ECSP045191A - "nuevos péptidos como inhibidores de la proteasa serina ns3 del virus de la hepatitis c" - Google Patents

"nuevos péptidos como inhibidores de la proteasa serina ns3 del virus de la hepatitis c"

Info

Publication number
ECSP045191A
ECSP045191A EC2004005191A ECSP045191A ECSP045191A EC SP045191 A ECSP045191 A EC SP045191A EC 2004005191 A EC2004005191 A EC 2004005191A EC SP045191 A ECSP045191 A EC SP045191A EC SP045191 A ECSP045191 A EC SP045191A
Authority
EC
Ecuador
Prior art keywords
hepatitis
virus
inhibitors
serine protease
new peptides
Prior art date
Application number
EC2004005191A
Other languages
English (en)
Inventor
Anil K Saksena
Viyyoor M Girijavallabhn
Raymond G Lovey
Edwin Jao
Frank Bennett
Cormick Jinping L Mc
Haiyan Wang
Russell E Pike
Stephane L Bogen
Tin-Yau Chan
Yi Tsung Liu
Zhaoning Zhu
F George Njoroge
Ashok Arasappan
Tejal Parekh
Ashit K Ganguly
Kevin X Chen
Srikanth Venkatraman
Henry A Vaccaro
Patrick A Pinto
Bama Santhanam
Scott Jeffrey Kemp
Odile Esther Levy
Wilvy Marguerita Lim
Susan Y Tamura
Wanli Wu
Siska Hendrata
Yuhua Huang
Jesse K Wong
Latha G Nair
Original Assignee
Schering Corp
Dendreon Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering Corp, Dendreon Corp filed Critical Schering Corp
Publication of ECSP045191A publication Critical patent/ECSP045191A/es

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0802Tripeptides with the first amino acid being neutral
    • C07K5/0804Tripeptides with the first amino acid being neutral and aliphatic
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0802Tripeptides with the first amino acid being neutral
    • C07K5/0812Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0827Tripeptides containing heteroatoms different from O, S, or N
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02Linear peptides containing at least one abnormal peptide link
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Virology (AREA)
  • Engineering & Computer Science (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La presente invención describe nuevos compuestos que tienen actividad inhibidora de la proteasa del HCV como también métodos para preparar dichos compuestos. En otra realización, la invención describe composiciones farmacéuticas que comprenden dichos compuestos como así también métodos para usarlos en el tratamiento de trastornos asociados con la proteasa del HCV.
EC2004005191A 2002-01-18 2004-07-15 "nuevos péptidos como inhibidores de la proteasa serina ns3 del virus de la hepatitis c" ECSP045191A (es)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10/052,386 US7244721B2 (en) 2000-07-21 2002-01-18 Peptides as NS3-serine protease inhibitors of hepatitis C virus

Publications (1)

Publication Number Publication Date
ECSP045191A true ECSP045191A (es) 2004-08-27

Family

ID=27609106

Family Applications (1)

Application Number Title Priority Date Filing Date
EC2004005191A ECSP045191A (es) 2002-01-18 2004-07-15 "nuevos péptidos como inhibidores de la proteasa serina ns3 del virus de la hepatitis c"

Country Status (28)

Country Link
US (2) US7244721B2 (es)
EP (1) EP1481000B1 (es)
JP (1) JP4563033B2 (es)
KR (1) KR101020355B1 (es)
CN (2) CN101792483A (es)
AR (1) AR038183A1 (es)
AT (1) ATE469914T1 (es)
AU (1) AU2009210423B2 (es)
BR (1) BR0306931A (es)
CA (1) CA2473032A1 (es)
CO (1) CO5650168A2 (es)
CY (1) CY1111225T1 (es)
DE (1) DE60332814D1 (es)
DK (1) DK1481000T3 (es)
EC (1) ECSP045191A (es)
IL (1) IL162815A0 (es)
MX (1) MXPA04006934A (es)
MY (1) MY140710A (es)
NO (1) NO20042792L (es)
NZ (1) NZ571073A (es)
PE (1) PE20030852A1 (es)
PL (1) PL372747A1 (es)
PT (1) PT1481000E (es)
RU (1) RU2404189C9 (es)
SI (1) SI1481000T1 (es)
TW (1) TWI334872B (es)
WO (1) WO2003062265A2 (es)
ZA (1) ZA200405304B (es)

Families Citing this family (164)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ298749B6 (cs) 1996-10-18 2008-01-16 Vertex Pharmaceuticals Incorporated Inhibitory serinových proteáz a farmaceutické prostředky s jejich obsahem
MXPA03000627A (es) 2000-07-21 2004-07-30 Schering Corp Nuevos peptidos como inhibidores de proteasa serina-ns3 del virus de la hepatitis c.
SV2003000617A (es) 2000-08-31 2003-01-13 Lilly Co Eli Inhibidores de la proteasa peptidomimetica ref. x-14912m
JP2003007697A (ja) * 2001-06-21 2003-01-10 Hitachi Kokusai Electric Inc 半導体装置の製造方法、基板処理方法および基板処理装置
MY140680A (en) 2002-05-20 2010-01-15 Bristol Myers Squibb Co Hepatitis c virus inhibitors
AR044694A1 (es) * 2003-06-17 2005-09-21 Schering Corp Proceso y compuestos intermedios para la preparacion de (1r, 2s,5s) - 3 azabiciclo [3,1,0] hexano-2- carboxamida, n- [3- amino-1- (ciclobutilmetil) - 2, 3 - dioxopropil] -3- [ (2s) - 2 - [[ [ 1,1- dimetiletil] amino] carbonilamino] -3,3-dimetil -1- oxobutil]-6,6 dimetilo
EP1633698A1 (en) 2003-06-17 2006-03-15 Schering Corporation Process and intermediates for the preparation of 3-(amino)-3-cyclobutylmethyl-2-hydroxy-propionamide or salts thereof
MXPA05013752A (es) * 2003-06-17 2006-03-08 Schering Corp Procedimiento e intermediarios para la preparacion de (1r,2s,5s)-6,6-dimetil-3-azabiciclo[3,1,0]exan-2-carboxilatos o sales de los mismos.
WO2005021584A2 (en) * 2003-08-26 2005-03-10 Schering Corporation Novel peptidomimetic ns3-serine protease inhibitors of hepatitis c virus
PE20050374A1 (es) 2003-09-05 2005-05-30 Vertex Pharma Inhibidores de proteasas de serina, en particular proteasa ns3-ns4a del vhc
US20110150835A1 (en) * 2003-09-26 2011-06-23 Schering Corporation Macrocyclic Inhibitors of Hepatitis C Virus NS3 Serine Protease
KR20060085248A (ko) * 2003-09-26 2006-07-26 쉐링 코포레이션 C형 간염 바이러스 ns3 세린 프로테아제의마크로사이클릭 억제제
US7491794B2 (en) * 2003-10-14 2009-02-17 Intermune, Inc. Macrocyclic compounds as inhibitors of viral replication
CA2549167A1 (en) * 2003-12-11 2005-06-30 Schering Corporation Inhibitors of hepatitis c virus ns3/ns4a serine protease
KR20120090077A (ko) 2004-01-30 2012-08-16 얀센 알 앤드 디 아일랜드 Hcv ns?3 세린 프로테아제 저해제
EP2311851A3 (en) * 2004-02-04 2011-05-25 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
UY28758A1 (es) 2004-02-20 2005-09-30 Boehringer Ingelheim Int Inhibidores de polimerasa viral
AU2005219824B2 (en) * 2004-02-27 2007-11-29 Merck Sharp & Dohme Corp. Novel ketoamides with cyclic p4's as inhibitors of ns3 serine protease of hepatitis c virus
US7192957B2 (en) * 2004-02-27 2007-03-20 Schering Corporation Compounds as inhibitors of hepatitis C virus NS3 serine protease
DE602005023224D1 (de) * 2004-02-27 2010-10-07 Schering Corp Neuartige Verbindungen als Hemmer von Hepatitis C-Virus NS3-Serinprotease
MY145081A (en) * 2004-02-27 2011-12-15 Schering Corp Sulfur compounds as inhibitors of hepatitis c virus ns3 serine protease
ES2328589T3 (es) * 2004-02-27 2009-11-16 Schering Corporation Compuestos de la prolina 3,4(ciclopentil) fusionados como inhibidores de la proteasa serina ns3 del virus de la hepatitis c.
CN1946690A (zh) * 2004-02-27 2007-04-11 先灵公司 用作丙型肝炎病毒ns3丝氨酸蛋白酶抑制剂的含环丁烯二酮基团化合物
US7205330B2 (en) * 2004-02-27 2007-04-17 Schering Corporation Inhibitors of hepatitis C virus NS3 protease
US7816326B2 (en) * 2004-02-27 2010-10-19 Schering Corporation Sulfur compounds as inhibitors of hepatitis C virus NS3 serine protease
AR049635A1 (es) * 2004-05-06 2006-08-23 Schering Corp (1r,2s,5s)-n-((1s)-3-amino-1-(ciclobutilmetil)-2,3-dioxopropil)-3-((2s)-2-((((1,1-dimetiletil)amino)carbonil)amino)-3,3-dimetil-1-oxobutil)-6,6-dimetil-3-azabiciclo(3.1.0)hexan-2-carboxamida como inhibidor de la ns3/ns4a serina proteasa del virus de la hepatitis c
CN1984922A (zh) * 2004-05-20 2007-06-20 先灵公司 用作丙型肝炎病毒ns3丝氨酸蛋白酶抑制剂的取代脯氨酸
CA2590962A1 (en) * 2004-12-06 2006-06-15 Siga Technologies, Inc. Sulfonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses
US8410149B2 (en) 2004-12-06 2013-04-02 Siga Technologies Inc. Sulfonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses
US7994221B2 (en) 2004-12-06 2011-08-09 Siga Technologies, Inc. Sulfonyl semicarbazides, carbonyl semicarbazides, semicarbazides and ureas, pharmaceutical compositions thereof, and methods for treating hemorrhagic fever viruses, including infections associated with arenaviruses
GB0426661D0 (en) * 2004-12-06 2005-01-05 Isis Innovation Pyrrolidine compounds
WO2006130687A2 (en) * 2005-06-02 2006-12-07 Schering Corporation Liver/plasma concentration ratio for dosing hepatitis c virus protease inhibitor
WO2006130686A2 (en) 2005-06-02 2006-12-07 Schering Corporation Hcv protease inhibitors in combination with food
US20060276406A1 (en) * 2005-06-02 2006-12-07 Schering Corporation Methods of treating hepatitis C virus
WO2006130554A2 (en) * 2005-06-02 2006-12-07 Schering Corporation Methods of treating hepatitis c virus
NZ563369A (en) * 2005-06-02 2011-03-31 Schering Corp Controlled-release formulation useful for treating disorders associated with hepatitus C virus
US20060276404A1 (en) * 2005-06-02 2006-12-07 Anima Ghosal Medicaments and methods combining a HCV protease inhibitor and an AKR competitor
US20060275366A1 (en) * 2005-06-02 2006-12-07 Schering Corporation Controlled-release formulation
WO2006130627A2 (en) * 2005-06-02 2006-12-07 Schering Corporation Methods for treating hepatitis c
CN101212970B (zh) * 2005-06-02 2010-07-21 先灵公司 Hcv蛋白酶抑制剂与表面活性剂的组合物
US20060281689A1 (en) * 2005-06-02 2006-12-14 Schering Corporation Method for modulating activity of HCV protease through use of a novel HCV protease inhibitor to reduce duration of treatment period
US7608592B2 (en) * 2005-06-30 2009-10-27 Virobay, Inc. HCV inhibitors
JP5249028B2 (ja) * 2005-07-25 2013-07-31 インターミューン・インコーポレーテッド C型肝炎ウイルス複製の新規大環状阻害剤
PE20070211A1 (es) 2005-07-29 2007-05-12 Medivir Ab Compuestos macrociclicos como inhibidores del virus de hepatitis c
CA2619659A1 (en) * 2005-08-19 2007-02-22 Vertex Pharmaceuticals Incorporated Processes and intermediates
US8399615B2 (en) * 2005-08-19 2013-03-19 Vertex Pharmaceuticals Incorporated Processes and intermediates
AR055395A1 (es) 2005-08-26 2007-08-22 Vertex Pharma Compuestos inhibidores de la actividad de la serina proteasa ns3-ns4a del virus de la hepatitis c
US7964624B1 (en) 2005-08-26 2011-06-21 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
GEP20104956B (en) 2005-10-11 2010-04-12 Array Biopharma Inc Compounds for inhibiting hepatitis c viral replication and use thereof
AR056805A1 (es) * 2005-11-14 2007-10-24 Schering Corp Un proceso para oxidacion para la preparcion de n- (3- amino-1- ( ciclobutilmetil) -2,3- dioxopropil ) -3-(n-(( ter-butilamino) carbonil )-3- metil- l- valil) -6,6- dimetil-3- azabiciclo (3.1.0) hexano -2- carboxamida y compuestos ralacionados
EP1963267B1 (en) * 2005-12-22 2013-08-14 Merck Sharp & Dohme Corp. Process for the preparation of 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane compounds and enantiomeric salts thereof
DK1966130T3 (da) 2005-12-23 2014-02-10 Zealand Pharma As Modificerede lysin-mimetiske forbindelser
US7816348B2 (en) 2006-02-03 2010-10-19 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
CA2643688A1 (en) * 2006-02-27 2007-08-30 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
WO2007109080A2 (en) 2006-03-16 2007-09-27 Vertex Pharmaceuticals Incorporated Deuterated hepatitis c protease inhibitors
WO2007120595A2 (en) * 2006-04-11 2007-10-25 Novartis Ag Amines for the treatment of hcv
CA2643680A1 (en) 2006-04-11 2007-11-22 Novartis Ag Hcv/hiv inhibitors and their uses
US7951823B2 (en) * 2006-05-23 2011-05-31 Irm Llc Compounds and compositions as channel activating protease inhibitors
KR20090024834A (ko) 2006-07-05 2009-03-09 인터뮨, 인크. C형 간염 바이러스 복제의 신규 억제제
EP2049474B1 (en) 2006-07-11 2015-11-04 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
US7659270B2 (en) * 2006-08-11 2010-02-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7759495B2 (en) * 2006-08-11 2010-07-20 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8329159B2 (en) * 2006-08-11 2012-12-11 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
JP2010500978A (ja) 2006-08-17 2010-01-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ウイルスポリメラーゼインヒビター
US8343477B2 (en) 2006-11-01 2013-01-01 Bristol-Myers Squibb Company Inhibitors of hepatitis C virus
US7772180B2 (en) 2006-11-09 2010-08-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7888464B2 (en) * 2006-11-16 2011-02-15 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7763584B2 (en) 2006-11-16 2010-07-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8003604B2 (en) 2006-11-16 2011-08-23 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2008073282A2 (en) * 2006-12-07 2008-06-19 Schering Corporation Ph sensitive matrix formulation
WO2008079266A2 (en) 2006-12-21 2008-07-03 Wyeth Synthesis of pyrrolidine compounds
WO2008074035A1 (en) 2006-12-27 2008-06-19 Abbott Laboratories Hcv protease inhibitors and uses thereof
KR20090108131A (ko) * 2007-02-09 2009-10-14 아이알엠 엘엘씨 채널 활성화 프로테아제 억제제로서의 화합물 및 조성물
WO2008106058A2 (en) * 2007-02-27 2008-09-04 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
GEP20125645B (en) 2007-02-27 2012-09-25 Vertex Pharma Co-crystals and pharmaceutical compositions comprising the same
JP2010522172A (ja) * 2007-03-23 2010-07-01 シェーリング コーポレイション Hcvns3プロテアーゼのp1−非エピメリ化ケトアミド阻害剤
KR20100024920A (ko) * 2007-05-03 2010-03-08 인터뮨, 인크. C형 간염 바이러스 복제의 신규 마크로사이클릭 저해제
MX2009012093A (es) 2007-05-10 2010-01-25 Intermune Inc Nuevos peptidos inhibidores de la replicacion del virus de la hepatitis c.
JP2010531871A (ja) 2007-07-03 2010-09-30 アクテリオン ファーマシューティカルズ リミテッド 3−アザ−ビシクロ[3.3.0]オクタン化合物
KR20100046047A (ko) 2007-07-27 2010-05-04 액테리온 파마슈티칼 리미티드 2-아자-비시클로[3.3.0]옥탄 유도체
EP2188274A4 (en) 2007-08-03 2011-05-25 Boehringer Ingelheim Int VIRAL POLYMERASE HEMMER
WO2009032198A1 (en) 2007-08-30 2009-03-12 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
BRPI0817881A2 (pt) * 2007-10-10 2015-03-31 Novartis Ag Compostos orgânicos e seus usos
WO2009076747A1 (en) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US8202996B2 (en) 2007-12-21 2012-06-19 Bristol-Myers Squibb Company Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide
CN102089274B (zh) * 2007-12-21 2014-09-10 默沙东公司 合成3-氨基-3-环丁基甲基-2-羟基丙酰胺或其盐的方法
CN101983188A (zh) 2008-04-01 2011-03-02 安斯泰来制药有限公司 吲哚啉酮化合物
KR20110005869A (ko) * 2008-04-15 2011-01-19 인터뮨, 인크. C형 간염 바이러스 복제의 신규한 마크로사이클릭 억제제
US8163921B2 (en) 2008-04-16 2012-04-24 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8044023B2 (en) 2008-05-29 2011-10-25 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7964560B2 (en) 2008-05-29 2011-06-21 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
KR20110040818A (ko) 2008-06-10 2011-04-20 노파르티스 아게 상피 나트륨 채널 차단제로서의 피라진 유도체
CA2728226A1 (en) 2008-06-24 2010-01-21 Codexis, Inc. Biocatalytic processes for the preparation of substantially stereomerically pure fused bicyclic proline compounds
RU2011103770A (ru) * 2008-07-03 2012-08-10 Вертекс Фармасьютикалз Инкорпорейтед (Us) ПОЛУЧЕНИЕ ЗАЩИЩЕННЫХ СЛОЖНЫХ α-КЕТО-β-АМИНОЭФИРОВ И АМИДОВ
US8188137B2 (en) 2008-08-15 2012-05-29 Avila Therapeutics, Inc. HCV protease inhibitors and uses thereof
US8207341B2 (en) 2008-09-04 2012-06-26 Bristol-Myers Squibb Company Process or synthesizing substituted isoquinolines
US8563505B2 (en) 2008-09-29 2013-10-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8044087B2 (en) 2008-09-29 2011-10-25 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8283310B2 (en) 2008-12-15 2012-10-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2010080874A1 (en) 2009-01-07 2010-07-15 Scynexis, Inc. Cyclosporine derivative for use in the treatment of hcv and hiv infection
AR075584A1 (es) * 2009-02-27 2011-04-20 Intermune Inc COMPOSICIONES TERAPEUTICAS QUE COMPRENDEN beta-D-2'-DESOXI-2'-FLUORO-2'-C-METILCITIDINA Y UN DERIVADO DE ACIDO ISOINDOL CARBOXILICO Y SUS USOS. COMPUESTO.
US20110182850A1 (en) * 2009-04-10 2011-07-28 Trixi Brandl Organic compounds and their uses
US8512690B2 (en) * 2009-04-10 2013-08-20 Novartis Ag Derivatised proline containing peptide compounds as protease inhibitors
US20120244122A1 (en) 2009-05-28 2012-09-27 Masse Craig E Peptides for the Treatment of HCV Infections
CA2763140A1 (en) 2009-05-29 2010-12-02 Schering Corporation Antiviral compounds composed of three linked aryl moieties to treat diseases such as hepatitis c
WO2010151488A1 (en) 2009-06-23 2010-12-29 Gilead Sciences, Inc. Combination of boceprevir with 5- ( { 6- [2, 4- bis (trifluoromethyl) phenyl] pyridazin-3 -yl } methyl) -2- (2 -fluorophenyl) -5h- imidazo [4, 5-c] pyridine for the treatment of hcv
EP2477980B1 (en) 2009-09-15 2016-06-08 Taigen Biotechnology Co., Ltd. Hcv protease inhibitors
WO2011038293A1 (en) * 2009-09-28 2011-03-31 Intermune, Inc. Cyclic peptide inhibitors of hepatitis c virus replication
AU2010324871A1 (en) 2009-11-25 2012-06-14 Merck Sharp & Dohme Corp. Fused tricyclic compounds and derivatives thereof useful for the treatment of viral diseases
CA2785488A1 (en) 2009-12-22 2011-07-21 Merck Sharp & Dohme Corp. Fused tricyclic compounds and methods of use thereof for the treatment of viral diseases
CA2791045A1 (en) 2010-02-25 2011-09-01 Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patieentenzorg A process for the preparation of substituted prolyl peptides and similar peptidomimetics
EP2545060B1 (en) 2010-03-09 2015-11-25 Merck Sharp & Dohme Corp. Fused tricyclic silyl compounds and methods of use thereof for the treatment of viral diseases
WO2012018534A2 (en) 2010-07-26 2012-02-09 Schering Corporation Substituted biphenylene compounds and methods of use thereof for the treatment of viral diseases
EP2621279B1 (en) 2010-09-29 2018-04-04 Merck Sharp & Dohme Corp. Fused tetracycle derivatives and methods of use thereof for the treatment of viral diseases
CN102010425B (zh) * 2010-11-04 2013-04-10 山东大学 1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸衍生物类组蛋白去乙酰化酶抑制剂及其应用
US9156872B2 (en) 2011-04-13 2015-10-13 Merck Sharp & Dohme Corp. 2′-azido substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
EP2696681B1 (en) 2011-04-13 2018-10-03 Merck Sharp & Dohme Corp. 2'-substituted nucleoside derivatives and methods of use thereof for the treatment of viral diseases
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8691757B2 (en) 2011-06-15 2014-04-08 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8822679B2 (en) * 2011-06-24 2014-09-02 California Institute Of Technology Quaternary heteroatom containing compounds
US20130267699A1 (en) 2011-06-24 2013-10-10 California Institute Of Technology Quaternary heteroatom containing compounds
WO2013033900A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Tetracyclic heterocycle compounds and methods of use thereof for the treatment of viral diseases
WO2013033899A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases
WO2013033901A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Heterocyclic-substituted benzofuran derivatives and methods of use thereof for the treatment of viral diseases
WO2013039876A1 (en) 2011-09-14 2013-03-21 Merck Sharp & Dohme Corp. Silyl-containing heterocyclic compounds and methods of use thereof for the treatment of viral diseases
CA2811203C (en) 2011-10-21 2015-05-05 Abbvie Inc. Methods for treating hcv
US8466159B2 (en) 2011-10-21 2013-06-18 Abbvie Inc. Methods for treating HCV
US8492386B2 (en) 2011-10-21 2013-07-23 Abbvie Inc. Methods for treating HCV
CN104023726A (zh) 2011-10-21 2014-09-03 艾伯维公司 用于治疗hcv的一种或多种daa的联合治疗(例如,与abt-072或abt-333)
US20130123325A1 (en) 2011-11-14 2013-05-16 Sven Ruf Use of boceprevir and related compounds in atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases
EP2794634B1 (en) * 2011-12-23 2018-01-24 Ipsen Manufacturing Ireland Limited Process for the synthesis of ghrelin analogues
AR091192A1 (es) 2012-05-30 2015-01-21 Chemo Iberica Sa Procedimiento multicomponente para la preparacion de compuestos biciclicos
WO2014053533A1 (en) 2012-10-05 2014-04-10 Sanofi Use of substituted 3-heteroaroylamino-propionic acid derivatives as pharmaceuticals for prevention/treatment of atrial fibrillation
SI2909205T1 (sl) 2012-10-19 2017-02-28 Bristol-Myers Squibb Company 9-metil substituiran heksadekahidrociklopropa(e)pirolo(1,2-A)(1,4)diazaciklopentadecinil karbamat derivati kot nestrukturalni 3 (NS3) proteazni inhibitorji za zdravljenje hepatitis C virusnih infekcij
EP2914598B1 (en) 2012-11-02 2017-10-18 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
EP2914613B1 (en) 2012-11-02 2017-11-22 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9409943B2 (en) 2012-11-05 2016-08-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9580463B2 (en) 2013-03-07 2017-02-28 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP3184095A1 (en) 2013-05-23 2017-06-28 IP Gesellschaft für Management mbH Administration units comprising polymorph 1 of 2-(2-methylamino-pyrimidin-4-yl]-1h-indole-5-carboxylic acid [(s)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide
CN103387510B (zh) * 2013-08-08 2015-09-09 苏州永健生物医药有限公司 一种β-氨基-alpha-羟基环丁基丁酰胺盐酸盐的合成方法
US10167298B2 (en) 2013-10-30 2019-01-01 Merck Sharp & Dohme Corp. Pseudopolymorphs of an HCV NS5A inhibitor and uses thereof
TWI659019B (zh) 2014-02-28 2019-05-11 日商帝人製藥股份有限公司 吡唑醯胺衍生物
US10421696B2 (en) 2014-12-18 2019-09-24 California Institute Of Technology Enantioselective synthesis of α-quaternary mannich adducts by palladium-catalyzed allylic alkylation
CN107922373A (zh) 2015-03-27 2018-04-17 加利福尼亚技术学院 使用低催化剂浓度和稳定的预催化剂的不对称催化脱羧烷基烷基化
WO2017156239A1 (en) 2016-03-11 2017-09-14 California Institute Of Technology Compositions and methods for acylating lactams
JP7129703B2 (ja) 2016-04-28 2022-09-02 エモリー ユニバーシティー アルキン含有ヌクレオチド及びヌクレオシド治療組成物並びにそれらに関連した使用
EP4257191A3 (en) 2016-06-21 2023-11-22 Orion Ophthalmology LLC Heterocyclic prolinamide derivatives
JP7076438B2 (ja) * 2016-06-21 2022-05-27 オリオン・オフサルモロジー・エルエルシー 脂肪族プロリンアミド誘導体
WO2017222914A1 (en) 2016-06-21 2017-12-28 Inception 4, Inc. Carbocyclic prolinamide derivatives
JP6989864B2 (ja) 2017-05-05 2022-02-03 ジーランド ファーマ,アー/エス ギャップ結合細胞間コミュニケーションモジュレータ及び糖尿病性眼疾患の治療のためのそれらの使用
US10358422B2 (en) 2017-11-01 2019-07-23 California Institute Of Technology Methods for enantioselective allylic alkylation of esters, lactones, and lactams with unactivated allylic alcohols
US11214568B2 (en) 2018-10-18 2022-01-04 California Institute Of Technology Gem-disubstituted pyrrolidines, piperazines, and diazepanes, and compositions and methods of making the same
WO2021226546A1 (en) * 2020-05-08 2021-11-11 The Board Of Trustees Of The Leland Stanford Junior University Protease inhibitors for treatment or prevention of coronavirus disease
WO2022013684A1 (en) 2020-07-11 2022-01-20 Pfizer Inc. Antiviral heteroaryl ketone derivatives
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US20240217930A1 (en) * 2021-04-01 2024-07-04 Heptares Therapeutics Limited Sars-cov-2 mpro inhibitor compounds
CA3224494A1 (en) 2021-07-09 2023-01-12 Koen Vandyck Anti-viral compounds
CN114149415A (zh) * 2021-07-26 2022-03-08 中国药科大学 一种拟肽类化合物及其衍生物、制备方法、药物组合物和应用
JP7810788B2 (ja) * 2021-08-02 2026-02-03 北京華益健康薬物研究中心 コロナウイルス感染症の治療又は予防のための3clプロテア-ゼ小分子阻害剤及びその用途
WO2023043816A1 (en) 2021-09-17 2023-03-23 Aligos Therapeutics, Inc. Anti-viral compounds for treating coronavirus, picornavirus, and norovirus infections
WO2023133174A1 (en) * 2022-01-07 2023-07-13 Merck Sharp & Dohme Llc Protease inhibitors for treating or preventing coronavirus infection
EP4649086A1 (en) * 2023-01-09 2025-11-19 Merck Sharp & Dohme LLC Protease inhibitors for treating or preventing coronavirus infection
WO2025201636A1 (en) 2023-03-31 2025-10-02 Syngenta Crop Protection Ag Pesticidally-active 2,2-dihalocyclopropyl compounds

Family Cites Families (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5496927A (en) 1985-02-04 1996-03-05 Merrell Pharmaceuticals Inc. Peptidase inhibitors
ZA86746B (en) 1985-02-04 1986-09-24 Merrell Dow Pharma Novel peptidase inhibitors
BR8807310A (pt) 1987-11-18 1990-03-13 Chiron Corp Polinucleotidio,polinucleotidio recombinante,vetor recombinante,celula hospedeira,sistema de expressao recombinante,celula transformada,polipeptidio,hcv,preparacao de polipeptidio,polipeptidio de hcv,polipeptidio purificado,polipeptidio recombinante,polipeptidio de fusao,anticorpo monoclonal,preparacao purificada de anticorpos policlonais,particula,sonda de polinucleotidio,kit anticorpo para epetopo de hcv,metodo para producao de polipeptidio,metodo para deteccao de acidos nucleicos de hcv,imunoensaio para detectar antigeno de hcv,imunoensaio para detectar anticorpos dirigidos contra antigeno de hcv,vacina para tratamento de infeccao de hcv,celula,celula infectada com hcv,metodo para producao de anticorpos para hcv e metodo para isolar cdna derivado do genoma de um agente infeccioso nao identificado
ZA897515B (en) 1988-10-07 1990-06-27 Merrell Dow Pharma Novel peptidase inhibitors
ATE132182T1 (de) 1989-02-01 1996-01-15 Asahi Glass Co Ltd Azeotrope oder azeotropähnliche zusammensetzung auf der basis von chlorfluorkohlenwasserstoffen
US5162500A (en) 1989-04-15 1992-11-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
US5359138A (en) 1989-04-15 1994-10-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Poststatin and related compounds or salts thereof
DE69133617D1 (de) 1990-04-04 2009-07-23 Novartis Vaccines & Diagnostic Protease von Hepatitis C Virus
JP2804817B2 (ja) 1990-04-13 1998-09-30 財団法人微生物化学研究会 3―アミノ―2―オキソ脂肪酸誘導体の製造法
JPH04149166A (ja) 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd 新規ケト酸アミド誘導体
WO1992011850A2 (en) 1990-12-28 1992-07-23 Cortex Pharmaceuticals, Inc. Use of calpain inhibitors in the inhibition and treatment of neurodegeneration
JP3439209B2 (ja) 1992-01-31 2003-08-25 アボツト・ラボラトリーズ Hcv蛋白のための哺乳動物発現システム
EP0650368A1 (en) 1992-06-24 1995-05-03 Cortex Pharmaceuticals, Inc. Use of calpain inhibitors in the inhibition and treatment of medical conditions associated with increased calpain activity
US5514694A (en) 1992-09-21 1996-05-07 Georgia Tech Research Corp Peptidyl ketoamides
US5414018A (en) 1993-09-24 1995-05-09 G. D. Searle & Co. Alkylaminoalkyl-terminated sulfide/sulfonyl-containing propargyl amino-diol compounds for treatment of hypertension
US5843450A (en) 1994-02-14 1998-12-01 Abbott Laboratories Hepatitis GB Virus synthetic peptides and uses thereof
IT1272179B (it) 1994-02-23 1997-06-16 Angeletti P Ist Richerche Bio Metodologia per riprodurre in vitro l'attivita' proteolitica della proteasi ns3 del virus hcv.
US5843752A (en) 1995-05-12 1998-12-01 Schering Corporation Soluble active hepatitis C virus protease
US5919765A (en) 1995-06-07 1999-07-06 Cor Therapeutics, Inc. Inhibitors of factor XA
GB9517022D0 (en) 1995-08-19 1995-10-25 Glaxo Group Ltd Medicaments
US5763576A (en) 1995-10-06 1998-06-09 Georgia Tech Research Corp. Tetrapeptide α-ketoamides
IL120310A (en) 1996-03-01 2002-02-10 Akzo Nobel Nv Serine protease inhibitors and pharmaceuticals containing them
US5633388A (en) 1996-03-29 1997-05-27 Viropharma Incorporated Compounds, compositions and methods for treatment of hepatitis C
IT1285158B1 (it) 1996-09-17 1998-06-03 Angeletti P Ist Richerche Bio Polipeptidi solubili con l'attivita' di serino-proteasi di ns3 del virus dell'epatite c, e procedimento per la loro preparazione e il
CN1238002A (zh) 1996-09-24 1999-12-08 普罗格特-甘布尔公司 含有蛋白水解酶、肽醛和硼酸源的液体洗涤剂
US5922757A (en) 1996-09-30 1999-07-13 The Regents Of The University Of California Treatment and prevention of hepatic disorders
CZ298749B6 (cs) * 1996-10-18 2008-01-16 Vertex Pharmaceuticals Incorporated Inhibitory serinových proteáz a farmaceutické prostředky s jejich obsahem
JP2001508418A (ja) 1996-12-27 2001-06-26 ベーリンガー インゲルハイム(カナダ)リミテッド ヒトサイトメガロウイルスプロテアーゼのペプチドミメティックインヒビター
WO1998037180A2 (en) 1997-02-22 1998-08-27 Abbott Laboratories Hcv fusion protease and polynucleotide encoding same
DE69829381T2 (de) 1997-08-11 2006-04-13 Boehringer Ingelheim (Canada) Ltd., Laval Hepatitis c inhibitor peptide
EP1012180B1 (en) 1997-08-11 2004-12-01 Boehringer Ingelheim (Canada) Ltd. Hepatitis c inhibitor peptide analogues
GB9809664D0 (en) 1998-05-06 1998-07-01 Hoffmann La Roche a-Ketoamide derivatives
GB9812523D0 (en) 1998-06-10 1998-08-05 Angeletti P Ist Richerche Bio Peptide inhibitors of hepatitis c virus ns3 protease
US6576613B1 (en) * 1998-07-24 2003-06-10 Corvas International, Inc. Title inhibitors of urokinase
JP2000256396A (ja) 1999-03-03 2000-09-19 Dainippon Pharmaceut Co Ltd 複素環式化合物およびその中間体ならびにエラスターゼ阻害剤
WO2001040262A1 (en) 1999-12-03 2001-06-07 Bristol-Myers Squibb Pharma Company Alpha-ketoamide inhibitors of hepatitis c virus ns3 protease
JP4806154B2 (ja) 2000-04-03 2011-11-02 バーテックス ファーマシューティカルズ インコーポレイテッド セリンプロテアーゼ、特にc型肝炎ウイルスns3プロテアーゼのインヒビター
JP4748911B2 (ja) * 2000-04-05 2011-08-17 シェーリング コーポレイション N−環状p2部分を含むc型肝炎ウイルスの大環状ns3‐セリンプロテアーゼ阻害剤
MXPA03000627A (es) * 2000-07-21 2004-07-30 Schering Corp Nuevos peptidos como inhibidores de proteasa serina-ns3 del virus de la hepatitis c.
SV2003000617A (es) 2000-08-31 2003-01-13 Lilly Co Eli Inhibidores de la proteasa peptidomimetica ref. x-14912m

Also Published As

Publication number Publication date
ATE469914T1 (de) 2010-06-15
DK1481000T3 (da) 2010-09-06
DE60332814D1 (de) 2010-07-15
IL162815A0 (en) 2005-11-20
AU2009210423B2 (en) 2012-11-15
MXPA04006934A (es) 2005-04-19
AR038183A1 (es) 2005-01-05
BR0306931A (pt) 2005-04-19
KR101020355B1 (ko) 2011-03-08
CO5650168A2 (es) 2006-06-30
CY1111225T1 (el) 2015-06-11
NZ571073A (en) 2010-04-30
WO2003062265A2 (en) 2003-07-31
CA2473032A1 (en) 2003-07-31
CN101792483A (zh) 2010-08-04
PL372747A1 (en) 2005-08-08
KR20040086272A (ko) 2004-10-08
US7244721B2 (en) 2007-07-17
ZA200405304B (en) 2006-03-29
NO20042792L (no) 2004-10-15
US20070232549A1 (en) 2007-10-04
AU2009210423A1 (en) 2009-09-17
PE20030852A1 (es) 2003-10-21
RU2404189C2 (ru) 2010-11-20
CN1633446A (zh) 2005-06-29
PT1481000E (pt) 2010-08-19
WO2003062265A3 (en) 2004-09-16
MY140710A (en) 2010-01-15
EP1481000A2 (en) 2004-12-01
TWI334872B (en) 2010-12-21
EP1481000B1 (en) 2010-06-02
US20070032433A1 (en) 2007-02-08
US7592316B2 (en) 2009-09-22
RU2404189C9 (ru) 2011-05-10
JP4563033B2 (ja) 2010-10-13
SI1481000T1 (sl) 2010-09-30
TW200307691A (en) 2003-12-16
RU2004125279A (ru) 2006-01-10
JP2005524628A (ja) 2005-08-18

Similar Documents

Publication Publication Date Title
ECSP034438A (es) Nuevos peptidos como inhibidores de ns-3-serina proteasa del virus de la hepatitis c
ECSP066626A (es) Nuevos inhibidores de la ns3/ns4a serina proteasa del virus de la hepatitis c
BRPI0508085A (pt) compostos de enxofre como inibidores da ns3 serina protease do vìrus da hepatite c
ECSP034439A (es) Nuevos peptidos como inhibidores de ns-3-serina proteasa del virus de la hepatitis c
BRPI0508186A (pt) compostos como inibidores de ns3 serina protease de vìrus da hepatite c
TW200602037A (en) Novel compounds as inhibitors of hepatitis C virus NS3 serine protease
AR029851A1 (es) Nuevos peptidos como inhibidores de ns3-serina proteasa del virus de hepatitis c
MY140710A (en) Novel peptides as ns3-serine protease inhibitors of hepatitis c virus
TWI265927B (en) Novel compounds as NS3-serine protease inhibitors of hepatitis C virus
BRPI0508217A (pt) cetamidas com p4's cìclico como inibidores de ns3 serina protease de vìrus de hepatite c
ECSP099685A (es) Compuestos de azufre como inhibidores de la serina proteasa ns3 del virus de la hepatitis c
ATE513844T1 (de) Acylsulfonamidverbindungen als inhibitoren der ns3-serinprotease des hepatitis-c-virus
AR030591A1 (es) Inhibidores de proteasa peptidomimetica
WO2005051980A8 (en) Depeptidized inhibitors of hepatitis c virus ns3 protease
ES2240446T3 (es) Inhibidores de serina proteasas, particularmente la proteasa ns3 del virus de la hepatitis c.
DK1556021T3 (da) Farmaceutiske sammensætninger omfattende flavonoider og menthol samt fremgangsmåder til behandling med brug af nævnte sammensætninger
MX2010004704A (es) Inhibidores macrociclicos de la ns3 serina proteasa del virus de la hepatitis c.
MX2009010205A (es) Inhibidores de cetoamida p1-no epimerizables de proteasa ns3 de virus de hepatitis c.
ATE469657T1 (de) Immunstimulatorische kombination zur vorbeugung und behandlung von hepatitis c
WO2009067225A3 (en) Boceprevir derivatives for the treatment of hcv infections
ATE475408T1 (de) Formulierungen von tipifarnib zur intravenösen verabreichung
BR112015021692A2 (pt) formulação de dosagem oral sólida de inibidor de hcv no estado amorfo