)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,2-{2-[(1R,2S)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺,2-(2-{2-[(1R,2S)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯基)-丙-2-醇,及2-{2-[(1S,2R)-2-(4-三氟甲基-苯基)-環丙基]-1H-苯并咪唑-5-基}-苯磺醯胺。
- 一種如申請專利範圍第1項之化合物之鹽類,其係由下列組成之群中選出:醋酸鹽、己二酸鹽、苯磺酸鹽、苯甲酸鹽、碳酸氫鹽、硫酸氫鹽、酒石酸氫鹽、硼酸鹽、溴化物、鈣鹽、樟腦磺酸鹽(camsylate或camphosulphonate)、碳酸鹽、氯化物、膽鹽、克拉維酸鹽(clavulanate)、檸檬酸鹽、二鹽酸鹽、二鈉鹽、依地酸鹽(edentate)、延胡索酸鹽、葡萄糖酸鹽、麩胺酸鹽、哈胺鹽、氫溴酸鹽、鹽酸鹽、碘化物、異硫代羥酸鹽、乳酸鹽、蘋果酸鹽、馬來酸鹽、扁桃酸鹽、甲磺酸鹽、硝酸鹽、油酸鹽、帕莫酸鹽、棕櫚酸鹽、磷酸鹽/磷酸氫鹽、水楊酸鹽、鈉鹽、硬脂酸鹽、硫酸鹽、琥珀酸鹽、酒石酸鹽、三羥甲基胺基甲烷鹽、甲苯磺酸鹽、三氯醋酸鹽及三氟醋酸。
- 如申請專利範圍第10項之鹽類,其中該鹽類係由二鈉鹽、鹽酸鹽及鈉鹽組成之群中選出。
- 一種醫藥組合物,其包含如申請專利範圍第1項之化合物及一或多種醫藥上可接受之載劑、賦形劑或稀釋劑。
- 一種供有此需要之對象治療VR1離子通道介導之疾病之醫藥組合物,其係包含一有效量之如申請專利範圍第1項之化合物。
- 如申請專利範圍第13項之醫藥組合物,其中該VR1離子通道介導之疾病為造成發炎疼痛、灼熱疼痛或術後疼痛之疾病所引起之慢性或急性疼痛。
- 如申請專利範圍第13項之醫藥組合物,其中該治療上有效量之如申請專利範圍第1項之化合物係在從約0.001mg/kg/天至約300mg/kg/天之範圍內。
- 一種如申請專利範圍第1項之化合物之用途,係用於製造供治療VR1離子通道介導疾病之醫藥品,其中該VR1離子通道介導之疾病為造成發炎疼痛、灼熱疼痛或術後疼痛之疾病所引起之慢性或急性疼痛。
- 一種製備如申請專利範圍第1項之化合物之方法,其包含下列步驟:步驟A. 將醛QQ1 與丙二酸及催化量之哌啶於吡啶中及升高的溫度下反應,得到酸QQ2 :
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