DE69829381T2 - Hepatitis c inhibitor peptide - Google Patents
Hepatitis c inhibitor peptide Download PDFInfo
- Publication number
- DE69829381T2 DE69829381T2 DE69829381T DE69829381T DE69829381T2 DE 69829381 T2 DE69829381 T2 DE 69829381T2 DE 69829381 T DE69829381 T DE 69829381T DE 69829381 T DE69829381 T DE 69829381T DE 69829381 T2 DE69829381 T2 DE 69829381T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- formula
- compound
- carboxyl
- optionally substituted
- Prior art date
- 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 - Lifetime
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title description 59
- 239000003112 inhibitor Substances 0.000 title description 25
- 208000006454 hepatitis Diseases 0.000 title 1
- 231100000283 hepatitis Toxicity 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 117
- 241000711549 Hepacivirus C Species 0.000 claims abstract description 58
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 38
- 150000002148 esters Chemical class 0.000 claims abstract description 30
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 15
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- 125000000464 thioxo group Chemical group S=* 0.000 claims abstract description 5
- -1 phenylmethoxycarbonyl Chemical group 0.000 claims description 122
- 125000000217 alkyl group Chemical group 0.000 claims description 111
- 238000000034 method Methods 0.000 claims description 68
- 239000000203 mixture Substances 0.000 claims description 65
- 230000015572 biosynthetic process Effects 0.000 claims description 49
- 238000003786 synthesis reaction Methods 0.000 claims description 46
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 150000001413 amino acids Chemical class 0.000 claims description 26
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 230000002829 reductive effect Effects 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 241000124008 Mammalia Species 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 13
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 12
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 208000005176 Hepatitis C Diseases 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000006224 2-tetrahydrofuranylmethyl group Chemical group [H]C([H])(*)C1([H])OC([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 241000700605 Viruses Species 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 7
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 7
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 claims description 6
- 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 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 208000010710 hepatitis C virus infection Diseases 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000002015 acyclic group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 108700012707 hepatitis C virus NS3 Proteins 0.000 claims description 4
- 230000010076 replication Effects 0.000 claims description 4
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 238000000338 in vitro Methods 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 2
- 125000003368 amide group Chemical class 0.000 claims 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 4
- 125000005978 1-naphthyloxy group Chemical group 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000005979 2-naphthyloxy group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 13
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract description 6
- 150000001408 amides Chemical class 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 5
- 150000003573 thiols Chemical group 0.000 abstract description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 1
- 150000003147 proline derivatives Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 123
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
- 239000000243 solution Substances 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- 101800001838 Serine protease/helicase NS3 Proteins 0.000 description 37
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 229940024606 amino acid Drugs 0.000 description 26
- 125000006239 protecting group Chemical group 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- 235000001014 amino acid Nutrition 0.000 description 25
- 238000012360 testing method Methods 0.000 description 25
- 239000000047 product Substances 0.000 description 24
- 239000011347 resin Substances 0.000 description 22
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- 239000007787 solid Substances 0.000 description 21
- 239000000758 substrate Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- 239000011780 sodium chloride Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
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- 238000005859 coupling reaction Methods 0.000 description 18
- 102000004196 processed proteins & peptides Human genes 0.000 description 18
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- 229940088598 enzyme Drugs 0.000 description 16
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 238000010168 coupling process Methods 0.000 description 15
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- 239000003921 oil Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 13
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 13
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
- C12N2770/00011—Details
- C12N2770/24011—Flaviviridae
- C12N2770/24211—Hepacivirus, e.g. hepatitis C virus, hepatitis G virus
- C12N2770/24222—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US5518697P | 1997-08-11 | 1997-08-11 | |
| US55186P | 1997-08-11 | ||
| PCT/CA1998/000765 WO1999007733A2 (en) | 1997-08-11 | 1998-08-10 | Hepatitis c inhibitor peptides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69829381D1 DE69829381D1 (en) | 2005-04-21 |
| DE69829381T2 true DE69829381T2 (de) | 2006-04-13 |
Family
ID=21996209
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69829381T Expired - Lifetime DE69829381T2 (de) | 1997-08-11 | 1998-08-10 | Hepatitis c inhibitor peptide |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1003775B1 (enExample) |
| JP (1) | JP4354632B2 (enExample) |
| AT (1) | ATE291032T1 (enExample) |
| AU (1) | AU757783B2 (enExample) |
| CA (1) | CA2294049A1 (enExample) |
| DE (1) | DE69829381T2 (enExample) |
| DK (1) | DK1003775T3 (enExample) |
| ES (1) | ES2241157T3 (enExample) |
| HU (1) | HUP0004853A3 (enExample) |
| IL (1) | IL134232A0 (enExample) |
| NZ (1) | NZ503262A (enExample) |
| PT (1) | PT1003775E (enExample) |
| WO (1) | WO1999007733A2 (enExample) |
Families Citing this family (174)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1299134B1 (it) * | 1998-02-02 | 2000-02-29 | Angeletti P Ist Richerche Bio | Procedimento per la produzione di peptidi con proprieta' inibitrici della proteasi ns3 del virus hcv, peptidi cosi' ottenibili e peptidi |
| GB9809664D0 (en) | 1998-05-06 | 1998-07-01 | Hoffmann La Roche | a-Ketoamide derivatives |
| US6323180B1 (en) | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
| AR022061A1 (es) * | 1998-08-10 | 2002-09-04 | Boehringer Ingelheim Ca Ltd | Peptidos inhibidores de la hepatitis c, una composicion farmaceutica que los contiene, el uso de los mismos para preparar una composicion farmaceutica, el uso de un producto intermedio para la preparacion de estos peptidos y un procedimiento para la preparacion de un peptido analogo de los mismos. |
| UA74546C2 (en) * | 1999-04-06 | 2006-01-16 | Boehringer Ingelheim Ca Ltd | Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition |
| US6608027B1 (en) | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
| AU5788800A (en) * | 1999-07-07 | 2001-01-22 | Du Pont Pharmaceuticals Company | Peptide boronic acid inhibitors of hepatitis c virus protease |
| US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
| WO2001007407A1 (en) * | 1999-07-26 | 2001-02-01 | Bristol-Myers Squibb Pharma Company | Lactam inhibitors of hepatitis c virus ns3 protease |
| WO2001040262A1 (en) | 1999-12-03 | 2001-06-07 | Bristol-Myers Squibb Pharma Company | Alpha-ketoamide inhibitors of hepatitis c virus ns3 protease |
| SI1385870T1 (sl) | 2000-07-21 | 2010-08-31 | Schering Corp | Peptidi kot NS3-serin proteazni inhibitorji virusa hepatitisa C |
| US7244721B2 (en) | 2000-07-21 | 2007-07-17 | Schering Corporation | Peptides as NS3-serine protease inhibitors of hepatitis C virus |
| CZ2003195A3 (cs) | 2000-07-21 | 2003-04-16 | Schering Corporation | Peptidové inhibitory serinové proteázy NS3 a farmaceutický prostředek |
| SV2003000617A (es) | 2000-08-31 | 2003-01-13 | Lilly Co Eli | Inhibidores de la proteasa peptidomimetica ref. x-14912m |
| US6846806B2 (en) | 2000-10-23 | 2005-01-25 | Bristol-Myers Squibb Company | Peptide inhibitors of Hepatitis C virus NS3 protein |
| AU2468802A (en) | 2000-12-15 | 2002-06-24 | Boehringer Ingelheim Ca Ltd | Purified active hcv ns2/3 protease |
| SK286630B6 (sk) | 2001-01-22 | 2009-02-05 | Merck & Co., Inc. | Nukleozidové deriváty, farmaceutický prostriedok s ich obsahom a ich použitie |
| WO2002070544A2 (en) * | 2001-03-02 | 2002-09-12 | Idun Pharmaceuticals, Inc. | Methods, compositions and kits for preserving antigenicity |
| DE60217114T2 (de) | 2001-07-11 | 2007-10-25 | Vertex Pharmaceuticals Inc., Cambridge | Verbrückte bizyklische serinproteaseinhibitoren |
| CU23245A1 (es) | 2001-07-16 | 2007-10-17 | Inst De Medicina Tropical Pedr | CADENAS QUIMéRICAS CODIFICANTES PARA PROTEINAS INDUCTORAS DE EFECTOS CONTRA VIRUS. PREPARADOS UTILIZANDO PROTEINAS QUIMéRICAS |
| NZ531681A (en) | 2001-10-24 | 2007-05-31 | Vertex Pharma | Inhibitors of serine protease, particularly hepatitis C virus NS3-NS4A protease, incorporating a fused ring system |
| US7119072B2 (en) | 2002-01-30 | 2006-10-10 | Boehringer Ingelheim (Canada) Ltd. | Macrocyclic peptides active against the hepatitis C virus |
| US7091184B2 (en) | 2002-02-01 | 2006-08-15 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
| US6642204B2 (en) | 2002-02-01 | 2003-11-04 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor tri-peptides |
| PL373399A1 (en) | 2002-04-11 | 2005-08-22 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
| DE60324552D1 (en) | 2002-05-20 | 2008-12-18 | Bristol Myers Squibb Co | Substituierte cycloalkyl p1' hepatitis c virus inhibitoren |
| MY140680A (en) * | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
| AU2003299519A1 (en) | 2002-05-20 | 2004-05-04 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| DE60334205D1 (en) | 2002-05-20 | 2010-10-28 | Bristol Myers Squibb Co | Heterocyclische sulfonamid-hepatitis-c-virus-hemmer |
| US20040033959A1 (en) * | 2002-07-19 | 2004-02-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical compositions for hepatitis C viral protease inhibitors |
| US20050075279A1 (en) | 2002-10-25 | 2005-04-07 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
| CA2516016C (en) | 2003-03-05 | 2012-05-29 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibiting compounds |
| US6908901B2 (en) | 2003-03-05 | 2005-06-21 | Boehringer Ingelheim International, Gmbh | Hepatitis C inhibitor peptide analogs |
| US7176208B2 (en) | 2003-04-18 | 2007-02-13 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
| EP2143727B1 (en) | 2003-04-18 | 2015-01-21 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
| ES2297424T3 (es) | 2003-05-21 | 2008-05-01 | Boehringer Ingelheim International Gmbh | Compuestos inhibidores de la hepatitis c. |
| MY148123A (en) | 2003-09-05 | 2013-02-28 | Vertex Pharma | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
| ES2361997T3 (es) | 2003-09-22 | 2011-06-27 | Boehringer Ingelheim International Gmbh | Péptidos macrocíclicos activos contra el virus de la hepatitis c. |
| KR20060130027A (ko) | 2003-10-10 | 2006-12-18 | 버텍스 파마슈티칼스 인코포레이티드 | 세린 프로테아제, 특히 ｈｃｖ ｎｓ3-ｎｓ4ａ 프로테아제의억제제 |
| OA13315A (en) | 2003-10-14 | 2007-04-13 | Intermune Inc | Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication. |
| EP1944042A1 (en) | 2003-10-27 | 2008-07-16 | Vertex Pharmceuticals Incorporated | Combinations for HCV treatment |
| US7494660B2 (en) | 2003-10-27 | 2009-02-24 | Vertex Pharmaceuticals Incorporated | HCV NS3-NS4A protease resistance mutants |
| US8187874B2 (en) | 2003-10-27 | 2012-05-29 | Vertex Pharmaceuticals Incorporated | Drug discovery method |
| US7132504B2 (en) | 2003-11-12 | 2006-11-07 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7309708B2 (en) | 2003-11-20 | 2007-12-18 | Birstol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7135462B2 (en) | 2003-11-20 | 2006-11-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| GB0500020D0 (en) | 2005-01-04 | 2005-02-09 | Novartis Ag | Organic compounds |
| WO2005070955A1 (en) | 2004-01-21 | 2005-08-04 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis c virus |
| DK1713823T3 (da) | 2004-01-30 | 2010-03-08 | Medivir Ab | HCV NS-3 serinproteaseinhibitorer |
| CN1938332B (zh) | 2004-02-04 | 2011-10-19 | 沃泰克斯药物股份有限公司 | 丝氨酸蛋白酶、特别是hcv ns3-ns4a蛋白酶的抑制剂 |
| US20050182252A1 (en) | 2004-02-13 | 2005-08-18 | Reddy K. R. | Novel 2'-C-methyl nucleoside derivatives |
| SG184700A1 (en) | 2004-02-20 | 2012-10-30 | Boehringer Ingelheim Int | Viral polymerase inhibitors |
| US20070049593A1 (en) | 2004-02-24 | 2007-03-01 | Japan Tobacco Inc. | Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor |
| EP1719773B1 (en) | 2004-02-24 | 2009-04-15 | Japan Tobacco, Inc. | Fused heterotetracyclic compounds and use tehreof as hcv polymerase inhibitor |
| EP1758453B1 (en) | 2004-06-15 | 2014-07-16 | Merck Sharp & Dohme Corp. | C-purine nucleoside analogs as inhibitors of rna-dependent rna viral polymerase |
| AU2005267421B2 (en) | 2004-06-24 | 2010-06-03 | Merck Sharp & Dohme Corp. | Nucleoside aryl phosphoramidates for the treatment of RNA-dependent RNA viral infection |
| HRP20070043A2 (hr) * | 2004-07-16 | 2007-07-31 | Gilead Sciences | Antivirusna sredstva |
| UY29016A1 (es) | 2004-07-20 | 2006-02-24 | Boehringer Ingelheim Int | Analogos de dipeptidos inhibidores de la hepatitis c |
| CA2573346C (en) | 2004-07-20 | 2011-09-20 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
| JP2008514723A (ja) | 2004-10-01 | 2008-05-08 | 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 | Ｈｃｖｎｓ３−ｎｓ４ａプロテアーゼの阻害 |
| US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
| US7323447B2 (en) | 2005-02-08 | 2008-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| EP1879607B1 (en) | 2005-05-02 | 2014-11-12 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| US7592336B2 (en) | 2005-05-10 | 2009-09-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| NZ563909A (en) | 2005-05-13 | 2011-10-28 | Virochem Pharma Inc | Thiophene derivatives and their use for the treatment or prevention of flavivirus infections |
| US7601686B2 (en) | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| AR057456A1 (es) | 2005-07-20 | 2007-12-05 | Merck & Co Inc | Inhibidores de la proteasa ns3 del vhc |
| GEP20105124B (en) | 2005-07-25 | 2010-11-25 | Array Biopharma Inc | Novel macrocyclic inhibitors of hepatitis c virus replication |
| PE20070211A1 (es) | 2005-07-29 | 2007-05-12 | Medivir Ab | Compuestos macrociclicos como inhibidores del virus de hepatitis c |
| AU2006275605B2 (en) | 2005-08-01 | 2011-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic peptides as HCV NS3 protease inhibitors |
| EP2402331A1 (en) | 2005-08-02 | 2012-01-04 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
| EP1915054A4 (en) | 2005-08-09 | 2010-09-01 | Merck Sharp & Dohme | CYCLIC ACETAL DERIVATIVES OF RIBONUCLEOSIDES FOR THE TREATMENT OF RNA-DEPENDENT RNA VIRUS INFECTIONS |
| CA2618682C (en) | 2005-08-12 | 2011-06-21 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| DE602006013492D1 (de) | 2005-08-19 | 2010-05-20 | Vertex Pharma | Verfahren und zwischenprodukte |
| 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 |
| CU23578A1 (es) | 2005-09-16 | 2010-09-30 | Ct Ingenieria Genetica Biotech | Proteína de la cápsida del virus dengue inductora de respuesta protectora y composición vacunal |
| BRPI0617274A2 (pt) | 2005-10-11 | 2011-07-19 | Intermune Inc | compostos e métodos para a inibição de replicação viral de hepatite c |
| US7772183B2 (en) | 2005-10-12 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7741281B2 (en) | 2005-11-03 | 2010-06-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| KR20140098867A (ko) | 2005-11-11 | 2014-08-08 | 버텍스 파마슈티칼스 인코포레이티드 | Ｃ형 간염 바이러스 변이체 |
| US7705138B2 (en) | 2005-11-11 | 2010-04-27 | Vertex Pharmaceuticals Incorporated | Hepatitis C virus variants |
| US7816348B2 (en) | 2006-02-03 | 2010-10-19 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| US8017612B2 (en) | 2006-04-18 | 2011-09-13 | Japan Tobacco Inc. | Piperazine compound and use thereof as a HCV polymerase inhibitor |
| GB0609492D0 (en) | 2006-05-15 | 2006-06-21 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| US9526769B2 (en) | 2006-06-06 | 2016-12-27 | Enanta Pharmaceuticals, Inc. | Macrocylic oximyl hepatitis C protease inhibitors |
| US8268776B2 (en) | 2006-06-06 | 2012-09-18 | Enanta Pharmaceuticals, Inc. | Macrocylic oximyl hepatitis C protease inhibitors |
| GB0612423D0 (en) | 2006-06-23 | 2006-08-02 | Angeletti P Ist Richerche Bio | Therapeutic agents |
| WO2008008776A2 (en) | 2006-07-11 | 2008-01-17 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| EP1886685A1 (en) | 2006-08-11 | 2008-02-13 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for modulating replication of hcv through the farnesoid x receptor (fxr) activation or inhibition |
| CN101506167A (zh) | 2006-08-17 | 2009-08-12 | 贝林格尔.英格海姆国际有限公司 | 病毒聚合酶抑制剂 |
| EP2076278B1 (en) | 2006-10-24 | 2015-05-06 | Merck Sharp & Dohme Corp. | Macrocyclic HCV NS3 protease inhibitors |
| CA2667146C (en) | 2006-10-24 | 2016-01-19 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
| AU2007309488B2 (en) | 2006-10-24 | 2012-10-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
| CA2667032A1 (en) | 2006-10-27 | 2008-05-15 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
| EP2086982B1 (en) | 2006-10-27 | 2018-08-29 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| CU23630A1 (es) * | 2006-10-30 | 2011-02-24 | Ct Ingenieria Genetica Biotech | Moléculas peptídicas quiméricas con propiedades antivirales contra los virus de la familia flaviviridae |
| 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 |
| NZ576780A (en) | 2006-11-15 | 2011-12-22 | Virochem Pharma Inc | Thiophene analogues for the treatment or prevention of flavivirus infections |
| 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 |
| US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| GB0625349D0 (en) | 2006-12-20 | 2007-01-31 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
| GB0625345D0 (en) | 2006-12-20 | 2007-01-31 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
| CN101815533A (zh) | 2007-05-04 | 2010-08-25 | 弗特克斯药品有限公司 | 用于治疗hcv感染的组合治疗 |
| MX2009013830A (es) | 2007-06-29 | 2010-03-01 | Gilead Sciences Inc | Compuestos antivirales. |
| KR101596524B1 (ko) | 2007-06-29 | 2016-02-22 | 길리애드 사이언시즈, 인코포레이티드 | 항바이러스 화합물 |
| AU2008277442A1 (en) | 2007-07-17 | 2009-01-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic indole derivatives for the treatment of hepatitis C infections |
| CN101754974B (zh) | 2007-07-19 | 2016-02-03 | Msd意大利有限公司 | 作为抗病毒剂的大环化合物 |
| US8242140B2 (en) | 2007-08-03 | 2012-08-14 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| GB0718575D0 (en) | 2007-09-24 | 2007-10-31 | Angeletti P Ist Richerche Bio | Nucleoside derivatives as inhibitors of viral polymerases |
| US8383583B2 (en) | 2007-10-26 | 2013-02-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic, pyridazinone-containing hepatitis C serine protease inhibitors |
| CA2708150A1 (en) | 2007-12-05 | 2009-06-18 | Enanta Pharmaceuticals, Inc. | Fluorinated tripeptide hcv serine protease inhibitors |
| EP2224920A4 (en) | 2007-12-06 | 2012-05-09 | Enanta Pharm Inc | PROCESS FOR THE PREPARATION OF MACROCYCLIC OXIMYL HEPATITIS C PROTEASE INHIBITORS |
| BRPI0821342A2 (pt) | 2007-12-19 | 2019-09-24 | Boehringer Ingelheim Int | inibidores da polimerase viral |
| 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 |
| MX2010010276A (es) | 2008-03-20 | 2011-03-25 | Enanta Pharm Inc | Compuestos macrociclicos fluorinados como inhibidores del virus de hepatitis c. |
| US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| DE102008020083A1 (de) | 2008-04-22 | 2009-10-29 | Dr. Ing. H.C. F. Porsche Aktiengesellschaft | Verfahren zur Fertigung von Kraftfahrzeugen |
| CA2720850A1 (en) | 2008-04-28 | 2009-11-05 | Merck Sharp & Dohme Corp. | Hcv ns3 protease 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 |
| KR101313675B1 (ko) | 2008-07-22 | 2013-10-02 | 이스티투토 디 리세르쉐 디 비올로지아 몰레콜라레 피. 안젤레티 에스.알.엘. | Ｈｃｖ ｎｓ3 프로테아제 억제제로서의 마크로사이클릭 퀴녹살린 화합물 |
| US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
| UY32099A (es) | 2008-09-11 | 2010-04-30 | Enanta Pharm Inc | Inhibidores macrocíclicos de serina proteasas de hepatitis c |
| US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2010039801A2 (en) | 2008-10-02 | 2010-04-08 | The J. David Gladstone Institutes | Methods of treating hepatitis c virus infection |
| US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| CN102271699A (zh) | 2009-01-07 | 2011-12-07 | 西尼克斯公司 | 用于治疗hcv和hiv感染的环孢菌素衍生物 |
| WO2010082050A1 (en) | 2009-01-16 | 2010-07-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic and 7-aminoalkyl-substituted benzoxazocines for treatment of hepatitis c infections |
| GB0900914D0 (en) | 2009-01-20 | 2009-03-04 | Angeletti P Ist Richerche Bio | Antiviral agents |
| US8975247B2 (en) | 2009-03-18 | 2015-03-10 | The Board Of Trustees Of The Leland Stanford Junion University | Methods and compositions of treating a flaviviridae family viral infection |
| WO2010132163A1 (en) | 2009-05-13 | 2010-11-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis c virus inhibitors |
| EP2459582B1 (en) | 2009-07-30 | 2015-05-27 | Merck Sharp & Dohme Corp. | Hepatitis c virus ns3 protease inhibitors |
| AU2010326225A1 (en) | 2009-11-25 | 2012-06-07 | Vertex Pharmaceuticals Incorporated | 5-alkynyl-thiophene-2-carboxylic acid derivatives and their use for the treatment or prevention of flavivirus infections |
| CA2784036A1 (en) | 2009-12-24 | 2011-06-30 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of flavivirus infections |
| CA2788155C (en) | 2010-01-27 | 2018-04-24 | AB Pharma Ltd. | Polyheterocyclic compounds highly potent as hcv inhibitors |
| WO2011119858A1 (en) | 2010-03-24 | 2011-09-29 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of flavivirus infections |
| AU2011232348A1 (en) | 2010-03-24 | 2012-10-11 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of Flavivirus infections |
| WO2011119860A1 (en) | 2010-03-24 | 2011-09-29 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of flavivirus infections |
| CA2794145A1 (en) | 2010-03-24 | 2011-09-29 | Vertex Pharmaceuticals Incorporated | Analogues for the treatment or prevention of flavivirus infections |
| WO2011156545A1 (en) | 2010-06-09 | 2011-12-15 | Vertex Pharmaceuticals Incorporated | Viral dynamic model for hcv combination therapy |
| EP2582717A2 (en) | 2010-06-15 | 2013-04-24 | Vertex Pharmaceuticals Incorporated | Hcv ns5b polymerase mutants |
| MX2012014918A (es) | 2010-06-28 | 2013-04-08 | Vertex Pharma | Compuestos y metodos para tratamiento o prevencion de infecciones por flavivirus. |
| EP2585448A1 (en) | 2010-06-28 | 2013-05-01 | Vertex Pharmaceuticals Incorporated | Compounds and methods for the treatment or prevention of flavivirus infections |
| AU2011292040A1 (en) | 2010-08-17 | 2013-03-07 | Vertex Pharmaceuticals Incorporated | Compounds and methods for the treatment or prevention of Flaviviridae viral infections |
| KR101894704B1 (ko) | 2010-09-21 | 2018-09-05 | 이난타 파마슈티칼스, 인코포레이티드 | 매크로사이클릭 프롤린 유도된 ｈｃｖ 세린 프로테아제 억제제 |
| JP2014502620A (ja) | 2010-12-30 | 2014-02-03 | エナンタ ファーマシューティカルズ インコーポレイテッド | 大環状ｃ型肝炎セリンプロテアーゼ阻害剤 |
| WO2012092411A2 (en) | 2010-12-30 | 2012-07-05 | Enanta Pharmaceuticals, Inc. | Phenanthridine macrocyclic hepatitis c serine protease inhibitors |
| WO2012107589A1 (en) | 2011-02-11 | 2012-08-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for the treatment and prevention of hcv infections |
| US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US10201584B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
| US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2012171332A1 (zh) | 2011-06-16 | 2012-12-20 | 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 |
| WO2013016499A1 (en) | 2011-07-26 | 2013-01-31 | Vertex Pharmaceuticals Incorporated | Methods for preparation of thiophene compounds |
| WO2013016501A1 (en) | 2011-07-26 | 2013-01-31 | Vertex Pharmaceuticals Incorporated | Formulations of thiophene compounds |
| EP2780026B1 (en) | 2011-11-15 | 2019-10-23 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
| AU2012347785B2 (en) | 2011-12-06 | 2017-03-16 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for treating viral diseases |
| WO2013106344A1 (en) | 2012-01-12 | 2013-07-18 | Ligand Pharmaceuticals, Inc. | 2 '-c-methyl nucleosides containing a cyclic phosphate diester of 1, 3-propanediol (2-oxo-[1, 3, 2]-dioxaphosphorinane) at position 5' |
| NZ630805A (en) | 2012-03-22 | 2016-01-29 | Alios Biopharma Inc | Pharmaceutical combinations comprising a thionucleotide analog |
| WO2014062196A1 (en) | 2012-10-19 | 2014-04-24 | 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 |
| WO2014071007A1 (en) | 2012-11-02 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| WO2014070974A1 (en) | 2012-11-05 | 2014-05-08 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| WO2014121418A1 (en) | 2013-02-07 | 2014-08-14 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c |
| WO2014121417A1 (en) | 2013-02-07 | 2014-08-14 | Merck Sharp & Dohme Corp. | Tetracyclic heterocycle compounds and methods of use thereof for the treatment of hepatitis c |
| US20150065439A1 (en) | 2013-02-28 | 2015-03-05 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions |
| EP2964664B1 (en) | 2013-03-07 | 2017-01-11 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
| EP3089757A1 (en) | 2014-01-03 | 2016-11-09 | AbbVie Inc. | Solid antiviral dosage forms |
| EP2899207A1 (en) | 2014-01-28 | 2015-07-29 | Amikana.Biologics | New method for testing HCV protease inhibition |
| KR102835299B1 (ko) | 2018-12-04 | 2025-07-18 | 브리스톨-마이어스 스큅 컴퍼니 | 다중 동위원소체 반응 모니터링에 의한 샘플내 보정 곡선을 사용한 분석 방법 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1133649C (zh) * | 1996-10-18 | 2004-01-07 | 沃泰克斯药物股份有限公司 | 丝氨酸蛋白酶、特别是丙型肝炎病毒ns3蛋白酶的抑制剂 |
-
1998
- 1998-08-10 EP EP98939450A patent/EP1003775B1/en not_active Expired - Lifetime
- 1998-08-10 DK DK98939450T patent/DK1003775T3/da active
- 1998-08-10 NZ NZ503262A patent/NZ503262A/xx unknown
- 1998-08-10 DE DE69829381T patent/DE69829381T2/de not_active Expired - Lifetime
- 1998-08-10 AU AU87956/98A patent/AU757783B2/en not_active Ceased
- 1998-08-10 IL IL13423298A patent/IL134232A0/xx not_active IP Right Cessation
- 1998-08-10 JP JP2000506235A patent/JP4354632B2/ja not_active Expired - Fee Related
- 1998-08-10 CA CA002294049A patent/CA2294049A1/en not_active Abandoned
- 1998-08-10 AT AT98939450T patent/ATE291032T1/de not_active IP Right Cessation
- 1998-08-10 WO PCT/CA1998/000765 patent/WO1999007733A2/en not_active Ceased
- 1998-08-10 HU HU0004853A patent/HUP0004853A3/hu unknown
- 1998-08-10 PT PT98939450T patent/PT1003775E/pt unknown
- 1998-08-10 ES ES98939450T patent/ES2241157T3/es not_active Expired - Lifetime
Also Published As
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| DK1003775T3 (da) | 2005-05-30 |
| WO1999007733A3 (en) | 1999-05-20 |
| ES2241157T3 (es) | 2005-10-16 |
| HUP0004853A3 (en) | 2001-12-28 |
| CA2294049A1 (en) | 1999-02-18 |
| DE69829381D1 (en) | 2005-04-21 |
| IL134232A0 (en) | 2001-04-30 |
| EP1003775B1 (en) | 2005-03-16 |
| PT1003775E (pt) | 2005-07-29 |
| HUP0004853A2 (hu) | 2001-05-28 |
| AU757783B2 (en) | 2003-03-06 |
| AU8795698A (en) | 1999-03-01 |
| JP2001512743A (ja) | 2001-08-28 |
| NZ503262A (en) | 2002-10-25 |
| JP4354632B2 (ja) | 2009-10-28 |
| EP1003775A2 (en) | 2000-05-31 |
| ATE291032T1 (de) | 2005-04-15 |
| WO1999007733A2 (en) | 1999-02-18 |
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