CN101228181A - Hcv ns3蛋白酶抑制剂 - Google Patents
Hcv ns3蛋白酶抑制剂 Download PDFInfo
- Publication number
- CN101228181A CN101228181A CN200680026414.5A CN200680026414A CN101228181A CN 101228181 A CN101228181 A CN 101228181A CN 200680026414 A CN200680026414 A CN 200680026414A CN 101228181 A CN101228181 A CN 101228181A
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- China
- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- carbonyl
- heteroaryl
- Prior art date
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- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 title 1
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 183
- 229910052760 oxygen Inorganic materials 0.000 claims description 164
- 229910052757 nitrogen Inorganic materials 0.000 claims description 150
- 150000001875 compounds Chemical class 0.000 claims description 148
- 238000002360 preparation method Methods 0.000 claims description 116
- -1 heterocyclic radical Chemical class 0.000 claims description 114
- 125000003118 aryl group Chemical group 0.000 claims description 98
- 125000001072 heteroaryl group Chemical group 0.000 claims description 73
- 229910052799 carbon Inorganic materials 0.000 claims description 59
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 39
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 29
- 229920006395 saturated elastomer Polymers 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 25
- 239000003443 antiviral agent Substances 0.000 claims description 23
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 20
- 125000001624 naphthyl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 13
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- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 13
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- 230000000694 effects Effects 0.000 claims description 7
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- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
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- 208000015181 infectious disease Diseases 0.000 abstract description 7
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 229
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 142
- 239000001301 oxygen Substances 0.000 description 135
- 238000000034 method Methods 0.000 description 124
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 79
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- 235000019439 ethyl acetate Nutrition 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
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- 239000000203 mixture Substances 0.000 description 56
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- 238000006243 chemical reaction Methods 0.000 description 51
- 150000003839 salts Chemical class 0.000 description 47
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 39
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 38
- 239000003921 oil Substances 0.000 description 37
- 235000019198 oils Nutrition 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- 238000001035 drying Methods 0.000 description 33
- 238000001704 evaporation Methods 0.000 description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- 238000005406 washing Methods 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 26
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- 239000011734 sodium Substances 0.000 description 26
- 229920002554 vinyl polymer Polymers 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
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- 230000008020 evaporation Effects 0.000 description 23
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 239000000284 extract Substances 0.000 description 20
- 239000010410 layer Substances 0.000 description 20
- 102000035195 Peptidases Human genes 0.000 description 19
- 108091005804 Peptidases Proteins 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- FNAZRRHPUDJQCJ-UHFFFAOYSA-N henicosane Chemical compound CCCCCCCCCCCCCCCCCCCCC FNAZRRHPUDJQCJ-UHFFFAOYSA-N 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 125000000623 heterocyclic group Chemical group 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
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- 239000000706 filtrate Substances 0.000 description 13
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 13
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 238000012546 transfer Methods 0.000 description 11
- IWUCXVSUMQZMFG-RGDLXGNYSA-N 1-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide Chemical compound N1=C(C(=O)N)N=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 IWUCXVSUMQZMFG-RGDLXGNYSA-N 0.000 description 10
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- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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- 150000001538 azepines Chemical class 0.000 description 8
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 8
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims (20)
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US60/724,566 | 2005-10-07 | ||
PCT/US2006/027831 WO2007015855A1 (en) | 2005-07-20 | 2006-07-14 | Hcv ns3 protease inhibitors |
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CN101228181A true CN101228181A (zh) | 2008-07-23 |
CN101228181B CN101228181B (zh) | 2013-09-18 |
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CN200680026414.5A Expired - Fee Related CN101228181B (zh) | 2005-07-20 | 2006-07-14 | Hcv ns3蛋白酶抑制剂 |
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CN (1) | CN101228181B (zh) |
UA (1) | UA90909C2 (zh) |
ZA (1) | ZA200800072B (zh) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102227435A (zh) * | 2008-09-29 | 2011-10-26 | 百时美施贵宝公司 | 丙型肝炎病毒抑制剂 |
CN102617705A (zh) * | 2012-02-16 | 2012-08-01 | 银杏树药业(苏州)有限公司 | 抑制丙肝病毒复制的大环类化合物 |
CN102827246A (zh) * | 2011-06-16 | 2012-12-19 | 爱博新药研发(上海)有限公司 | 抑制丙型肝炎病毒的大环状杂环化合物及其制备和应用 |
CN103717067A (zh) * | 2010-12-14 | 2014-04-09 | 默沙东公司 | 制备大环内酰胺的方法与中间体 |
CN103874414A (zh) * | 2011-08-19 | 2014-06-18 | 默沙东公司 | 用于制备大环内酰胺类的方法和中间体 |
CN104718211A (zh) * | 2012-08-08 | 2015-06-17 | 默沙东公司 | Hcv ns3蛋白酶抑制剂 |
CN109678787A (zh) * | 2018-12-31 | 2019-04-26 | 南京晓庄学院 | 一种新的hcv病毒ns3/4a抑制剂合成中间体及合成方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4557714B2 (ja) * | 2002-05-10 | 2010-10-06 | メディミューン,エルエルシー | EphA2モノクローナル抗体およびその使用法 |
-
2006
- 2006-07-14 CN CN200680026414.5A patent/CN101228181B/zh not_active Expired - Fee Related
- 2006-07-14 UA UAA200802000A patent/UA90909C2/ru unknown
-
2008
- 2008-01-03 ZA ZA200800072A patent/ZA200800072B/xx unknown
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102227435A (zh) * | 2008-09-29 | 2011-10-26 | 百时美施贵宝公司 | 丙型肝炎病毒抑制剂 |
CN103717067A (zh) * | 2010-12-14 | 2014-04-09 | 默沙东公司 | 制备大环内酰胺的方法与中间体 |
CN102827246A (zh) * | 2011-06-16 | 2012-12-19 | 爱博新药研发(上海)有限公司 | 抑制丙型肝炎病毒的大环状杂环化合物及其制备和应用 |
CN103874414A (zh) * | 2011-08-19 | 2014-06-18 | 默沙东公司 | 用于制备大环内酰胺类的方法和中间体 |
CN102617705A (zh) * | 2012-02-16 | 2012-08-01 | 银杏树药业(苏州)有限公司 | 抑制丙肝病毒复制的大环类化合物 |
CN102617705B (zh) * | 2012-02-16 | 2014-12-31 | 上海纬诺医药科技有限公司 | 抑制丙肝病毒复制的大环类化合物 |
CN104718211A (zh) * | 2012-08-08 | 2015-06-17 | 默沙东公司 | Hcv ns3蛋白酶抑制剂 |
CN109678787A (zh) * | 2018-12-31 | 2019-04-26 | 南京晓庄学院 | 一种新的hcv病毒ns3/4a抑制剂合成中间体及合成方法 |
Also Published As
Publication number | Publication date |
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UA90909C2 (en) | 2010-06-10 |
ZA200800072B (en) | 2010-06-30 |
CN101228181B (zh) | 2013-09-18 |
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