CA2508990C - Compounds and methods for the treatment or prevention of flavivirus infections - Google Patents

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Publication number

CA2508990C

CA2508990C CA2508990A CA2508990A CA2508990C CA 2508990 C CA2508990 C CA 2508990C CA 2508990 A CA2508990 A CA 2508990A CA 2508990 A CA2508990 A CA 2508990A CA 2508990 C CA2508990 C CA 2508990C

Authority

CA

Canada

Prior art keywords

methyl

phenyl

cyclohexyl

amino

carboxylic acid

Prior art date

2002-12-10

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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• 150000001875 compounds Chemical class 0.000 title claims abstract description 210
• 238000000034 method Methods 0.000 title description 25
• 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 69
• 241000710781 Flaviviridae Species 0.000 claims abstract description 17
• 208000036142 Viral infection Diseases 0.000 claims abstract description 13
• 230000009385 viral infection Effects 0.000 claims abstract description 13
• -1 cyano, hydroxyimino Chemical group 0.000 claims description 269
• 125000000217 alkyl group Chemical group 0.000 claims description 86
• 125000000623 heterocyclic group Chemical group 0.000 claims description 84
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 79
• 125000003118 aryl group Chemical group 0.000 claims description 63
• 125000003545 alkoxy group Chemical group 0.000 claims description 48
• 229910052736 halogen Inorganic materials 0.000 claims description 45
• 150000002367 halogens Chemical class 0.000 claims description 44
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
• 230000003612 virological effect Effects 0.000 claims description 44
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 42
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 41
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 41
• 239000003795 chemical substances by application Substances 0.000 claims description 40
• 125000001424 substituent group Chemical group 0.000 claims description 33
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
• 229910052703 rhodium Inorganic materials 0.000 claims description 28
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
• 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 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 23
• 125000004104 aryloxy group Chemical group 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 229910052757 nitrogen Inorganic materials 0.000 claims description 18
• 125000000018 nitroso group Chemical group N(=O)* 0.000 claims description 17
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 15
• 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 11
• 229940121759 Helicase inhibitor Drugs 0.000 claims description 11
• 229940123066 Polymerase inhibitor Drugs 0.000 claims description 11
• 229940122055 Serine protease inhibitor Drugs 0.000 claims description 11
• 101710102218 Serine protease inhibitor Proteins 0.000 claims description 11
• 239000003001 serine protease inhibitor Substances 0.000 claims description 11
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 9
• 230000000694 effects Effects 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 8
• 125000004122 cyclic group Chemical group 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 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 7
• 125000000304 alkynyl group Chemical group 0.000 claims description 7
• 239000003242 anti bacterial agent Substances 0.000 claims description 7
• 230000000692 anti-sense effect Effects 0.000 claims description 7
• 229960000329 ribavirin Drugs 0.000 claims description 7
• 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 7
• 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 6
• 125000003725 azepanyl group Chemical group 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 230000002401 inhibitory effect Effects 0.000 claims description 6
• 229920006395 saturated elastomer Polymers 0.000 claims description 6
• 229940021747 therapeutic vaccine Drugs 0.000 claims description 6
• 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 5
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 5
• 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 5
• 102000053642 Catalytic RNA Human genes 0.000 claims description 5
• 108090000994 Catalytic RNA Proteins 0.000 claims description 5
• 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 5
• 229930105110 Cyclosporin A Natural products 0.000 claims description 5
• 108010036949 Cyclosporine Proteins 0.000 claims description 5
• 102000014150 Interferons Human genes 0.000 claims description 5
• 108010050904 Interferons Proteins 0.000 claims description 5
• 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 5
• 244000272459 Silybum marianum Species 0.000 claims description 5
• 235000010841 Silybum marianum Nutrition 0.000 claims description 5
• 108010046075 Thymosin Proteins 0.000 claims description 5
• 102000007501 Thymosin Human genes 0.000 claims description 5
• 229960004308 acetylcysteine Drugs 0.000 claims description 5
• DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 5
• 229960003805 amantadine Drugs 0.000 claims description 5
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 229960001265 ciclosporin Drugs 0.000 claims description 5
• 229930182912 cyclosporin Natural products 0.000 claims description 5
• 229940079322 interferon Drugs 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 239000001301 oxygen Substances 0.000 claims description 5
• 108091092562 ribozyme Proteins 0.000 claims description 5
• 229910052717 sulfur Inorganic materials 0.000 claims description 5
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims description 5
• 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 5
• HQBQRPMEFPOVLG-UHFFFAOYSA-N 3-[(4-methoxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(OC)CCC1N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C(=O)C1CCC(C)CC1 HQBQRPMEFPOVLG-UHFFFAOYSA-N 0.000 claims description 4
• 241001024304 Mino Species 0.000 claims description 4
• HSEDSCPERRHAHJ-UHFFFAOYSA-N 3-[(4-carboxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CCC(C(O)=O)CC1 HSEDSCPERRHAHJ-UHFFFAOYSA-N 0.000 claims description 3
• YFLXLTMBSIBJFX-UHFFFAOYSA-N 3-[(4-hydroxyiminocyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CCC(=NO)CC1 YFLXLTMBSIBJFX-UHFFFAOYSA-N 0.000 claims description 3
• 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims description 3
• 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims description 3
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
• 125000002837 carbocyclic group Chemical group 0.000 claims description 3
• 125000005842 heteroatom Chemical group 0.000 claims description 3
• 159000000000 sodium salts Chemical group 0.000 claims description 3
• 239000011593 sulfur Substances 0.000 claims description 3
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
• 125000004437 phosphorous atom Chemical group 0.000 claims description 2
• 229910052698 phosphorus Inorganic materials 0.000 claims description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 4
• CKVYPTIWERNFSU-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CCC(O)CC1 CKVYPTIWERNFSU-UHFFFAOYSA-N 0.000 claims 3
• 239000003963 antioxidant agent Substances 0.000 claims 3
• PWKUJELUZICZFM-UHFFFAOYSA-N 3-[(3-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CC(O)CCC1 PWKUJELUZICZFM-UHFFFAOYSA-N 0.000 claims 2
• HWYFKCSXDHOHRG-UHFFFAOYSA-N 3-[(4-hydroxy-4-methylcyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CCC(C)(O)CC1 HWYFKCSXDHOHRG-UHFFFAOYSA-N 0.000 claims 2
• KQNJFWKYCOSRHN-UHFFFAOYSA-N 3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]-5-(4-methoxyphenyl)thiophene-2-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1=CC(N(C2CCC(O)CC2)C(=O)C2CCC(C)CC2)=C(C(O)=O)S1 KQNJFWKYCOSRHN-UHFFFAOYSA-N 0.000 claims 2
• PLAQJAAXXUBONJ-UHFFFAOYSA-N 3-[(4-methylcyclohexanecarbonyl)-(4-oxocyclohexyl)amino]-5-phenylthiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC=CC=1)C(O)=O)C1CCC(=O)CC1 PLAQJAAXXUBONJ-UHFFFAOYSA-N 0.000 claims 2
• BSMQCGKRWGBIGP-UHFFFAOYSA-N 5-(3,4-difluorophenyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=C(F)C(F)=CC=1)C(O)=O)C1CCC(O)CC1 BSMQCGKRWGBIGP-UHFFFAOYSA-N 0.000 claims 2
• GYEQPFHUEQWUQN-UHFFFAOYSA-N 5-(4-acetylphenyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC(=CC=1)C(C)=O)C(O)=O)C1CCC(O)CC1 GYEQPFHUEQWUQN-UHFFFAOYSA-N 0.000 claims 2
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 2
• 230000017105 transposition Effects 0.000 claims 2
• GLSJXMDZIWHNGM-UHFFFAOYSA-N 5-(3-fluorophenyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=C(F)C=CC=1)C(O)=O)C1CCC(O)CC1 GLSJXMDZIWHNGM-UHFFFAOYSA-N 0.000 claims 1
• RVDSTMCXOBCISN-UHFFFAOYSA-N 5-(4-chlorophenyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC(Cl)=CC=1)C(O)=O)C1CCC(O)CC1 RVDSTMCXOBCISN-UHFFFAOYSA-N 0.000 claims 1
• CSSMOEFQRXOWMG-UHFFFAOYSA-N 5-(4-fluorophenyl)-3-[(4-hydroxycyclohexyl)-(4-methylcyclohexanecarbonyl)amino]thiophene-2-carboxylic acid Chemical compound C1CC(C)CCC1C(=O)N(C1=C(SC(=C1)C=1C=CC(F)=CC=1)C(O)=O)C1CCC(O)CC1 CSSMOEFQRXOWMG-UHFFFAOYSA-N 0.000 claims 1
• CKVYPTIWERNFSU-JNXHAIIESA-N O[C@@H]1CC[C@H](CC1)N(C1=C(SC(=C1)C1=CC=CC=C1)C(=O)O)C(=O)C1CCC(CC1)C Chemical compound O[C@@H]1CC[C@H](CC1)N(C1=C(SC(=C1)C1=CC=CC=C1)C(=O)O)C(=O)C1CCC(CC1)C CKVYPTIWERNFSU-JNXHAIIESA-N 0.000 claims 1
• CKVYPTIWERNFSU-MWKAWSJZSA-N O[C@@H]1CC[C@H](CC1)N(C1=C(SC(=C1)C1=CC=CC=C1)C(=O)O)C(=O)[C@@H]1CC[C@@H](CC1)C Chemical compound O[C@@H]1CC[C@H](CC1)N(C1=C(SC(=C1)C1=CC=CC=C1)C(=O)O)C(=O)[C@@H]1CC[C@@H](CC1)C CKVYPTIWERNFSU-MWKAWSJZSA-N 0.000 claims 1
• CKVYPTIWERNFSU-WHUJAJFLSA-N O[C@H]1CC[C@H](CC1)N(C1=C(SC(=C1)C1=CC=CC=C1)C(=O)O)C(=O)C1CCC(CC1)C Chemical compound O[C@H]1CC[C@H](CC1)N(C1=C(SC(=C1)C1=CC=CC=C1)C(=O)O)C(=O)C1CCC(CC1)C CKVYPTIWERNFSU-WHUJAJFLSA-N 0.000 claims 1
• 125000005843 halogen group Chemical group 0.000 claims 1
• 125000001183 hydrocarbyl group Chemical group 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 142
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 115
• 238000005481 NMR spectroscopy Methods 0.000 description 86
• 239000000203 mixture Substances 0.000 description 78
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
• 101150041968 CDC13 gene Proteins 0.000 description 62
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 62
• WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 58
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
• 239000002253 acid Substances 0.000 description 55
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 50
• 239000002904 solvent Substances 0.000 description 46
• NKLCHDQGUHMCGL-UHFFFAOYSA-N cyclohexylidenemethanone Chemical group O=C=C1CCCCC1 NKLCHDQGUHMCGL-UHFFFAOYSA-N 0.000 description 42
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
• 229910052938 sodium sulfate Inorganic materials 0.000 description 36
• 235000011152 sodium sulphate Nutrition 0.000 description 36
• 239000012044 organic layer Substances 0.000 description 35
• 239000007832 Na2SO4 Substances 0.000 description 33
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
• 239000008346 aqueous phase Substances 0.000 description 29
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• 239000012267 brine Substances 0.000 description 27
• 238000006243 chemical reaction Methods 0.000 description 27
• 239000010410 layer Substances 0.000 description 27
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
• 238000003756 stirring Methods 0.000 description 27
• 239000007787 solid Substances 0.000 description 25
• 239000003480 eluent Substances 0.000 description 24
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 23
• 241000711549 Hepacivirus C Species 0.000 description 23
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 20
• 238000010992 reflux Methods 0.000 description 19
• 238000010898 silica gel chromatography Methods 0.000 description 18
• QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 18
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 17
• 238000004237 preparative chromatography Methods 0.000 description 16
• 238000000746 purification Methods 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• 125000000041 C6-C10 aryl group Chemical group 0.000 description 15
• 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 15
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 15
• 239000004480 active ingredient Substances 0.000 description 14
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
• 239000003921 oil Substances 0.000 description 13
• 238000005160 1H NMR spectroscopy Methods 0.000 description 12
• 239000000284 extract Substances 0.000 description 12
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
• 238000003818 flash chromatography Methods 0.000 description 11
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
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