TWI532735B - 9,9,10,10-tetrafluoro-9,10-dihydrophene hepatitis C Virus inhibitors and their use - Google Patents
9,9,10,10-tetrafluoro-9,10-dihydrophene hepatitis C Virus inhibitors and their use Download PDFInfo
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- TWI532735B TWI532735B TW103146591A TW103146591A TWI532735B TW I532735 B TWI532735 B TW I532735B TW 103146591 A TW103146591 A TW 103146591A TW 103146591 A TW103146591 A TW 103146591A TW I532735 B TWI532735 B TW I532735B
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- Prior art keywords
- alkyl
- group
- fluorenyl
- alkoxy
- groups
- Prior art date
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- 241000711549 Hepacivirus C Species 0.000 title claims description 53
- 239000003112 inhibitor Substances 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 287
- 150000001875 compounds Chemical class 0.000 claims description 204
- -1 amino fluorenyl Chemical group 0.000 claims description 170
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 85
- 238000002360 preparation method Methods 0.000 claims description 85
- 125000003545 alkoxy group Chemical group 0.000 claims description 81
- 229910052736 halogen Inorganic materials 0.000 claims description 64
- 150000002367 halogens Chemical class 0.000 claims description 64
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 60
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 58
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 48
- 125000001072 heteroaryl group Chemical group 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 46
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 26
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 25
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 23
- 125000003277 amino group Chemical group 0.000 claims description 23
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 15
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 15
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 125000001544 thienyl group Chemical group 0.000 claims description 13
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
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- 239000003814 drug Substances 0.000 claims description 9
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 9
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 9
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000001425 triazolyl group Chemical group 0.000 claims description 9
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical compound C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 6
- ROPLCSFPUPWHGJ-UHFFFAOYSA-N hydroxycyanamide Chemical compound ONC#N ROPLCSFPUPWHGJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 5
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
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- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 5
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 5
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- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
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- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
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- IBOFVQJTBBUKMU-UHFFFAOYSA-N 4,4'-methylene-bis-(2-chloroaniline) Chemical compound C1=C(Cl)C(N)=CC=C1CC1=CC=C(N)C(Cl)=C1 IBOFVQJTBBUKMU-UHFFFAOYSA-N 0.000 claims 1
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- 125000004442 acylamino group Chemical group 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 claims 1
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- 238000006243 chemical reaction Methods 0.000 description 72
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- 238000000034 method Methods 0.000 description 38
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 34
- 239000000651 prodrug Substances 0.000 description 32
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- 239000012453 solvate Substances 0.000 description 32
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- 239000007858 starting material Substances 0.000 description 21
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
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- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C25/00—Compounds containing at least one halogen atom bound to a six-membered aromatic ring
- C07C25/18—Polycyclic aromatic halogenated hydrocarbons
- C07C25/22—Polycyclic aromatic halogenated hydrocarbons with condensed rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310754318 | 2013-12-31 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201524973A TW201524973A (zh) | 2015-07-01 |
| TWI532735B true TWI532735B (zh) | 2016-05-11 |
Family
ID=53493209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW103146591A TWI532735B (zh) | 2013-12-31 | 2014-12-31 | 9,9,10,10-tetrafluoro-9,10-dihydrophene hepatitis C Virus inhibitors and their use |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US9512108B2 (enExample) |
| EP (1) | EP3091010A4 (enExample) |
| JP (1) | JP2017536329A (enExample) |
| KR (1) | KR101857689B1 (enExample) |
| CN (2) | CN105873922B (enExample) |
| AU (1) | AU2014375584B2 (enExample) |
| CA (1) | CA2935089C (enExample) |
| TW (1) | TWI532735B (enExample) |
| WO (1) | WO2015101215A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107266424A (zh) * | 2016-04-07 | 2017-10-20 | 南京圣和药业股份有限公司 | 二氢菲类化合物及其制备方法 |
| CN108623569A (zh) * | 2017-03-21 | 2018-10-09 | 南京圣和药业股份有限公司 | 9,10-二氢菲类化合物的制备方法 |
| CN108623570A (zh) * | 2017-03-21 | 2018-10-09 | 南京圣和药业股份有限公司 | 9,10-二氢菲类化合物、其制备方法及用途 |
| CN108619102A (zh) * | 2017-03-21 | 2018-10-09 | 南京圣和药业股份有限公司 | 一种包含丙型肝炎病毒抑制剂的药物组合物及其制备方法 |
| CN108623568B (zh) * | 2017-03-21 | 2022-04-19 | 南京汇诚制药有限公司 | 9,10二氢菲类丙型肝炎病毒抑制剂的盐型及其制备 |
| CN109419806B (zh) * | 2017-08-23 | 2023-06-20 | 南京圣和药业股份有限公司 | 抗病毒组合物及其应用 |
| CN114890916A (zh) * | 2022-04-25 | 2022-08-12 | 常州吉恩药业有限公司 | 一种n-甲氧羰基-l-叔亮氨酸的制备方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19524230A1 (de) * | 1995-07-04 | 1997-01-09 | Hoechst Ag | Fluorierte Phenanthren-Derivate und ihre Verwendung in flüssigkristallinen Mischungen |
| US6455744B1 (en) * | 2001-01-23 | 2002-09-24 | Air Products And Chemicals, Inc. | Synthesis of vicinal difluoro aromatics and intermediates thereof |
| MX363732B (es) * | 2009-05-13 | 2019-04-01 | Gilead Pharmasset Llc Star | Compuestos antivirales. |
| TWI548629B (zh) * | 2010-11-17 | 2016-09-11 | 吉李德製藥公司 | 抗病毒化合物 |
| CA2845321A1 (en) * | 2011-08-24 | 2013-02-28 | Glaxosmithkline Llc | Combination treatments for hepatitis c |
-
2014
- 2014-12-26 CA CA2935089A patent/CA2935089C/en not_active Expired - Fee Related
- 2014-12-26 KR KR1020167011524A patent/KR101857689B1/ko not_active Expired - Fee Related
- 2014-12-26 WO PCT/CN2014/095043 patent/WO2015101215A1/zh not_active Ceased
- 2014-12-26 EP EP14876481.4A patent/EP3091010A4/en not_active Withdrawn
- 2014-12-26 AU AU2014375584A patent/AU2014375584B2/en not_active Ceased
- 2014-12-26 CN CN201480071487.0A patent/CN105873922B/zh active Active
- 2014-12-26 JP JP2016531709A patent/JP2017536329A/ja active Pending
- 2014-12-26 US US15/030,990 patent/US9512108B2/en not_active Expired - Fee Related
- 2014-12-29 CN CN201410835606.7A patent/CN104744444B/zh active Active
- 2014-12-31 TW TW103146591A patent/TWI532735B/zh not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN105873922B (zh) | 2018-08-14 |
| CN105873922A (zh) | 2016-08-17 |
| KR20160058187A (ko) | 2016-05-24 |
| JP2017536329A (ja) | 2017-12-07 |
| CA2935089A1 (en) | 2015-07-09 |
| TW201524973A (zh) | 2015-07-01 |
| CN104744444B (zh) | 2019-02-26 |
| KR101857689B1 (ko) | 2018-05-14 |
| CA2935089C (en) | 2018-11-27 |
| AU2014375584B2 (en) | 2017-11-09 |
| US9512108B2 (en) | 2016-12-06 |
| EP3091010A1 (en) | 2016-11-09 |
| CN104744444A (zh) | 2015-07-01 |
| EP3091010A4 (en) | 2017-10-04 |
| US20160297804A1 (en) | 2016-10-13 |
| WO2015101215A1 (zh) | 2015-07-09 |
| AU2014375584A1 (en) | 2016-07-07 |
| HK1222845A1 (zh) | 2017-07-14 |
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| Date | Code | Title | Description |
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| MM4A | Annulment or lapse of patent due to non-payment of fees |