JP5276582B2 - 抗ウイルス剤としての五環インドール誘導体 - Google Patents
抗ウイルス剤としての五環インドール誘導体 Download PDFInfo
- Publication number
- JP5276582B2 JP5276582B2 JP2009508506A JP2009508506A JP5276582B2 JP 5276582 B2 JP5276582 B2 JP 5276582B2 JP 2009508506 A JP2009508506 A JP 2009508506A JP 2009508506 A JP2009508506 A JP 2009508506A JP 5276582 B2 JP5276582 B2 JP 5276582B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- cyclohexyl
- ring
- pyrrolo
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000003443 antiviral agent Substances 0.000 title description 3
- 150000002475 indoles Chemical class 0.000 title description 2
- 229940054051 antipsychotic indole derivative Drugs 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 173
- 150000001875 compounds Chemical class 0.000 claims description 121
- 229910052739 hydrogen Inorganic materials 0.000 claims description 85
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 71
- 125000003545 alkoxy group Chemical group 0.000 claims description 70
- 239000001257 hydrogen Substances 0.000 claims description 67
- -1 hydroxyoxadiazolyl Chemical group 0.000 claims description 64
- 229910052736 halogen Inorganic materials 0.000 claims description 63
- 229910052760 oxygen Inorganic materials 0.000 claims description 61
- 125000005842 heteroatom Chemical group 0.000 claims description 56
- 229910052717 sulfur Inorganic materials 0.000 claims description 51
- 150000002367 halogens Chemical class 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 150000002431 hydrogen Chemical class 0.000 claims description 40
- WULHWYZFPFHCPV-UHFFFAOYSA-N pyrrolo[3,2-d][2]benzazepine-7-carboxylic acid Chemical compound N1=CC=C2C=NC=C3C(=C21)C=CC=C3C(=O)O WULHWYZFPFHCPV-UHFFFAOYSA-N 0.000 claims description 34
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 28
- 125000006413 ring segment Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- ZTOKLXGDTUVKJO-UHFFFAOYSA-N methyl 6h-1-benzazepine-7-carboxylate Chemical compound N1=CC=CC=C2CC(C(=O)OC)=CC=C21 ZTOKLXGDTUVKJO-UHFFFAOYSA-N 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000004429 atom Chemical group 0.000 claims description 20
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 239000005973 Carvone Substances 0.000 claims description 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 6
- SFVYUAJWNYVQDB-UHFFFAOYSA-N 2h-1,2-benzoxazocine Chemical compound O1NC=CC=CC2=CC=CC=C21 SFVYUAJWNYVQDB-UHFFFAOYSA-N 0.000 claims description 5
- WBQKUUFKFBIIGA-UHFFFAOYSA-N C1=CC(=C2C=NC=C3C=NC=CN3C2=C1)C(=O)O Chemical compound C1=CC(=C2C=NC=C3C=NC=CN3C2=C1)C(=O)O WBQKUUFKFBIIGA-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- AITNCBOXVZOQQC-UHFFFAOYSA-N 14-cyclohexyl-5-methyl-7,8-dihydroimidazo[4,5,1-jk]indolo[1,2-d][1,4]-benzodiazepine-11-carboxylic acid Chemical compound C12=CC=C(C(O)=O)C=C2N2CCN(C3=4)C(C)=NC3=CC=CC=4C2=C1C1CCCCC1 AITNCBOXVZOQQC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- YYKDCKAFZRTPEQ-UHFFFAOYSA-N 7H-indolo[2,1-a][2]benzazepine-7-carboxylic acid Chemical compound C1=CC=CC=2C=CC(N3C(C21)=CC=2C=CC=CC23)C(=O)O YYKDCKAFZRTPEQ-UHFFFAOYSA-N 0.000 claims description 3
- YAYHUAKOMQJTIK-UHFFFAOYSA-N 9,12-diazatetracyclo[10.7.0.02,7.013,18]nonadeca-1(19),2,4,6,8,10,13,15,17-nonaene-17-carboxylic acid Chemical compound C1=CC=CC=2C=NC=CN3C(C=21)=CC=1C(=CC=CC=13)C(=O)O YAYHUAKOMQJTIK-UHFFFAOYSA-N 0.000 claims description 3
- XHVYIHFFQVDUSX-UHFFFAOYSA-N C1=CC2=C3C=CN=C3C=NC=C2C(=C1)C(=O)O Chemical compound C1=CC2=C3C=CN=C3C=NC=C2C(=C1)C(=O)O XHVYIHFFQVDUSX-UHFFFAOYSA-N 0.000 claims description 3
- MJDONOKZTOLSKP-UHFFFAOYSA-N 11-cyclohexyl-2-[2-(dimethylamino)ethyl]-1,2,3,4,17,17a-hexahydro-6h-indolo[2,1-a]pyrazino[2,1-d][2,5]-benzodiazocine-14-carboxylic acid Chemical compound C1C(CCN(C)C)CCC(CN2C=CN=CC2=2)=C1C1CC3=CC=C(C(O)=O)C=C3N1C=2C1CCCCC1 MJDONOKZTOLSKP-UHFFFAOYSA-N 0.000 claims description 2
- RTQBGZGSWQAZHL-UHFFFAOYSA-N 13-cyclohexyl-6,7-dihydro-4h-indolo[4',3':3,4,5]azepino[1,2-a]indole-10-carboxylic acid Chemical compound C=12C(C3=4)=CC=CC=4NC=C3CCN2C2=CC(C(=O)O)=CC=C2C=1C1CCCCC1 RTQBGZGSWQAZHL-UHFFFAOYSA-N 0.000 claims description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 14
- JLWSZXGCTYXADY-UHFFFAOYSA-N pyrrolo[3,2-d][2]benzazepine Chemical compound N1=CC=C2C=NC=C3C(=C21)C=CC=C3 JLWSZXGCTYXADY-UHFFFAOYSA-N 0.000 claims 9
- CBWBTGXYYAVXJC-UHFFFAOYSA-N 14'-cyclohexyl-1-[2-(dimethylamino)ethyl]spiro[azetidine-3,7'-indolo[1,2-e][1,5]benzoxazocine]-11'-carboxylic acid Chemical compound C1N(CCN(C)C)CC21CN1C3=CC(C(O)=O)=CC=C3C(C3CCCCC3)=C1C1=CC=CC=C1OC2 CBWBTGXYYAVXJC-UHFFFAOYSA-N 0.000 claims 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 2
- 150000008038 benzoazepines Chemical class 0.000 claims 2
- AHOTVVDUKWNCKP-UHFFFAOYSA-N 1'-benzyl-19-cyclohexylspiro[8-oxa-12-azatetracyclo[10.7.0.02,7.013,18]nonadeca-1(19),2,4,6,13(18),14,16-heptaene-10,3'-azetidine]-15-carboxylic acid Chemical compound C=12C3=CC=CC=C3OCC3(CN(CC=4C=CC=CC=4)C3)CN2C2=CC(C(=O)O)=CC=C2C=1C1CCCCC1 AHOTVVDUKWNCKP-UHFFFAOYSA-N 0.000 claims 1
- PJXFQKVZEASZLW-UHFFFAOYSA-N 16-cyclohexyl-3-methyl-9,14-diazapentacyclo[12.7.0.02,7.08,12.015,20]henicosa-1(21),2(7),4,8,10,12,15(20),16,18-nonaene-11-carboxylic acid Chemical compound CC1C=CCC(C2=NC=C(C2=CN2C3=4)C(O)=O)=C1C2=CC3=CC=CC=4C1CCCCC1 PJXFQKVZEASZLW-UHFFFAOYSA-N 0.000 claims 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims 1
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 claims 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims 1
- BGHWDQSKCIBAAL-UHFFFAOYSA-N 6h-1-benzazepine-7-carboxylic acid Chemical compound N1=CC=CC=C2CC(C(=O)O)=CC=C21 BGHWDQSKCIBAAL-UHFFFAOYSA-N 0.000 claims 1
- KKNREZWFCFXTHI-UHFFFAOYSA-N C(=O)(O)C1=CN=C2C1=CN1C(C3C2CCCC3C)=CC=2C(=CC=C(C=21)C1CCCCC1)OC Chemical compound C(=O)(O)C1=CN=C2C1=CN1C(C3C2CCCC3C)=CC=2C(=CC=C(C=21)C1CCCCC1)OC KKNREZWFCFXTHI-UHFFFAOYSA-N 0.000 claims 1
- JIIPKLADCLPENE-UHFFFAOYSA-N C1=CC2=C(C=NC=C3C2=CC(=N3)C(=O)O)C(=C1)C(=O)O Chemical compound C1=CC2=C(C=NC=C3C2=CC(=N3)C(=O)O)C(=C1)C(=O)O JIIPKLADCLPENE-UHFFFAOYSA-N 0.000 claims 1
- FVXQPEZPSOQOPQ-UHFFFAOYSA-N C1=CC=C2C(=C1)C=C3N2C=C4C=CN=C4C5=CC=CC=C53 Chemical compound C1=CC=C2C(=C1)C=C3N2C=C4C=CN=C4C5=CC=CC=C53 FVXQPEZPSOQOPQ-UHFFFAOYSA-N 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 207
- 239000000243 solution Substances 0.000 description 145
- 239000000203 mixture Substances 0.000 description 139
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 124
- 235000019439 ethyl acetate Nutrition 0.000 description 103
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- 239000011734 sodium Substances 0.000 description 59
- 239000000463 material Substances 0.000 description 58
- 239000012267 brine Substances 0.000 description 56
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
- 239000002904 solvent Substances 0.000 description 55
- 239000003039 volatile agent Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- 238000003756 stirring Methods 0.000 description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 239000000047 product Substances 0.000 description 44
- 238000003818 flash chromatography Methods 0.000 description 42
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 37
- 238000006243 chemical reaction Methods 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- 229920006395 saturated elastomer Polymers 0.000 description 36
- 238000001704 evaporation Methods 0.000 description 32
- 230000008020 evaporation Effects 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000000034 method Methods 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 238000004007 reversed phase HPLC Methods 0.000 description 14
- 229910000104 sodium hydride Inorganic materials 0.000 description 14
- 125000000524 functional group Chemical group 0.000 description 13
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- 239000003643 water by type Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000002243 precursor Substances 0.000 description 11
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 9
- 238000012512 characterization method Methods 0.000 description 9
- 238000004108 freeze drying Methods 0.000 description 9
- AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- DCBDOYDVQJVXOH-UHFFFAOYSA-N azane;1h-indole Chemical compound N.C1=CC=C2NC=CC2=C1 DCBDOYDVQJVXOH-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000006260 foam Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 6
- 239000013058 crude material Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000002953 preparative HPLC Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 5
- 239000007821 HATU Substances 0.000 description 5
- 208000005176 Hepatitis C Diseases 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000006880 cross-coupling reaction Methods 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 5
- ZPRQXVPYQGBZON-UHFFFAOYSA-N 2-bromo-1h-indole Chemical compound C1=CC=C2NC(Br)=CC2=C1 ZPRQXVPYQGBZON-UHFFFAOYSA-N 0.000 description 4
- IRTCJFCIQKNFPP-UHFFFAOYSA-N 2-methyl-1,4-dioxane Chemical compound CC1COCCO1 IRTCJFCIQKNFPP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- BTGLLBWASGWDEF-UHFFFAOYSA-N methyl 1-[(1-benzylimidazol-2-yl)methyl]-3-cyclohexyl-2-[2-(hydroxymethyl)phenyl]indole-6-carboxylate Chemical compound C=1C=CC=C(CO)C=1C=1N(CC=2N(C=CN=2)CC=2C=CC=CC=2)C2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 BTGLLBWASGWDEF-UHFFFAOYSA-N 0.000 description 1
- GRGJBPRVOQWAGR-UHFFFAOYSA-N methyl 1-[2-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-methoxy-3-oxopropyl]-2-bromo-3-cyclohexylindole-6-carboxylate Chemical compound C12=CC=C(C(=O)OC)C=C2N(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(Br)=C1C1CCCCC1 GRGJBPRVOQWAGR-UHFFFAOYSA-N 0.000 description 1
- RNVAKWQLXIBZDR-UHFFFAOYSA-N methyl 2-(3-acetamido-2-aminophenyl)-3-cyclohexyl-1h-indole-6-carboxylate Chemical compound C=1C=CC(NC(C)=O)=C(N)C=1C=1NC2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 RNVAKWQLXIBZDR-UHFFFAOYSA-N 0.000 description 1
- CNLNJMUQJUCVSR-UHFFFAOYSA-N methyl 2-[3-acetamido-2-[(2-chloroacetyl)amino]phenyl]-3-cyclohexyl-1h-indole-6-carboxylate Chemical compound C=1C=CC(NC(C)=O)=C(NC(=O)CCl)C=1C=1NC2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 CNLNJMUQJUCVSR-UHFFFAOYSA-N 0.000 description 1
- YLEPWICFSDSZIM-UHFFFAOYSA-N methyl 3-cyclohexyl-1-(2,2-dimethoxyethyl)-2-(2-ethenylphenyl)indole-6-carboxylate Chemical compound C12=CC=C(C(=O)OC)C=C2N(CC(OC)OC)C(C=2C(=CC=CC=2)C=C)=C1C1CCCCC1 YLEPWICFSDSZIM-UHFFFAOYSA-N 0.000 description 1
- JPRHBRPAZQFQCF-UHFFFAOYSA-N methyl 3-cyclohexyl-1-prop-2-ynyl-2-[2-[tri(propan-2-yl)silyloxymethyl]phenyl]indole-6-carboxylate Chemical compound C=1C=CC=C(CO[Si](C(C)C)(C(C)C)C(C)C)C=1C=1N(CC#C)C2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 JPRHBRPAZQFQCF-UHFFFAOYSA-N 0.000 description 1
- BYUPUGIWGKLIPH-UHFFFAOYSA-N methyl 3-cyclohexyl-2-(2-ethenylphenyl)-1h-indole-6-carboxylate Chemical compound C=1C=CC=C(C=C)C=1C=1NC2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 BYUPUGIWGKLIPH-UHFFFAOYSA-N 0.000 description 1
- YYRKDUZWMBHTAY-UHFFFAOYSA-N methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1h-indole-6-carboxylate Chemical compound C=1C=CC=C(O)C=1C=1NC2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 YYRKDUZWMBHTAY-UHFFFAOYSA-N 0.000 description 1
- WMEZTJDHKHZZKD-UHFFFAOYSA-N methyl 3-cyclohexyl-2-(2-phenylmethoxyphenyl)-1h-indole-6-carboxylate Chemical compound C=1C=CC=C(OCC=2C=CC=CC=2)C=1C=1NC2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 WMEZTJDHKHZZKD-UHFFFAOYSA-N 0.000 description 1
- ZMLCFVZLECWTSV-UHFFFAOYSA-N methyl 3-cyclohexyl-2-[2-[tri(propan-2-yl)silyloxymethyl]phenyl]-1h-indole-6-carboxylate Chemical compound C=1C=CC=C(CO[Si](C(C)C)(C(C)C)C(C)C)C=1C=1NC2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 ZMLCFVZLECWTSV-UHFFFAOYSA-N 0.000 description 1
- FZTFFZDJCNLWHX-UHFFFAOYSA-N methyl 4-acetamido-13-cyclohexyl-6-oxo-5,7-dihydroindolo[1,2-d][1,4]benzodiazepine-10-carboxylate Chemical compound C=12C3=CC=CC(NC(C)=O)=C3NC(=O)CN2C2=CC(C(=O)OC)=CC=C2C=1C1CCCCC1 FZTFFZDJCNLWHX-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
- 229940078490 n,n-dimethylglycine Drugs 0.000 description 1
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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- OIXVKQDWLFHVGR-WQDIDPJDSA-N neomycin B sulfate Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO OIXVKQDWLFHVGR-WQDIDPJDSA-N 0.000 description 1
- 229940053050 neomycin sulfate Drugs 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
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- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
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- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- NKTROCRBBTZUPL-UHFFFAOYSA-N pyrazino[1,2-a][1,4]benzodiazepine Chemical compound N1=CC2=CC=CC=C2N2C=CN=CC2=C1 NKTROCRBBTZUPL-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- ACNRTYKOPZDRCO-UHFFFAOYSA-N tert-butyl n-(2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC=O ACNRTYKOPZDRCO-UHFFFAOYSA-N 0.000 description 1
- LVHGGVGVAUJQBB-UHFFFAOYSA-N tert-butyl n-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC=C1B1OC(C)(C)C(C)(C)O1 LVHGGVGVAUJQBB-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| GB0608928.8 | 2006-05-08 | ||
| GBGB0608928.8A GB0608928D0 (en) | 2006-05-08 | 2006-05-08 | Therapeutic agents |
| PCT/GB2007/050239 WO2007129119A1 (en) | 2006-05-08 | 2007-05-04 | Pentacyclic indole derivatives as antiviral agents |
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| JP2009536189A JP2009536189A (ja) | 2009-10-08 |
| JP2009536189A5 JP2009536189A5 (enExample) | 2013-04-18 |
| JP5276582B2 true JP5276582B2 (ja) | 2013-08-28 |
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| JP (1) | JP5276582B2 (enExample) |
| CN (1) | CN101437826A (enExample) |
| AU (1) | AU2007246850B2 (enExample) |
| CA (1) | CA2651226A1 (enExample) |
| GB (1) | GB0608928D0 (enExample) |
| WO (1) | WO2007129119A1 (enExample) |
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| US20070049593A1 (en) | 2004-02-24 | 2007-03-01 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
| US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
| US8003624B2 (en) | 2005-08-25 | 2011-08-23 | Schering Corporation | Functionally selective ALPHA2C adrenoreceptor agonists |
| GB0608928D0 (en) | 2006-05-08 | 2006-06-14 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| US7456166B2 (en) * | 2006-05-17 | 2008-11-25 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| US7541351B2 (en) | 2007-01-11 | 2009-06-02 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7541352B2 (en) | 2007-02-02 | 2009-06-02 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7517872B2 (en) | 2007-02-22 | 2009-04-14 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7998951B2 (en) | 2007-03-05 | 2011-08-16 | Bristol-Myers Squibb Company | HCV NS5B inhibitors |
| US7541353B2 (en) | 2007-03-14 | 2009-06-02 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7538102B2 (en) | 2007-03-14 | 2009-05-26 | Bristol-Myers Squibb Company | Compounds for the treatment of Hepatitis C |
| US7521444B2 (en) | 2007-03-14 | 2009-04-21 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7547690B2 (en) | 2007-03-14 | 2009-06-16 | Bristol-Myers Squibb Company | Compounds for the treatment of Hepatitis C |
| US7538103B2 (en) | 2007-03-15 | 2009-05-26 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| AU2008277442A1 (en) | 2007-07-17 | 2009-01-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic indole derivatives for the treatment of hepatitis C infections |
| US8143243B2 (en) | 2007-08-09 | 2012-03-27 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7652004B2 (en) | 2007-08-09 | 2010-01-26 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US7642251B2 (en) | 2007-08-09 | 2010-01-05 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US8129367B2 (en) | 2007-11-21 | 2012-03-06 | Bristol-Myers Squibb Company | Compounds for the treatment of Hepatitis C |
| US8124601B2 (en) | 2007-11-21 | 2012-02-28 | Bristol-Myers Squibb Company | Compounds for the treatment of Hepatitis C |
| EP2234977A4 (en) | 2007-12-19 | 2011-04-13 | Boehringer Ingelheim Int | VIRAL POLYMERASE INHIBITORS |
| US20090197856A1 (en) * | 2007-12-21 | 2009-08-06 | Genelabs Technologies, Inc. | Antiviral compounds |
| US8138171B2 (en) | 2008-03-27 | 2012-03-20 | Bristol-Myers Squibb Company | Dioxolane and dioxolanone fused indolobenzadiazepine HCV NS5B inhibitors |
| ATE531373T1 (de) * | 2008-03-27 | 2011-11-15 | Bristol Myers Squibb Co | Aromatische heterocyclische kondensierte indolobenzadiazepin-hcv-ns5b-inhibitoren |
| KR20100126560A (ko) | 2008-03-27 | 2010-12-01 | 브리스톨-마이어스 스큅 컴퍼니 | 피롤리딘 융합된 인돌로벤자디아제핀 ｈｃｖ ｎｓ5ｂ 억제제 |
| US8178523B2 (en) | 2008-03-27 | 2012-05-15 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| US8133884B2 (en) | 2008-05-06 | 2012-03-13 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| KR20110116136A (ko) | 2009-01-07 | 2011-10-25 | 싸이넥시스, 인크. | Ｈｃｖ 및 ｈｉｖ 감염의 치료에 사용하기 위한 사이클로스포린 유도체 |
| WO2010082050A1 (en) | 2009-01-16 | 2010-07-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic and 7-aminoalkyl-substituted benzoxazocines for treatment of hepatitis c infections |
| US8143244B2 (en) | 2009-02-26 | 2012-03-27 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
| KR20120106942A (ko) | 2009-10-30 | 2012-09-27 | 베링거 인겔하임 인터내셔날 게엠베하 | Ｂｉ２０１３３５, 인터페론 알파 및 리바비린을 포함하는 ｈｃｖ 병용 치료요법을 위한 투여 용법 |
| MX2012007076A (es) * | 2009-12-18 | 2012-07-20 | Boehringer Ingelheim Int | Terapia combinada de hcv. |
| EP2886632A1 (en) | 2013-02-19 | 2015-06-24 | LUKOIL Marine Lubricants Germany GmbH | Process and apparatus for the preparation of a cylinder oil |
| US12703680B2 (en) | 2019-11-21 | 2026-08-11 | University Of Utah Research Foundation | TRPV4 receptor ligands |
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| US5206382A (en) | 1991-06-27 | 1993-04-27 | Fidia Georgetown Institute For The Neurosciences | Indole derivatives, pharmaceutical compositions and methods of treating neurological and psychiatric disorders |
| IT1278077B1 (it) | 1995-05-25 | 1997-11-17 | Angeletti P Ist Richerche Bio | Metodologia per riprodurre in vitro le attivita' di rna polimerasi rna-dipendente e di nucleotidiltransferasi terminale codificate dal |
| ES2156725B1 (es) | 1999-05-07 | 2002-03-01 | Consejo Superior Investigacion | Derivados de dioxidos n,n- y n,x-disustituidos de 1,2,6-tiadiazina fusionadas y procedimiento de obtencion. |
| EP2050822B1 (en) | 2001-01-23 | 2013-07-31 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Hepatitis C virus replicons and replicon enhanced cells |
| TW200400963A (en) | 2002-05-21 | 2004-01-16 | Wyeth Corp | R-enantiomers of pyranoindole derivatives and the use thereof for the treatment of hepatitis C virus infection or disease |
| US7223785B2 (en) | 2003-01-22 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| GB0307891D0 (en) | 2003-04-04 | 2003-05-14 | Angeletti P Ist Richerche Bio | Chemical compounds,compositions and uses |
| US20050239767A1 (en) | 2003-10-28 | 2005-10-27 | Chan Michael K | Intermolecular SNAr of the heterocycle-activated nitro and fluoro groups-application in the synthesis of polyazamacrocyclic ligands |
| US20050119318A1 (en) | 2003-10-31 | 2005-06-02 | Hudyma Thomas W. | Inhibitors of HCV replication |
| CN1922174A (zh) | 2004-02-20 | 2007-02-28 | 贝林格尔·英格海姆国际有限公司 | 病毒聚合酶抑制剂 |
| US20070049593A1 (en) | 2004-02-24 | 2007-03-01 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
| WO2005080399A1 (ja) | 2004-02-24 | 2005-09-01 | Japan Tobacco Inc. | ４環縮合複素環化合物及びそのｈｃｖポリメラーゼ阻害剤としての利用 |
| GB0413087D0 (en) | 2004-06-11 | 2004-07-14 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| UY29017A1 (es) | 2004-07-16 | 2006-02-24 | Boehringer Ingelheim Int | Inhibidores de polimerasa viral |
| US7153848B2 (en) * | 2004-08-09 | 2006-12-26 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
| US7795247B2 (en) | 2004-10-26 | 2010-09-14 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Tetracyclic indole derivatives as antiviral agents |
| RU2007119562A (ru) * | 2004-10-26 | 2008-12-10 | Институто Ди Ричерке Ди Биолоджиа Молеколаре П Анджелетти Спа (It) | Тетрациклические производные индолов в качестве противовирусных агентов |
| US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
| GB0518390D0 (en) | 2005-09-09 | 2005-10-19 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| US7399758B2 (en) | 2005-09-12 | 2008-07-15 | Meanwell Nicholas A | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
| US7473688B2 (en) | 2005-09-13 | 2009-01-06 | Bristol-Myers Squibb Company | Indolobenzazepine HCV NS5B inhibitors |
| GB0522881D0 (en) * | 2005-11-10 | 2005-12-21 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| GB0608928D0 (en) | 2006-05-08 | 2006-06-14 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| GB0609492D0 (en) | 2006-05-15 | 2006-06-21 | Angeletti P Ist Richerche Bio | Therapeutic agents |
-
2006
- 2006-05-08 GB GBGB0608928.8A patent/GB0608928D0/en not_active Ceased
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2007
- 2007-05-04 CA CA002651226A patent/CA2651226A1/en not_active Abandoned
- 2007-05-04 US US12/299,833 patent/US8232390B2/en not_active Expired - Fee Related
- 2007-05-04 JP JP2009508506A patent/JP5276582B2/ja not_active Expired - Fee Related
- 2007-05-04 WO PCT/GB2007/050239 patent/WO2007129119A1/en not_active Ceased
- 2007-05-04 EP EP07733660A patent/EP2027125A1/en not_active Withdrawn
- 2007-05-04 CN CNA2007800166679A patent/CN101437826A/zh active Pending
- 2007-05-04 AU AU2007246850A patent/AU2007246850B2/en not_active Ceased
Also Published As
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|---|---|
| EP2027125A1 (en) | 2009-02-25 |
| WO2007129119A1 (en) | 2007-11-15 |
| US20100009959A1 (en) | 2010-01-14 |
| JP2009536189A (ja) | 2009-10-08 |
| US8232390B2 (en) | 2012-07-31 |
| CN101437826A (zh) | 2009-05-20 |
| AU2007246850A1 (en) | 2007-11-15 |
| AU2007246850B2 (en) | 2012-07-05 |
| GB0608928D0 (en) | 2006-06-14 |
| CA2651226A1 (en) | 2007-11-15 |
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