MX2007014117A - Compuestos y metodos para el tratamiento o prevencion de infecciones de flavivirus. - Google Patents
Compuestos y metodos para el tratamiento o prevencion de infecciones de flavivirus.Info
- Publication number
- MX2007014117A MX2007014117A MX2007014117A MX2007014117A MX2007014117A MX 2007014117 A MX2007014117 A MX 2007014117A MX 2007014117 A MX2007014117 A MX 2007014117A MX 2007014117 A MX2007014117 A MX 2007014117A MX 2007014117 A MX2007014117 A MX 2007014117A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- trans
- methyl
- amino
- cyclohexanecarbonyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 331
- 238000000034 method Methods 0.000 title claims description 69
- 206010054261 Flavivirus infection Diseases 0.000 title description 4
- 230000002265 prevention Effects 0.000 title description 4
- 241000711549 Hepacivirus C Species 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 239000012453 solvate Substances 0.000 claims abstract description 22
- 208000036142 Viral infection Diseases 0.000 claims abstract description 18
- 230000009385 viral infection Effects 0.000 claims abstract description 18
- 241000700605 Viruses Species 0.000 claims abstract description 11
- 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 542
- -1 -C (O) O-C 4 alkyl Chemical group 0.000 claims description 535
- 125000000623 heterocyclic group Chemical group 0.000 claims description 131
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 117
- 239000002253 acid Substances 0.000 claims description 102
- 125000001072 heteroaryl group Chemical group 0.000 claims description 88
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 85
- 125000003118 aryl group Chemical group 0.000 claims description 75
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 73
- 229910052736 halogen Inorganic materials 0.000 claims description 72
- 125000003545 alkoxy group Chemical group 0.000 claims description 71
- 150000002367 halogens Chemical class 0.000 claims description 71
- 229910052757 nitrogen Inorganic materials 0.000 claims description 69
- 125000003342 alkenyl group Chemical group 0.000 claims description 64
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 59
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 59
- 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 53
- 125000000304 alkynyl group Chemical group 0.000 claims description 52
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 49
- 230000003612 virological effect Effects 0.000 claims description 47
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 45
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 42
- 229910052799 carbon Inorganic materials 0.000 claims description 40
- 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 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 35
- 239000003795 chemical substances by application Substances 0.000 claims description 35
- 102000014150 Interferons Human genes 0.000 claims description 29
- 108010050904 Interferons Proteins 0.000 claims description 29
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 239000003112 inhibitor Substances 0.000 claims description 27
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 25
- 125000004104 aryloxy group Chemical group 0.000 claims description 25
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000004043 oxo group Chemical group O=* 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 18
- 150000002923 oximes Chemical class 0.000 claims description 17
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 15
- 241000710781 Flaviviridae Species 0.000 claims description 15
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 13
- 108060004795 Methyltransferase Proteins 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 12
- 108020004684 Internal Ribosome Entry Sites Proteins 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 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 11
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 11
- 229940079322 interferon Drugs 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 10
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 10
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 10
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 9
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 239000003001 serine protease inhibitor Substances 0.000 claims description 9
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 8
- 230000002519 immonomodulatory effect Effects 0.000 claims description 8
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical group C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 241000710780 Bovine viral diarrhea virus 1 Species 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
- 239000003937 drug carrier Substances 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 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
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 5
- QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical group C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims description 5
- 108010022999 Serine Proteases Proteins 0.000 claims description 5
- 102000012479 Serine Proteases Human genes 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 5
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 5
- 229910052705 radium Inorganic materials 0.000 claims description 5
- 229910052703 rhodium Inorganic materials 0.000 claims description 5
- 229910052701 rubidium Inorganic materials 0.000 claims description 5
- VSIYJQNFMOOGCU-UHFFFAOYSA-N 1-(cyclohexen-1-yl)cyclohexene Chemical group C1CCCC(C=2CCCCC=2)=C1 VSIYJQNFMOOGCU-UHFFFAOYSA-N 0.000 claims description 4
- HQUCUQJOQOFEQW-SAABIXHNSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCC(=O)CC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1CCC(=O)CC1 HQUCUQJOQOFEQW-SAABIXHNSA-N 0.000 claims description 4
- MGIDOELNCIGRPO-VJVRBHMKSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=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=1CCCCC=1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 MGIDOELNCIGRPO-VJVRBHMKSA-N 0.000 claims description 4
- LBFROQIFJOYWFA-HDRKRICHSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(Br)=C1)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(Br)=C1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 LBFROQIFJOYWFA-HDRKRICHSA-N 0.000 claims description 4
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 4
- 229960003805 amantadine Drugs 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 4
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 4
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229940021747 therapeutic vaccine Drugs 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 3
- 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 3
- 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 3
- FPARYJXWWMDFFU-KQEUCTNFSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C1C=CCCC1)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)C1C=CCCC1)C(O)=O)[C@@H]1CC[C@@H](O)CC1 FPARYJXWWMDFFU-KQEUCTNFSA-N 0.000 claims description 3
- NHRHXDMGFVGNRU-JCNLHEQBSA-N C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1COCOC1 Chemical compound C1C[C@@H](C)CC[C@@H]1C(=O)N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C1COCOC1 NHRHXDMGFVGNRU-JCNLHEQBSA-N 0.000 claims description 3
- GZPCNCMYPJUFCL-BIAGXBKMSA-N C1C[C@@H](OC)CC[C@@H]1N(C1=C(SC=C1)C(O)=O)C(=O)[C@@H]1CC[C@@H](C)CC1 Chemical compound C1C[C@@H](OC)CC[C@@H]1N(C1=C(SC=C1)C(O)=O)C(=O)[C@@H]1CC[C@@H](C)CC1 GZPCNCMYPJUFCL-BIAGXBKMSA-N 0.000 claims description 3
- SNHOCYVWFCETLM-XHPGVBHPSA-N C1C[C@@H](OCOC)CC[C@@H]1N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C(=O)[C@@H]1CC[C@@H](C)CC1 Chemical compound C1C[C@@H](OCOC)CC[C@@H]1N(C1=C(SC(=C1)C=1CCCCC=1)C(O)=O)C(=O)[C@@H]1CC[C@@H](C)CC1 SNHOCYVWFCETLM-XHPGVBHPSA-N 0.000 claims description 3
- 102000053642 Catalytic RNA Human genes 0.000 claims description 3
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 3
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- 102000013462 Interleukin-12 Human genes 0.000 claims description 3
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- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 3
- 244000272459 Silybum marianum Species 0.000 claims description 3
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- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 108091092562 ribozyme Proteins 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 150000003536 tetrazoles Chemical class 0.000 claims description 3
- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 claims description 3
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- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
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- WTEVQBCEXWBHNA-JXMROGBWSA-N geranial Chemical compound CC(C)=CCC\C(C)=C\C=O WTEVQBCEXWBHNA-JXMROGBWSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
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- 229960002897 heparin Drugs 0.000 description 1
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- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
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- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
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- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 1
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- 238000011534 incubation Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 238000012739 integrated shape imaging system Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- WYXXLXHHWYNKJF-UHFFFAOYSA-N isocarvacrol Natural products CC(C)C1=CC=C(O)C(C)=C1 WYXXLXHHWYNKJF-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
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- 238000012417 linear regression Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical group 0.000 description 1
- JTCYOTDMLABHJJ-UHFFFAOYSA-M lithium;5-bromo-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound [Li+].C1CC(C)CCC1C(=O)N(C1=C(SC(Br)=C1)C([O-])=O)C1CCC(O)CC1 JTCYOTDMLABHJJ-UHFFFAOYSA-M 0.000 description 1
- 230000004904 long-term response Effects 0.000 description 1
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- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- WWOYCMCZTZTIGU-UHFFFAOYSA-L magnesium;2-carboxybenzenecarboperoxoate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].OOC(=O)C1=CC=CC=C1C([O-])=O.OOC(=O)C1=CC=CC=C1C([O-])=O WWOYCMCZTZTIGU-UHFFFAOYSA-L 0.000 description 1
- 150000002691 malonic acids Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229950003168 merimepodib Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- JCVZXXSBCISMLJ-LURJTMIESA-N methyl (2s)-2-isocyanato-3-methylbutanoate Chemical compound COC(=O)[C@H](C(C)C)N=C=O JCVZXXSBCISMLJ-LURJTMIESA-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
- GVIDKWMNFNCELI-UHFFFAOYSA-N methyl 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-tributylstannylthiophene-2-carboxylate Chemical compound S1C([Sn](CCCC)(CCCC)CCCC)=CC(N(C2CCC(O)CC2)C(=O)C2CCC(C)CC2)=C1C(=O)OC GVIDKWMNFNCELI-UHFFFAOYSA-N 0.000 description 1
- FUFKLFUHAOZTRC-UHFFFAOYSA-N methyl 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound S1C=CC(N(C2CCC(O)CC2)C(=O)C2CCC(C)CC2)=C1C(=O)OC FUFKLFUHAOZTRC-UHFFFAOYSA-N 0.000 description 1
- XCGYGTXIMOMXFU-UHFFFAOYSA-N methyl 3-[1,3-dihydroxypropan-2-yl-(4-methylcyclohexanecarbonyl)amino]-5-(4,4-dimethylcyclohexyl)thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2CCC(C)(C)CC2)=CC=1N(C(CO)CO)C(=O)C1CCC(C)CC1 XCGYGTXIMOMXFU-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
- 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
- VONOFJWOVOTLIO-UHFFFAOYSA-N methyl 5-bromo-3-[(4-fluorocyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound S1C(Br)=CC(N(C2CCC(F)CC2)C(=O)C2CCC(C)CC2)=C1C(=O)OC VONOFJWOVOTLIO-UHFFFAOYSA-N 0.000 description 1
- YMZBNCXRVMHBHA-UHFFFAOYSA-N methyl 5-cyclohex-2-en-1-yl-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylate Chemical compound COC(=O)C=1SC(C2C=CCCC2)=CC=1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1 YMZBNCXRVMHBHA-UHFFFAOYSA-N 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
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- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
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- 230000008569 process Effects 0.000 description 1
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- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- LFULEKSKNZEWOE-UHFFFAOYSA-N propanil Chemical compound CCC(=O)NC1=CC=C(Cl)C(Cl)=C1 LFULEKSKNZEWOE-UHFFFAOYSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 1
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- 238000002821 scintillation proximity assay Methods 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
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- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
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- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 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
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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
- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-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
- OWIOJZLDFONFSU-UHFFFAOYSA-N tetradecan-4-one Chemical compound CCCCCCCCCCC(=O)CCC OWIOJZLDFONFSU-UHFFFAOYSA-N 0.000 description 1
- HNUUPXWCBTYKDR-UHFFFAOYSA-N tetradecane-2,4-dione Chemical compound CCCCCCCCCCC(=O)CC(C)=O HNUUPXWCBTYKDR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 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
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
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- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
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- 150000003577 thiophenes Chemical class 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 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
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229950002810 valopicitabine Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Classifications
-
- 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
-
- 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
- C07D333/40—Thiophene-2-carboxylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- 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
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- 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
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- 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
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- 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
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| PCT/CA2006/000786 WO2006119646A1 (en) | 2005-05-13 | 2006-05-15 | Compounds and methods for the treatment or prevention of flavivirus infections |
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-
2006
- 2006-05-15 BR BRPI0610283-2A patent/BRPI0610283A2/pt not_active IP Right Cessation
- 2006-05-15 CN CN2006800248617A patent/CN101218224B/zh not_active Expired - Fee Related
- 2006-05-15 EP EP06741500A patent/EP1879879B1/en active Active
- 2006-05-15 EP EP12004718.8A patent/EP2546246A3/en not_active Withdrawn
- 2006-05-15 CN CN2012101163717A patent/CN102718744A/zh active Pending
- 2006-05-15 CA CA2607359A patent/CA2607359C/en not_active Expired - Fee Related
- 2006-05-15 JP JP2008510379A patent/JP5030947B2/ja not_active Expired - Fee Related
- 2006-05-15 WO PCT/CA2006/000786 patent/WO2006119646A1/en not_active Ceased
- 2006-05-15 KR KR1020077028215A patent/KR20080016597A/ko not_active Ceased
- 2006-05-15 EA EA200702493A patent/EA016071B1/ru not_active IP Right Cessation
- 2006-05-15 US US11/433,749 patent/US7569600B2/en not_active Expired - Fee Related
- 2006-05-15 EP EP12004696A patent/EP2543664A1/en not_active Withdrawn
- 2006-05-15 NZ NZ563909A patent/NZ563909A/en not_active IP Right Cessation
- 2006-05-15 MX MX2007014117A patent/MX2007014117A/es active IP Right Grant
- 2006-05-15 AU AU2006246227A patent/AU2006246227B2/en not_active Ceased
- 2006-05-15 SG SG201002905-6A patent/SG161315A1/en unknown
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- 2006-05-15 AP AP2007004245A patent/AP2007004245A0/xx unknown
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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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- 2012-03-09 US US13/416,565 patent/US8674118B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20120164103A1 (en) | 2012-06-28 |
| EA016071B1 (ru) | 2012-01-30 |
| HK1112910A1 (en) | 2008-09-19 |
| EP1879879B1 (en) | 2013-03-27 |
| CN102718744A (zh) | 2012-10-10 |
| US20100093775A1 (en) | 2010-04-15 |
| AU2006246227A1 (en) | 2006-11-16 |
| JP2008540463A (ja) | 2008-11-20 |
| EP2546246A3 (en) | 2013-04-24 |
| KR20080016597A (ko) | 2008-02-21 |
| EA200702493A1 (ru) | 2008-04-28 |
| CN101218224A (zh) | 2008-07-09 |
| JP5030947B2 (ja) | 2012-09-19 |
| WO2006119646A1 (en) | 2006-11-16 |
| EP2546246A2 (en) | 2013-01-16 |
| AU2006246227B2 (en) | 2011-04-28 |
| US20060276533A1 (en) | 2006-12-07 |
| ES2415742T3 (es) | 2013-07-26 |
| US7569600B2 (en) | 2009-08-04 |
| CN101218224B (zh) | 2013-05-08 |
| EP1879879A4 (en) | 2010-03-10 |
| SG161315A1 (en) | 2010-05-27 |
| CA2607359C (en) | 2011-08-09 |
| BRPI0610283A2 (pt) | 2010-10-19 |
| US8158675B2 (en) | 2012-04-17 |
| NZ563909A (en) | 2011-10-28 |
| CA2607359A1 (en) | 2006-11-16 |
| EP1879879A1 (en) | 2008-01-23 |
| ZA200709727B (en) | 2008-11-26 |
| AP2007004245A0 (en) | 2007-12-31 |
| US8674118B2 (en) | 2014-03-18 |
| EP2543664A1 (en) | 2013-01-09 |
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