ES2548286T3 - Nuevos inhibidores del virus de la hepatitis C - Google Patents
Nuevos inhibidores del virus de la hepatitis C Download PDFInfo
- Publication number
- ES2548286T3 ES2548286T3 ES11784875.4T ES11784875T ES2548286T3 ES 2548286 T3 ES2548286 T3 ES 2548286T3 ES 11784875 T ES11784875 T ES 11784875T ES 2548286 T3 ES2548286 T3 ES 2548286T3
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- mmol
- alkyl
- methyl
- compound
- optionally substituted
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- 239000003112 inhibitor Substances 0.000 title claims description 20
- 241000711549 Hepacivirus C Species 0.000 title description 43
- 150000001875 compounds Chemical class 0.000 claims abstract description 210
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 67
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 45
- 239000001257 hydrogen Substances 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 25
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 17
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000006413 ring segment Chemical group 0.000 claims abstract description 6
- 229910052702 rhenium Inorganic materials 0.000 claims abstract description 5
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 5
- 229910003827 NRaRb Inorganic materials 0.000 claims abstract description 4
- 229910052701 rubidium Inorganic materials 0.000 claims abstract description 4
- -1 2,2-dimethylcyclopropyl Chemical group 0.000 claims description 100
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- 108010050904 Interferons Proteins 0.000 claims description 16
- 102000014150 Interferons Human genes 0.000 claims description 16
- 239000002777 nucleoside Substances 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 14
- 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 14
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 229940047124 interferons Drugs 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
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- 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 10
- 229940124597 therapeutic agent Drugs 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 208000010710 hepatitis C virus infection Diseases 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 7
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 229940124771 HCV-NS3 protease inhibitor Drugs 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 108700008776 hepatitis C virus NS-5 Proteins 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 6
- 150000002431 hydrogen Chemical group 0.000 abstract description 6
- 125000001475 halogen functional group Chemical group 0.000 abstract 4
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- 238000000034 method Methods 0.000 description 69
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- 239000002253 acid Substances 0.000 description 52
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 40
- 239000000047 product Substances 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 35
- 239000000460 chlorine Substances 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 32
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- DEKJPODSYVPCPW-ZGZXFVETSA-N 4-(aminomethyl)-N-[(12E,15S)-17,19-diazatricyclo[14.2.1.02,7]nonadeca-1(18),2,4,6,12,16-hexaen-15-yl]cyclohexane-1-carboxamide Chemical compound NCC1CCC(CC1)C(=O)N[C@H]1C\C=C\CCCCc2ccccc2-c2cnc1[nH]2 DEKJPODSYVPCPW-ZGZXFVETSA-N 0.000 description 23
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- 238000006243 chemical reaction Methods 0.000 description 22
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 238000003556 assay Methods 0.000 description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- 125000006239 protecting group Chemical group 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
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- IPOCOANFUVSCLZ-UHFFFAOYSA-N 6-fluoropyridine-3-carbonyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C=N1 IPOCOANFUVSCLZ-UHFFFAOYSA-N 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 11
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 10
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- 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
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (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)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
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| US410267P | 2002-09-13 | ||
| US41026710P | 2010-11-04 | 2010-11-04 | |
| US201161444046P | 2011-02-17 | 2011-02-17 | |
| US201161444046P | 2011-02-17 | ||
| US201161492267P | 2011-06-01 | 2011-06-01 | |
| US201161492267P | 2011-06-01 | ||
| PCT/US2011/059061 WO2012061552A1 (en) | 2010-11-04 | 2011-11-03 | Novel inhibitors of hepatitis c virus |
Publications (1)
| Publication Number | Publication Date |
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| ES2548286T3 true ES2548286T3 (es) | 2015-10-15 |
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| ES11784875.4T Active ES2548286T3 (es) | 2010-11-04 | 2011-11-03 | Nuevos inhibidores del virus de la hepatitis C |
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| EP (1) | EP2635571B1 (enExample) |
| JP (1) | JP5891235B2 (enExample) |
| CN (1) | CN103189371B (enExample) |
| AR (1) | AR083757A1 (enExample) |
| CA (1) | CA2814534A1 (enExample) |
| ES (1) | ES2548286T3 (enExample) |
| TW (1) | TW201249827A (enExample) |
| WO (1) | WO2012061552A1 (enExample) |
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| ES2816565T3 (es) * | 2007-06-12 | 2021-04-05 | Technolines Llc | Métodos y sistemas de trazado láser de alta velocidad y alta potencia |
| EP2853531A3 (en) * | 2009-06-11 | 2015-08-12 | AbbVie Bahamas Ltd. | Antiviral compounds |
| US8937150B2 (en) | 2009-06-11 | 2015-01-20 | Abbvie Inc. | Anti-viral compounds |
| NZ605440A (en) | 2010-06-10 | 2014-05-30 | Abbvie Bahamas Ltd | Solid compositions comprising an hcv inhibitor |
| CA2814534A1 (en) * | 2010-11-04 | 2012-05-10 | Theravance, Inc. | Novel inhibitors of hepatitis c virus |
| US8552047B2 (en) | 2011-02-07 | 2013-10-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US9546160B2 (en) | 2011-05-12 | 2017-01-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
| RS55701B1 (sr) | 2011-06-22 | 2017-07-31 | Purdue Pharma Lp | Trpv1 antagonisti koji uključuju dihidroksi supstituent i njihove upotrebe |
| AR088630A1 (es) * | 2011-11-03 | 2014-06-25 | Theravance Inc | Inhibidores del virus de la hepatitis c |
| US9034832B2 (en) | 2011-12-29 | 2015-05-19 | Abbvie Inc. | Solid compositions |
| US9326973B2 (en) | 2012-01-13 | 2016-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| CA2869908C (en) * | 2012-04-25 | 2018-02-20 | Theravance Biopharma R&D Ip, Llc | Hepatitis c virus inhibitors |
| LT2850075T (lt) | 2012-04-25 | 2017-05-10 | Theravance Biopharma R&D Ip, Llc | Piperazino-piperidino junginiai, kaip hepatito c viruso inhibitoriai |
| WO2013165796A1 (en) * | 2012-05-03 | 2013-11-07 | Theravance, Inc. | Crystalline form of a pyridyl-piperazinyl hepatitis c virus inhibitor |
| US11484534B2 (en) | 2013-03-14 | 2022-11-01 | Abbvie Inc. | Methods for treating HCV |
| US9717712B2 (en) | 2013-07-02 | 2017-08-01 | Bristol-Myers Squibb Company | Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus |
| US20150023913A1 (en) | 2013-07-02 | 2015-01-22 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
| JP2016527232A (ja) | 2013-07-17 | 2016-09-08 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Ｈｃｖの治療に使用するためのビフェニル誘導体を含む組み合わせ |
| WO2015103490A1 (en) | 2014-01-03 | 2015-07-09 | Abbvie, Inc. | Solid antiviral dosage forms |
| US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| CN105175401A (zh) * | 2015-10-16 | 2015-12-23 | 北京康立生医药技术开发有限公司 | 一种依匹哌唑的制备方法 |
| CN112480084B (zh) * | 2017-11-27 | 2021-09-21 | 常州寅盛药业有限公司 | 反应路线简单的达卡他韦起始原料的合成方法 |
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| GB0421908D0 (en) * | 2004-10-01 | 2004-11-03 | Angeletti P Ist Richerche Bio | New uses |
| PL1940786T3 (pl) * | 2005-09-16 | 2010-12-31 | Arrow Therapeutics Ltd | Pochodne bifenylowe i ich zastosowanie w leczeniu zapalenia wątroby typu C |
| US8329159B2 (en) * | 2006-08-11 | 2012-12-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7659270B2 (en) | 2006-08-11 | 2010-02-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7745636B2 (en) | 2006-08-11 | 2010-06-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| CN101558059B (zh) * | 2006-08-11 | 2014-12-03 | 百时美施贵宝公司 | 丙型肝炎病毒抑制剂 |
| US8303944B2 (en) | 2006-08-11 | 2012-11-06 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7910722B2 (en) * | 2007-07-05 | 2011-03-22 | Florida State University Research Foundation | RNAi therapeutic for treatment of hepatitis C infection |
| CN101998952B (zh) | 2008-02-12 | 2014-10-08 | 百时美施贵宝公司 | 丙型肝炎病毒抑制剂 |
| WO2010065668A1 (en) | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
| WO2010094977A1 (en) | 2009-02-23 | 2010-08-26 | Arrow Therapeutics Limited | Novel biphenyl compounds useful for the treatment of hepatitis c |
| US20120040977A1 (en) | 2009-02-23 | 2012-02-16 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
| US8822700B2 (en) | 2009-09-11 | 2014-09-02 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| EP2475254A4 (en) | 2009-09-11 | 2013-05-22 | Enanta Pharm Inc | HEPATITIS C-VIRUS HEMMER |
| US8653070B2 (en) | 2009-12-14 | 2014-02-18 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| US8377980B2 (en) | 2009-12-16 | 2013-02-19 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| EP2575819A4 (en) | 2010-06-04 | 2013-11-27 | Enanta Pharm Inc | INHIBITORS OF HEPATITIS C VIRUS |
| CA2814534A1 (en) * | 2010-11-04 | 2012-05-10 | Theravance, Inc. | Novel inhibitors of hepatitis c virus |
| AR088630A1 (es) | 2011-11-03 | 2014-06-25 | Theravance Inc | Inhibidores del virus de la hepatitis c |
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2011
- 2011-11-03 CA CA2814534A patent/CA2814534A1/en not_active Abandoned
- 2011-11-03 US US13/288,216 patent/US8921372B2/en not_active Expired - Fee Related
- 2011-11-03 EP EP11784875.4A patent/EP2635571B1/en active Active
- 2011-11-03 WO PCT/US2011/059061 patent/WO2012061552A1/en not_active Ceased
- 2011-11-03 JP JP2013537808A patent/JP5891235B2/ja not_active Expired - Fee Related
- 2011-11-03 ES ES11784875.4T patent/ES2548286T3/es active Active
- 2011-11-03 CN CN201180053127.4A patent/CN103189371B/zh not_active Expired - Fee Related
- 2011-11-04 AR ARP110104114A patent/AR083757A1/es not_active Application Discontinuation
- 2011-11-04 TW TW100140412A patent/TW201249827A/zh unknown
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2014
- 2014-11-12 US US14/539,039 patent/US9260414B2/en not_active Expired - Fee Related
Also Published As
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| US20120114600A1 (en) | 2012-05-10 |
| US9260414B2 (en) | 2016-02-16 |
| CN103189371A (zh) | 2013-07-03 |
| CN103189371B (zh) | 2015-04-01 |
| JP5891235B2 (ja) | 2016-03-22 |
| TW201249827A (en) | 2012-12-16 |
| US8921372B2 (en) | 2014-12-30 |
| JP2013544812A (ja) | 2013-12-19 |
| CA2814534A1 (en) | 2012-05-10 |
| AR083757A1 (es) | 2013-03-20 |
| EP2635571A1 (en) | 2013-09-11 |
| WO2012061552A1 (en) | 2012-05-10 |
| EP2635571B1 (en) | 2015-08-12 |
| US20150071878A1 (en) | 2015-03-12 |
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