CA2607359C - Compounds and methods for the treatment or prevention of flavivirus infections - Google Patents
Compounds and methods for the treatment or prevention of flavivirus infections Download PDFInfo
- Publication number
- CA2607359C CA2607359C CA2607359A CA2607359A CA2607359C CA 2607359 C CA2607359 C CA 2607359C CA 2607359 A CA2607359 A CA 2607359A CA 2607359 A CA2607359 A CA 2607359A CA 2607359 C CA2607359 C CA 2607359C
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- CA
- Canada
- Prior art keywords
- alkyl
- trans
- methyl
- optionally substituted
- thiophene
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 361
- 238000000034 method Methods 0.000 title description 54
- 206010054261 Flavivirus infection Diseases 0.000 title description 6
- 238000011282 treatment Methods 0.000 title description 6
- 230000002265 prevention Effects 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 195
- 239000012453 solvate Substances 0.000 claims abstract description 182
- 241000711549 Hepacivirus C Species 0.000 claims abstract description 34
- 208000036142 Viral infection Diseases 0.000 claims abstract description 17
- 230000009385 viral infection Effects 0.000 claims abstract description 17
- 241000700605 Viruses Species 0.000 claims abstract description 6
- 241000710777 Classical swine fever virus Species 0.000 claims abstract description 4
- 208000001490 Dengue Diseases 0.000 claims abstract description 3
- 206010012310 Dengue fever Diseases 0.000 claims abstract description 3
- 241000710842 Japanese encephalitis virus Species 0.000 claims abstract description 3
- 241000710772 Yellow fever virus Species 0.000 claims abstract description 3
- 208000025729 dengue disease Diseases 0.000 claims abstract description 3
- 229940051021 yellow-fever virus Drugs 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 340
- -1 substituted Chemical class 0.000 claims description 300
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 220
- 125000000623 heterocyclic group Chemical group 0.000 claims description 149
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 131
- 125000001072 heteroaryl group Chemical group 0.000 claims description 129
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 123
- 229910052736 halogen Inorganic materials 0.000 claims description 113
- 150000002367 halogens Chemical class 0.000 claims description 109
- 125000003545 alkoxy group Chemical group 0.000 claims description 102
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 97
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 94
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 93
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 92
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 90
- 125000000304 alkynyl group Chemical group 0.000 claims description 85
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 83
- 125000003342 alkenyl group Chemical group 0.000 claims description 82
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 81
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 76
- 229910052757 nitrogen Inorganic materials 0.000 claims description 74
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 73
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 70
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 57
- 125000004043 oxo group Chemical group O=* 0.000 claims description 53
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 49
- 230000003612 virological effect Effects 0.000 claims description 48
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 46
- 125000004104 aryloxy group Chemical group 0.000 claims description 43
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 41
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 40
- 239000003795 chemical substances by application Substances 0.000 claims description 39
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 37
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 37
- 239000003112 inhibitor Substances 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 23
- 102000014150 Interferons Human genes 0.000 claims description 22
- 108010050904 Interferons Proteins 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 150000002923 oximes Chemical class 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 16
- 241000710781 Flaviviridae Species 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 12
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229940079322 interferon Drugs 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
- 239000003001 serine protease inhibitor Substances 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 9
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 9
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 claims description 9
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- 108060004795 Methyltransferase Proteins 0.000 claims description 7
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical group C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 claims description 7
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- HQUCUQJOQOFEQW-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(4-oxocyclohexyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCC(=O)CC1 HQUCUQJOQOFEQW-UHFFFAOYSA-N 0.000 claims description 6
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 6
- 108091005804 Peptidases Proteins 0.000 claims description 6
- 239000004365 Protease Substances 0.000 claims description 6
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 6
- 230000000692 anti-sense effect Effects 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 229960000329 ribavirin Drugs 0.000 claims description 6
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 6
- VSIYJQNFMOOGCU-UHFFFAOYSA-N 1-(cyclohexen-1-yl)cyclohexene Chemical group C1CCCC(C=2CCCCC=2)=C1 VSIYJQNFMOOGCU-UHFFFAOYSA-N 0.000 claims description 5
- MGIDOELNCIGRPO-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCC(O)CC1 MGIDOELNCIGRPO-UHFFFAOYSA-N 0.000 claims description 5
- NRWYAVDHRVTITK-UPRSBDKSSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCC=1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCC=1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 NRWYAVDHRVTITK-UPRSBDKSSA-N 0.000 claims description 5
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 5
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 5
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Chemical group C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 229940021747 therapeutic vaccine Drugs 0.000 claims description 5
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 4
- QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical group C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims description 4
- RNEQXUALSHFBCE-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-(4-oxocyclohexen-1-yl)thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCC(=O)CC=1)C(O)=O)C1CCC(O)CC1 RNEQXUALSHFBCE-UHFFFAOYSA-N 0.000 claims description 4
- JVSQRBKXYYHNAL-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-(4-phenoxycyclohexen-1-yl)thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1CCC(CC=1)OC=1C=CC=CC=1)C(O)=O)C1CCC(O)CC1 JVSQRBKXYYHNAL-UHFFFAOYSA-N 0.000 claims description 4
- AMOXNTAMLUCWJT-UHFFFAOYSA-N 5-(4,4-dimethylcyclohexyl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C1CCC(C)(C)CC1)C(O)=O)C(=O)C1CCC(C)CC1 AMOXNTAMLUCWJT-UHFFFAOYSA-N 0.000 claims description 4
- OFOMFFOXKMZUIW-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-(n-(4-methylcyclohexanecarbonyl)anilino)thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C=1C=CC=CC=1)C1=C(C(O)=O)SC(C=2CCCCC=2)=C1 OFOMFFOXKMZUIW-UHFFFAOYSA-N 0.000 claims description 4
- GJNZQSSHAVNWFW-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(2,4-dichlorobenzoyl)-propan-2-ylamino]thiophene-2-carboxylic acid Chemical compound C1=C(C=2CCCCC=2)SC(C(O)=O)=C1N(C(C)C)C(=O)C1=CC=C(Cl)C=C1Cl GJNZQSSHAVNWFW-UHFFFAOYSA-N 0.000 claims description 4
- OSZNFYRPACBWAD-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[(4-ethoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(OCC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C(=O)C1CCC(C)CC1 OSZNFYRPACBWAD-UHFFFAOYSA-N 0.000 claims description 4
- SNHOCYVWFCETLM-UHFFFAOYSA-N 5-(cyclohexen-1-yl)-3-[[4-(methoxymethoxy)cyclohexyl]-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(OCOC)CCC1N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C(=O)C1CCC(C)CC1 SNHOCYVWFCETLM-UHFFFAOYSA-N 0.000 claims description 4
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- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 4
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
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- OGJDZVITLCFAII-UHFFFAOYSA-N methyl 2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate Chemical compound C1CC(=CC(=O)OC)CCC21OCCO2 OGJDZVITLCFAII-UHFFFAOYSA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- KMTPLRIOOJYJQD-UHFFFAOYSA-N methyl 3-(1,4-dioxaspiro[4.5]decan-8-ylamino)thiophene-2-carboxylate Chemical compound S1C=CC(NC2CCC3(CC2)OCCO3)=C1C(=O)OC KMTPLRIOOJYJQD-UHFFFAOYSA-N 0.000 description 1
- BQQHXIZCAPCAQE-UHFFFAOYSA-N methyl 3-amino-5-(4,4-dimethylcyclohexen-1-yl)thiophene-2-carboxylate Chemical compound NC1=C(C(=O)OC)SC(C=2CCC(C)(C)CC=2)=C1 BQQHXIZCAPCAQE-UHFFFAOYSA-N 0.000 description 1
- TWEQNZZOOFKOER-UHFFFAOYSA-N methyl 3-aminothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1N TWEQNZZOOFKOER-UHFFFAOYSA-N 0.000 description 1
- UEARGZRWCIVDOO-UHFFFAOYSA-N methyl 3-anilino-5-(cyclohexen-1-yl)thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1NC1=CC=CC=C1 UEARGZRWCIVDOO-UHFFFAOYSA-N 0.000 description 1
- PEGSJNCGPSIJOX-UHFFFAOYSA-N methyl 3-bromothiophene-2-carboxylate Chemical compound COC(=O)C=1SC=CC=1Br PEGSJNCGPSIJOX-UHFFFAOYSA-N 0.000 description 1
- XSKFBQUERIPAKH-UHFFFAOYSA-N methyl 5-(1,4-dioxaspiro[4.5]decan-8-yl)-3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C1CCC2(CC1)OCCO2)C(=O)OC)C(=O)C1CCC(C)CC1 XSKFBQUERIPAKH-UHFFFAOYSA-N 0.000 description 1
- XHDJCEAGKSIJBB-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexen-1-yl)-3-[[4-(methoxymethoxy)cyclohexyl]-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound C1CC(OCOC)CCC1N(C1=C(SC(=C1)C=1CCC(C)(C)CC=1)C(=O)OC)C(=O)C1CCC(C)CC1 XHDJCEAGKSIJBB-UHFFFAOYSA-N 0.000 description 1
- IPICGJKKANUVMD-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2CCC(C)(C)CC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1 IPICGJKKANUVMD-UHFFFAOYSA-N 0.000 description 1
- NBXAFBUAJVRUIU-UHFFFAOYSA-N methyl 5-(4,4-dimethylcyclohexyl)-3-[(4-methylcyclohexanecarbonyl)-[4-(1,2,4-triazol-1-yl)cyclohexyl]amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2CCC(C)(C)CC2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCC1N1C=NC=N1 NBXAFBUAJVRUIU-UHFFFAOYSA-N 0.000 description 1
- ATEZBAUSRGJRTP-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-(n-(4-methylcyclohexanecarbonyl)anilino)thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C=1C=CC=CC=1)C(=O)C1CCC(C)CC1 ATEZBAUSRGJRTP-UHFFFAOYSA-N 0.000 description 1
- UDFZVRTZRTUZLH-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(3-oxo-2-azaspiro[4.5]decan-8-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1NC(CC1)CCC21CNC(=O)C2 UDFZVRTZRTUZLH-UHFFFAOYSA-N 0.000 description 1
- HEZJUUMFRVLDCN-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(1-pyrimidin-5-ylpiperidin-4-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCN1C1=CN=CN=C1 HEZJUUMFRVLDCN-UHFFFAOYSA-N 0.000 description 1
- PYNHJVXZJFCQHI-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(2-methyl-3-oxo-2-azaspiro[4.5]decan-8-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C(CC1)CCC21CN(C)C(=O)C2 PYNHJVXZJFCQHI-UHFFFAOYSA-N 0.000 description 1
- PFVAJVRMWSPGKC-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-(3-oxo-2,5,6,7,8,8a-hexahydro-1h-indolizin-7-yl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C1CC2N(C(CC2)=O)CC1)C(=O)C1CCC(C)CC1 PFVAJVRMWSPGKC-UHFFFAOYSA-N 0.000 description 1
- UJPXPQITBKABOQ-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[(4-methylcyclohexanecarbonyl)-[1-(2-methylpropanoyl)piperidin-4-yl]amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCN(C(=O)C(C)C)CC1 UJPXPQITBKABOQ-UHFFFAOYSA-N 0.000 description 1
- WUDQZNWCZNXVSM-UHFFFAOYSA-N methyl 5-(cyclohexen-1-yl)-3-[1,3-dioxan-5-yl-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1COCOC1 WUDQZNWCZNXVSM-UHFFFAOYSA-N 0.000 description 1
- FRKRFOAZSVJFDM-UHFFFAOYSA-N methyl 5-bromo-3-[(1,3-dimethyl-2,4-dioxo-1,3-diazaspiro[4.5]decan-8-yl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound S1C(Br)=CC(N(C2CCC3(CC2)C(N(C)C(=O)N3C)=O)C(=O)C2CCC(C)CC2)=C1C(=O)OC FRKRFOAZSVJFDM-UHFFFAOYSA-N 0.000 description 1
- DNVFEPOGJHDYMJ-UHFFFAOYSA-N methyl 5-bromo-3-[(2,2-dimethyl-1,3-dioxan-5-yl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound S1C(Br)=CC(N(C2COC(C)(C)OC2)C(=O)C2CCC(C)CC2)=C1C(=O)OC DNVFEPOGJHDYMJ-UHFFFAOYSA-N 0.000 description 1
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- UODPHKFUTYRNDZ-UHFFFAOYSA-N methyl 5-cyclohex-2-en-1-yl-3-[(4-methylcyclohexanecarbonyl)-(4-oxocyclohexyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2C=CCCC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1 UODPHKFUTYRNDZ-UHFFFAOYSA-N 0.000 description 1
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- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
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- 102220065682 rs77311724 Human genes 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
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
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- XZPVPNZTYPUODG-UHFFFAOYSA-M sodium;chloride;dihydrate Chemical compound O.O.[Na+].[Cl-] XZPVPNZTYPUODG-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
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- NHKZSTHOYNWEEZ-AFCXAGJDSA-N taribavirin Chemical compound N1=C(C(=N)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NHKZSTHOYNWEEZ-AFCXAGJDSA-N 0.000 description 1
- 229950006081 taribavirin Drugs 0.000 description 1
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- BBAWEDCPNXPBQM-GDEBMMAJSA-N telaprevir Chemical compound N([C@H](C(=O)N[C@H](C(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)N[C@@H](CCC)C(=O)C(=O)NC1CC1)C(C)(C)C)C1CCCCC1)C(=O)C1=CN=CC=N1 BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
- 108010017101 telaprevir Proteins 0.000 description 1
- GFNMJSGQSWLTOR-UHFFFAOYSA-N tert-butyl 4-[[5-(cyclohexen-1-yl)-2-methoxycarbonylthiophen-3-yl]-(4-methylcyclohexanecarbonyl)amino]piperidine-1-carboxylate Chemical compound COC(=O)C=1SC(C=2CCCCC=2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCN(C(=O)OC(C)(C)C)CC1 GFNMJSGQSWLTOR-UHFFFAOYSA-N 0.000 description 1
- WYVFPGFWUKBXPZ-UHFFFAOYSA-N tert-butyl n-(4-oxocyclohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CCC(=O)CC1 WYVFPGFWUKBXPZ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
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- 229960000790 thymol Drugs 0.000 description 1
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- 235000010487 tragacanth Nutrition 0.000 description 1
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- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- CMHHITPYCHHOGT-UHFFFAOYSA-N tributylborane Chemical compound CCCCB(CCCC)CCCC CMHHITPYCHHOGT-UHFFFAOYSA-N 0.000 description 1
- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D333/40—Thiophene-2-carboxylic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
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- Gastroenterology & Hepatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Thiazole And Isothizaole Compounds (AREA)
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| NZ (1) | NZ563909A (enExample) |
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| AU2002344854B2 (en) * | 2001-06-11 | 2008-11-06 | Vertex Pharmaceuticals (Canada) Incorporated | Thiophene derivatives as antiviral agents for flavivirus infection |
| CN101218224B (zh) * | 2005-05-13 | 2013-05-08 | Viro化学制药公司 | 治疗或预防黄病毒感染的组合物和方法 |
| PT2104674E (pt) | 2006-11-15 | 2013-07-26 | Virochem Pharma Inc | Análogos de tiofeno para o tratamento ou prevenção de infeções por flavivírus |
| US8148390B2 (en) * | 2007-03-12 | 2012-04-03 | Merck, Sharp & Dohme, Corp. | Monocyclic anilide spirolactam CGRP receptor antagonists |
| SI2308514T1 (sl) | 2007-03-23 | 2013-09-30 | To-Bbb Holding B.V. | Konjugati za prenos zdravila preko krvno-moĹľganske pregrade |
| ES2381410T3 (es) | 2007-05-04 | 2012-05-28 | Vertex Pharmceuticals Incorporated | Terapia de combinación paa el tratamiento de infecciones por VHC |
| EP2148678A4 (en) | 2007-05-23 | 2010-08-04 | Siga Technologies Inc | ANTIVIRAL DRUGS FOR THE TREATMENT AND PREVENTION OF DENGUE INFECTION |
| GB0712393D0 (en) * | 2007-06-26 | 2007-08-01 | Smithkline Beecham Corp | Compounds |
| WO2009076747A1 (en) | 2007-12-19 | 2009-06-25 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| US20110212986A1 (en) * | 2008-08-21 | 2011-09-01 | Health Research, Inc. | Anti-flavivirus therapeutic |
| WO2010080874A1 (en) | 2009-01-07 | 2010-07-15 | Scynexis, Inc. | Cyclosporine derivative for use in the treatment of hcv and hiv infection |
| JP5327744B2 (ja) * | 2009-03-13 | 2013-10-30 | 国立大学法人 鹿児島大学 | ジフェニルメタン誘導体を有効成分とする抗ウイルス剤 |
| TW201116525A (en) * | 2009-07-21 | 2011-05-16 | Gilead Sciences Inc | Inhibitors of flaviviridae viruses |
| KR20120081123A (ko) | 2009-09-09 | 2012-07-18 | 길리애드 사이언시즈, 인코포레이티드 | 플라비비리대 바이러스의 억제제 |
| US8618307B2 (en) | 2009-09-16 | 2013-12-31 | Calcimedica, Inc. | Compounds that modulate intracellular calcium |
| JP2013512247A (ja) | 2009-11-25 | 2013-04-11 | バーテックス ファーマシューティカルズ インコーポレイテッド | フラビウイルス感染症の治療または予防のための５−アルキニル−チオフェン−２−カルボン酸誘導体およびそれらの使用 |
| KR20120123678A (ko) | 2010-01-15 | 2012-11-09 | 길리애드 사이언시즈, 인코포레이티드 | 플라비비리다에 바이러스의 억제제 |
| PE20130281A1 (es) * | 2010-01-15 | 2013-03-08 | Gilead Sciences Inc | Derivados de acido 5-alquinil-3-amida-2-tiofeno-carboxilico como inhibidores del virus flaviviridae |
| EP2585447A2 (en) | 2010-06-28 | 2013-05-01 | Vertex Pharmaceuticals Incorporated | Compounds and methods for the treatment or prevention of flavivirus infections |
| JP2013531011A (ja) | 2010-06-28 | 2013-08-01 | バーテックス ファーマシューティカルズ インコーポレイテッド | フラビウイルス感染の処置または予防のための化合物および方法 |
| MX2013001869A (es) | 2010-08-17 | 2013-06-28 | Vertex Pharma | Compuestos y metodos para el tratamiento o prevencion de infecciones virales por flaviviridae. |
| WO2012083105A1 (en) | 2010-12-17 | 2012-06-21 | Cocrystal Discovery, Inc. | Inhibitors of hepatitis c virus polymerase |
| US20130203706A1 (en) * | 2011-06-28 | 2013-08-08 | Vertex Pharmaceuticals Incorporated | Compounds and methods for the treatment or prevention of flavivirus infections |
| EP2734515B1 (en) | 2011-07-13 | 2015-11-04 | Gilead Sciences, Inc. | Thiophen-2-carboxylic acid derivatives useful as inhibitors of flaviviridae viruses |
| CN103059042B (zh) * | 2011-10-18 | 2015-10-07 | 银杏树药业(苏州)有限公司 | 噻吩类衍生物及其在药学中的用途 |
| US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
| US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
| CA2811203C (en) | 2011-10-21 | 2015-05-05 | Abbvie Inc. | Methods for treating hcv |
| CN104023726A (zh) | 2011-10-21 | 2014-09-03 | 艾伯维公司 | 用于治疗hcv的一种或多种daa的联合治疗(例如，与abt-072或abt-333) |
| CN103087052A (zh) * | 2011-10-31 | 2013-05-08 | 上海壹志医药科技有限公司 | 噻吩衍生物及其药物用途 |
| WO2014055142A1 (en) | 2012-06-20 | 2014-04-10 | Cocrystal Discovery, Inc. | Inhibitors of hepatitis c virus polymerase |
| US8759544B2 (en) | 2012-08-17 | 2014-06-24 | Gilead Sciences, Inc. | Synthesis of an antiviral compound |
| US8841340B2 (en) | 2012-08-17 | 2014-09-23 | Gilead Sciences, Inc. | Solid forms of an antiviral compound |
| US8927741B2 (en) | 2012-08-17 | 2015-01-06 | Gilead Sciences, Inc. | Synthesis of an antiviral compound |
| TWI731854B (zh) | 2015-03-23 | 2021-07-01 | 美商共結晶製藥公司 | Ｃ型肝炎病毒聚合酶之抑制劑 |
| JP7129703B2 (ja) | 2016-04-28 | 2022-09-02 | エモリー ユニバーシティー | アルキン含有ヌクレオチド及びヌクレオシド治療組成物並びにそれらに関連した使用 |
| CN106467477A (zh) * | 2016-08-26 | 2017-03-01 | 天津雅奥科技发展有限公司 | 一种合成化合物（1‑环丙基‑1‑氰基‑4‑环己酮）的新方法 |
| CN112203652A (zh) | 2018-05-09 | 2021-01-08 | 共晶制药公司 | 用于治疗hcv的组合疗法 |
| EA202190046A1 (ru) | 2018-06-19 | 2021-03-24 | Новартис Аг | N-замещенные производные тетрагидротиенопиридина и их применение |
| CN110592172B (zh) * | 2019-10-29 | 2021-05-28 | 华中农业大学 | 利用CRISPR/Cas9敲除文库技术筛选JEV抗性基因的方法与靶点 |
| CN111518015A (zh) * | 2020-05-20 | 2020-08-11 | 上海合全药物研发有限公司 | 一种叔丁基-8-氧亚基-2-氮杂螺[4.5]癸烷-2-甲酸基酯的制备方法 |
| CN113861176B (zh) * | 2021-09-28 | 2023-11-03 | 北京凯因格领生物技术有限公司 | 一种黄病毒抑制剂 |
| EP4282862A1 (en) * | 2022-05-25 | 2023-11-29 | Irbm S.P.A. | Flavivirus inhibitors |
| IL325120A (en) * | 2023-06-05 | 2026-02-01 | Celloram Inc | Fatty acid binding protein (FABP) inhibitors, methods of use and methods of preparation |
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-
2006
- 2006-05-15 CN CN2006800248617A patent/CN101218224B/zh not_active Expired - Fee Related
- 2006-05-15 BR BRPI0610283-2A patent/BRPI0610283A2/pt not_active IP Right Cessation
- 2006-05-15 KR KR1020077028215A patent/KR20080016597A/ko not_active Ceased
- 2006-05-15 US US11/433,749 patent/US7569600B2/en not_active Expired - Fee Related
- 2006-05-15 AU AU2006246227A patent/AU2006246227B2/en not_active Ceased
- 2006-05-15 NZ NZ563909A patent/NZ563909A/en not_active IP Right Cessation
- 2006-05-15 AP AP2007004245A patent/AP2007004245A0/xx unknown
- 2006-05-15 WO PCT/CA2006/000786 patent/WO2006119646A1/en not_active Ceased
- 2006-05-15 EP EP12004718.8A patent/EP2546246A3/en not_active Withdrawn
- 2006-05-15 EP EP06741500A patent/EP1879879B1/en not_active Expired - Lifetime
- 2006-05-15 CA CA2607359A patent/CA2607359C/en not_active Expired - Fee Related
- 2006-05-15 MX MX2007014117A patent/MX2007014117A/es active IP Right Grant
- 2006-05-15 ES ES06741500T patent/ES2415742T3/es not_active Expired - Lifetime
- 2006-05-15 EA EA200702493A patent/EA016071B1/ru not_active IP Right Cessation
- 2006-05-15 JP JP2008510379A patent/JP5030947B2/ja not_active Expired - Fee Related
- 2006-05-15 SG SG201002905-6A patent/SG161315A1/en unknown
- 2006-05-15 CN CN2012101163717A patent/CN102718744A/zh active Pending
- 2006-05-15 EP EP12004696A patent/EP2543664A1/en not_active Withdrawn
-
2007
- 2007-11-12 ZA ZA200709727A patent/ZA200709727B/xx unknown
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- 2009-07-24 US US12/508,893 patent/US8158675B2/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| SG161315A1 (en) | 2010-05-27 |
| EP2543664A1 (en) | 2013-01-09 |
| ES2415742T3 (es) | 2013-07-26 |
| US20100093775A1 (en) | 2010-04-15 |
| WO2006119646A1 (en) | 2006-11-16 |
| US20060276533A1 (en) | 2006-12-07 |
| US7569600B2 (en) | 2009-08-04 |
| AU2006246227A1 (en) | 2006-11-16 |
| AP2007004245A0 (en) | 2007-12-31 |
| EP1879879A4 (en) | 2010-03-10 |
| JP2008540463A (ja) | 2008-11-20 |
| CA2607359A1 (en) | 2006-11-16 |
| CN102718744A (zh) | 2012-10-10 |
| US8158675B2 (en) | 2012-04-17 |
| EA200702493A1 (ru) | 2008-04-28 |
| EP2546246A3 (en) | 2013-04-24 |
| US20120164103A1 (en) | 2012-06-28 |
| EP1879879A1 (en) | 2008-01-23 |
| ZA200709727B (en) | 2008-11-26 |
| EA016071B1 (ru) | 2012-01-30 |
| BRPI0610283A2 (pt) | 2010-10-19 |
| MX2007014117A (es) | 2008-02-05 |
| JP5030947B2 (ja) | 2012-09-19 |
| EP2546246A2 (en) | 2013-01-16 |
| CN101218224B (zh) | 2013-05-08 |
| NZ563909A (en) | 2011-10-28 |
| HK1112910A1 (en) | 2008-09-19 |
| US8674118B2 (en) | 2014-03-18 |
| CN101218224A (zh) | 2008-07-09 |
| AU2006246227B2 (en) | 2011-04-28 |
| KR20080016597A (ko) | 2008-02-21 |
| EP1879879B1 (en) | 2013-03-27 |
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