WO2004103996A1 - Hepatitis c inhibitor compounds - Google Patents
Hepatitis c inhibitor compounds Download PDFInfo
- Publication number
- WO2004103996A1 WO2004103996A1 PCT/CA2004/000750 CA2004000750W WO2004103996A1 WO 2004103996 A1 WO2004103996 A1 WO 2004103996A1 CA 2004000750 W CA2004000750 W CA 2004000750W WO 2004103996 A1 WO2004103996 A1 WO 2004103996A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- cycloalkyl
- compound according
- substituted
- compound
- Prior art date
Links
- 0 Cc(c(OC)ccc1)c1NC(C(OC)=O)=C* Chemical compound Cc(c(OC)ccc1)c1NC(C(OC)=O)=C* 0.000 description 6
- GALLMPFNVWUCGD-INEUFUBQSA-N C=C[C@H](C1)[C@]1(C(O)=O)N Chemical compound C=C[C@H](C1)[C@]1(C(O)=O)N GALLMPFNVWUCGD-INEUFUBQSA-N 0.000 description 1
- BJNJKOKPKYNBHD-UHFFFAOYSA-N CC(C)C1COCC1 Chemical compound CC(C)C1COCC1 BJNJKOKPKYNBHD-UHFFFAOYSA-N 0.000 description 1
- LCYIDKYBMDQDOZ-IWTSBMLOSA-N CC(C)Nc1nc(-c2nc(cc(c(OCCC(C)(C)[C@@H](C(N(CCC3)C3C(N[C@](C3)(C3C=C)C(O)=O)=O)=O)NC(OC3CCCC3)=O)c3)OC)c3c(O)c2)c[s]1 Chemical compound CC(C)Nc1nc(-c2nc(cc(c(OCCC(C)(C)[C@@H](C(N(CCC3)C3C(N[C@](C3)(C3C=C)C(O)=O)=O)=O)NC(OC3CCCC3)=O)c3)OC)c3c(O)c2)c[s]1 LCYIDKYBMDQDOZ-IWTSBMLOSA-N 0.000 description 1
- VZPWDIDCIACBOM-UHFFFAOYSA-N CCC1(C)COCOC1 Chemical compound CCC1(C)COCOC1 VZPWDIDCIACBOM-UHFFFAOYSA-N 0.000 description 1
- SDUMAMAOIIPHHC-GVHPTDIKSA-N CCc1nc(-c2cc(O[C@H](C[C@H]3C(N[C@](C4)(C4C=[O]4)C4=O)=O)CN3C(C(C(C)(C)C)NC(NC3CCCC3)=O)=O)c(ccc(OC)c3C)c3n2)c[s]1 Chemical compound CCc1nc(-c2cc(O[C@H](C[C@H]3C(N[C@](C4)(C4C=[O]4)C4=O)=O)CN3C(C(C(C)(C)C)NC(NC3CCCC3)=O)=O)c(ccc(OC)c3C)c3n2)c[s]1 SDUMAMAOIIPHHC-GVHPTDIKSA-N 0.000 description 1
- LVXQPSXJHNIWRE-CSKARUKUSA-N COC(/C=C(\C(OC)=O)/Nc(cccc1)c1OC)=O Chemical compound COC(/C=C(\C(OC)=O)/Nc(cccc1)c1OC)=O LVXQPSXJHNIWRE-CSKARUKUSA-N 0.000 description 1
- JFWIAQNNAPXWLS-UHFFFAOYSA-N COC(c1nc(c(OC)ccc2)c2c(O)c1)=O Chemical compound COC(c1nc(c(OC)ccc2)c2c(O)c1)=O JFWIAQNNAPXWLS-UHFFFAOYSA-N 0.000 description 1
- LIKRVBALRTXTPS-UHFFFAOYSA-N Cc(c(OC)c1)cc(c(O)c2)c1nc2C(OC)=O Chemical compound Cc(c(OC)c1)cc(c(O)c2)c1nc2C(OC)=O LIKRVBALRTXTPS-UHFFFAOYSA-N 0.000 description 1
- XCQBWOYLMVFXLP-DHZHZOJOSA-N Cc(c(OC)c1)ccc1N/C(/C(OC)=O)=C/C(OC)=O Chemical compound Cc(c(OC)c1)ccc1N/C(/C(OC)=O)=C/C(OC)=O XCQBWOYLMVFXLP-DHZHZOJOSA-N 0.000 description 1
- OPXLVWLFDKRYRB-UHFFFAOYSA-N Cc(c(OC)ccc1)c1N Chemical compound Cc(c(OC)ccc1)c1N OPXLVWLFDKRYRB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
-
- 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
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
- HCV hepatitis C virus
- the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
- Hepatitis C virus is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 200 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.
- HCV The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver disease has not been thoroughly elucidated. It is not known how HCV interacts with and evades the host immune system. In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established. Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulin treatment for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure prophylaxis measures, so in the near-term, hopes are firmly pinned on antiviral interventions.
- interferon was the only available therapy of proven benefit approved in the clinic for patients with chronic hepatitis C.
- the sustained response rate is low, and interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients.
- interferon in combination with ribavirin has been approved for patients non-responsive to IFN alone.
- the side effects caused by IFN are not alleviated with this combination therapy.
- Pegylated forms of interferons such as PEG-lntron® and Pegasys® can apparently partially address these deleterious side-effects but antiviral drugs still remain the avenue of choice for oral treatment of HCV.
- HCV is an enveloped positive strand RNA virus in the Flaviviridae family.
- the single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins.
- NS structural and non-structural
- the generation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases.
- the first one cleaves at the NS2-NS3 junction (henceforth referred to as NS2/3 protease); the second one is a serine protease contained within the N- terminal region of NS3 (NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites.
- the NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components.
- NS3 protease The complex formation of the NS3 protease with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites.
- the NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities.
- NS5B is a RNA-dependent RNA polymerase that is involved in the replication of HCV.
- a general strategy for the development of antiviral agents is to inactivate virally encoded enzymes that are essential for the replication of the virus.
- NS3/NS4A protease may represent a dual therapeutic target, the inhibition of which may both block viral replication and restore interferon response of HCV infected cells.
- R 2 is an unsubstituted or mono- or disubstituted quinolinyl residue as defined therein, are described as hepatitis C viral NS3 protease inhibitors, an enzyme essential for the replication of the hepatitis C virus.
- the present invention provides tripeptide compounds that have improved potency against the HCV NS3 protease. Furthermore, compounds being highly active in cell culture are provided.
- An advantage of one aspect of the present invention resides in the fact that compounds according to this invention specifically inhibit the NS3 protease and do not show significant inhibitory activity against other human serine proteases such as human leukocyte elastase (HLE), or cysteine proteases such as human liver cathepsin B (Cat B).
- HLE human leukocyte elastase
- Cat B cysteine proteases
- compounds as provided by this invention exhibit unexpected advantages. In general they show one or more of the following advantages:
- B is (C ⁇ . ⁇ o)alkyl, (C 3-7 )cycloalkyl, or (C 1-4 )alkyl-(C - )cycloalkyl, a) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri- substituted with (C ⁇ .
- alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di- substituted with substituents selected from hydroxy and ⁇ -(C ⁇ alkyl; and c) wherein each of said alkyl groups may be mono-, di- or tri-substituted with halogen; and d) wherein each of said cycloalkyl groups being 4-, 5-, 6- or 7-membered having optionally one (for the 4-, 5, 6, or 7-membered) or two (for the 5-, 6- or 7-membered) -CH 2 -groups not directly linked to each other replaced by -O- such that the O-atom is linked to the group X via at least two C- atoms;
- X is O or NH;
- R 3 is (C 2 - 8 )alkyl, (C 3 . 7 )cycloalkyl or (C 1-3 )alkyl-(C3. 7 )cycloalkyl, wherein each of said alkyl, cycloalkyl, and alkyl-cycloalkyl groups may be mono-, di- or tri- substituted with (C 1-4 )alkyl;
- L° is H, halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(C 1-4 )alkyl or -N((C 1-4 )alkyl) 2 ;
- L 1 , L 2 are each independently halogen, cyano, (C 1- )alkyl, -S-(C 1 ⁇ )alkyl, -SO-(C ⁇ -4 )alkyl, or-SO 2 -(C 1-4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms; and either 1 or L 2 (but not both at the same time) may also be H; or
- L° and L 1 or L° and 2 may be covalently bonded to form, together with the two C-atoms to which they are linked, a 5- or 6-membered carbocyclic ring wherein one or two -CH 2 -groups not being directly linked to each other may be replaced each independently by -O- or NR a wherein R a is H or (C 1-4 )alkyl, and wherein said carbo- or heterocyclic ring is optionally mono- or di-substituted with (C 1-4 )aikyl;
- R 2 is R 20 , -NR 22 COR 20 , -NR 22 COOR 20 -NR 22 R 21 and -NR 22 CONR 21 R 23 , wherein R 20 is selected from (C . a )alkyl, (C 3-7 )cycloalkyl and (C 1- )alkyl- (C 3-7 )cycloaIkyl, wherein said cycloalkyl and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C ⁇ _ 3 )alkyl;
- R 21 is H or R 20 as defined above, R 22 and R 23 are independently selected from H and methyl,
- R 1 is ethyl or vinyl
- R c is hydroxy or NHSO 2 R s wherein R s is (C ⁇ -6 )alkyl, (C 3-7 )cycloalkyl, (C ⁇ . 6 )alkyl- (C 3-7 )cycloaIkyl, phenyl, naphthyl, pyridinyl, (C 1-4 )alkyl-phenyl, (C 1-4 )alkyl- naphthyl or (C -4 )alkyl-pyridinyl; each of which optionally being mono-, di- or tri-substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 )alkyl, O-(C 1 .
- R N2 and R N1 are linked, together with the nitrogen to which they are bonded, to form a 3- to 7-membered monocyclic saturated or unsaturated heterocycle or a 9- or 10-membered bicyclic saturated or unsaturated heterocycle, each of which optionally containing from one to three further heteroatoms independently selected from N, S and O, and each of which being optionally substituted with one or more substituents independently selected from halogen, (C 1-6 )alkyl, hydroxy, cyano, ⁇ -(d ⁇ alkyl, -NH 2 , -NH(C 1-4 )alkyl, -CO-NH 2) -CO-NH(C 1-4 )alkyl, -CO-N((C ⁇ -4 )alkyl) 2 , -COOH, and -COO(C 1-6 )alkyl;
- composition comprising an anti-hepatitis C virally effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, in admixture with at least one pharmaceutically acceptable carrier medium or auxiliary agent.
- the pharmaceutical composition according to this invention further comprises a therapeuticaily effective amount of at least one other antiviral agent.
- Another important aspect of the invention involves a method of treating or ⁇ preventing a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of a compound of formula I, a pharmaceutically acceptable salt or ester thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
- a compound of formula I or a pharmaceutically acceptable salt or ester thereof, as described herein, for the manufacture of a medicament for the treatment or prevention of hepatitis C viral infection in mammal.
- P1 , P2, and P3 refer to the position of the amino acid residues starting from the C-ferminus end of the peptide analogs and extending towards the N-terminus (i.e. P1 refers to position 1 from the C-terminus, P2: second position from the C-terminus, etc.) (see Berger A. & Schechter I., Transactions of the Royal Society London series B257. 249-264 (1970)).
- (1 R, 2S)-vinyl-ACCA refers to a compound of formula:
- (C 1 . n )alkyl as used herein, either alone or in combination with another substituent, means acyclic, straight or branched chain alkyl substituents containing from 1 to n carbon atoms.
- “(C ⁇ -6 )alkyr includes, but is not limited to, methyl, ethyl, n- propyl, n-butyl, 1-methylethyl (i-propyl), 1-methylpropyl, 2-methylpropyl,.1,1- dimethylethyl (te/f-butyl), pentyl and hexyl.
- Me and Pr denote a methyl group and n-propyl respectively.
- (C 3-7 )cycloalky . r as used herein, either alone or in combination with another substituent, means a cycloalkyl substituent containing from 3 to 7 carbon atoms and includes, but is not limited to, cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
- (C ⁇ -n )alkyl-(C 3 . 7 )cycloalkyl as used herein means an alkylene radical containing 1 to n carbon atoms to which a cycloalkyl radical containing from 3 to 7 carbon atoms is directly linked;and includes, but is not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl and cycloheptylpropyl.
- aryl or "C 6 or C 10 aryl” as used herein interchangeably, either alone or in combination with another radical, means either an aromatic monocyclic group containing 6 carbon atoms or an aromatic bicyclic group containing 10 carbon atoms.
- Aryl includes, but is not limited to, phenyl, 1 -naphthyl or 2-naphthyl.
- (C ⁇ -n )alkyl-aryl means an alkyl radical containing from 1 to n carbon atoms to which an aryl is bonded.
- Examples of (C 1-3 )alkyl-aryl include, but are not limited to, benzyl (phenylmethyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl.
- O-(C ⁇ -n )alkyl or "(C 1-n )alkoxy" as used herein, either alone or in combination with another radical, means the radical -O-(C ⁇ -n )alky! wherein alkyl is as defined above containing from 1 to n carbon atoms, and includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy.
- alkyl is as defined above containing from 1 to n carbon atoms, and includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy.
- the latter radical is known commonly as terf-butoxy.
- halo or halogen as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.
- pharmaceutically acceptable ester as used herein, either alone or in combination with another substituent, means esters of the compound of formula I in which any of the carboxyl functions of the molecule, but preferably the carboxy terminus, is replaced by an alkoxycarbonyl function:
- the R moiety of the ester is selected from alkyl (including, but not limited to,, methyl, ethyl, n-propyl, t-butyl, n-butyl); alkoxyalkyl (including, but not limited to methoxymethyl); alkoxyacyl (including, but not limited to acetoxymethyl); alkyl-aryl (including, but not limited to benzyl); aryloxyalkyl (including, but not limited to phenoxymethyl); aryl (including, but not limited to phenyl), optionally substituted with halogen, (C ⁇ -4 )alkyl or (C 1- )alkoxy.
- alkyl including, but not limited to,, methyl, ethyl, n-propyl, t-butyl, n-butyl
- alkoxyalkyl including, but not limited to methoxymethyl
- alkoxyacyl including, but not limited to acetoxymethyl
- any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly 1 to 6 carbon atoms.
- Any aryl moiety present in such esters advantageously comprises a phenyl group.
- esters may be a C 1-16 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro or trifluoromethyl.
- pharmaceutically acceptable salt means a salt of a compound of formula (I) which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use.
- pharmaceutically-acceptable acid addition salts and pharmaceutically-acceptable base addition salts. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19.
- pharmaceutically-acceptable acid addition salt means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid, formic acid, fu aric acid, 2-hydroxyethane- sulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid,
- pharmaceutically-acceptable base addition salt means those salts which retain the biological effectiveness and properties of the free acids and whic are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
- Salts derived from pharmaceutically- acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, tetramethyiammonium compounds, tetraethyl
- mammal as it is used herein is meant to encompass humans, as well as non-human mammals which are susceptible to infection by hepatitis C virus including domestic animais, such as cows, pigs, horses, dogs and cats, and non- domestic animals.
- antiviral agent means an agent (compound or biological) that is effective to inhibit the formation and/or replication of a virus in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from: another anti-HCV agent, HIV inhibitor, HAV inhibitor and HBV inhibitor.
- Antiviral agents include, for example, ribavirin, amantadine, VX-497 (merimepodib, Vertex Pharmaceuticals), VX-498 (Vertex Pharmaceuticals), Levovirin, Viramidine, Ceplene (maxamine), XTL-001 and XTL-002 (XTL Biopharmaceuticals).
- other anti-HCV agent means those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms of disease.
- agents can be selected from: immunomodulatory agents, inhibitors of HCV NS3 protease, inhibitors of HCV polymerase or inhibitors of another target in the HCV life cycle.
- immunomodulatory agent means those agents (compounds or biologicals) that are effective to enhance or potentiate the immune system response in a mammal.
- Immunomodulatory agents include, for example, class I interferons (such as ⁇ , ⁇ -, ⁇ - , ⁇ - and ⁇ -interferons, consensus interferons and asialo-interferons), class II interferons (such as ⁇ -interferons) and pegylated forms thereof.
- inhibitor of HCV NS3 protease means an agent (compound or biological) that is effective to inhibit the function of HCV NS3 protease in a mammal.
- Inhibitors of HCV NS3 protease include, for example, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 02/060926, WO 03/053349, WO 03/099316 or WO 03/099274, and the Vertex pre- development candidate identified as VX-950.
- inhibitor of HCV polymerase means an agent (compound or biological) that is effective to inhibit the function of an HCV polymerase in a mammal. This includes, for example, inhibitors of HCV NS5B polymerase. Inhibitors of HCV polymerase include non-nucleosides, for example, those compounds described in: • US Application No. 60/441 ,674 filed January 22, 2003, herein incorporated by reference in its entirety (Boehringer Ingelheim), • US Application No.
- inhibitors of HCV polymerase also include nucleoside analogs, for example, those compounds described in: WO 04/007512 (Merck/lsis), WO 04/003000 (Idenix), WO 04/002999 (Idenix), WO 04/0002422 (Idenix), WO 04/003138 (Merck), WO 03/105770 (Merck), WO 03/105770 (Merck), WO 03/093290 (Genelabs), WO 03/087298 (Biocryst), WO 03/062256 (Ribapharm), WO 03/062255 (Ribapharm), WO 03/061385 (Ribapharm), WO 03/026675 (Idenix), WO 03/026589 (Idenix), WO 03/020222 (Merck), WO 03/000713 (Glaxo), WO 02/100415 (Hoffmann-La Roche), WO 02/1094289 (Hoffmann-
- inhibitor of another target in the HCV life cycle means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HCV in a mammal other than by inhibiting the function of the HCV NS3 protease. This includes agents that interfere with either host or HCV viral mechanisms necessary for the formation and/or replication of HCV in a mammal.
- Inhibitors of another target in the HCV life cycle include, for example, agents that inhibit a target selected from helicase, NS2/3 protease and internal ribosome entry site (IRES).
- Specific examples of inhibitors of another target in the HCV life cycle include ISIS-14803 (ISIS Pharmaceuticals).
- HIV inhibitor means an agents (compound or biological) that is effective to inhibit the formation and/or replication of HIV in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HIV in a mammal. HIV inhibitors include, for example, nucleoside inhibitors, non-nucleoside inhibitors, protease inhibitors, fusion inhibitors and integrase inhibitors.
- HAV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HAV in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HAV in a mammal.
- HAV inhibitors include Hepatitis A vaccines, for example, Havrix ® (GlaxoSmithKline), VAQTA ® (Merck) and Avaxim ® (Aventis Pasteur).
- HBV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HBV in a mammal. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HBV in a mammal.
- HBV inhibitors include, for example, agents that inhibit HBV viral DNA polymerase or HBV vaccines.
- HBV inhibitors include Lamivudine (Epivir-HBV ® ), Adefovir Dipivoxil, Entecavir, FTC (Coviracil ® ), DAPD (DXG), L-FMAU (Clevudine ® ), AM365 (Amrad), Ldt (Telbivudine), monoval-LdC (Valtorcitabine), ACH-126,443 (L-Fd4C) (Achiilion), ' MCC478 (Eli Lilly), Racivir (RCV), Fluoro-L and D nucleosides, Robustafiavone, ICN 2001-3 (ICN), Bam 205 (Novelos), XTL-001 (XTL), Imino-Sugars (Nonyl-DNJ) (Synergy), HepBzyme; and immunomodulator products such as: interferon alpha 2b, HE2000 (Hollis-Eden), Theradi
- Thymosin alpha-1 Zadaxin ®
- HBV DNA vaccine PowderJect
- HBV DNA vaccine Jefferon Center
- HBV antigen OraGen
- BayHep B ® Bayer
- Nabi-HB ® Nabi and Anti-hepatitis B (Cangene)
- HBV vaccine products such as the following: Engerix B, Recombivax HB, GenHevac B, Hepacare, Bio-Hep B, TwinRix, Comvax, Hexavac.
- class I interferon means an interferon selected from a group of interferons that all bind to receptor type I. This includes both naturally and synthetically produced class I interferons. Examples of class I interferons include ⁇ -; ⁇ -, ⁇ -, ⁇ - and ⁇ -interferons, consensus interferons, asialo-interferons and pegylated forms thereof.
- class II interferon as used herein means an interferon selected from a group of interferons that all bind to receptor type II. Examples of class II interferons include ⁇ -interferons.
- ⁇ antiviral agents ribavirin or amantadine
- ⁇ immunomodulatory agents class I interferons, class II interferons or pegylated forms thereof;
- ⁇ HCV polymerase inhibitors nucleoside analogs or non-nucleosides
- ⁇ inhibitor of another target in the HCV life cycle that inhibits a target selected from: NS3 helicase, NS2/3 protease or internal ribosome entry site (IRES);
- ⁇ HIV inhibitors nucleosidic inhibitors, non-nucleosidic inhibitors, protease inhibitors, fusion inhibitors or integrase inhibitors; or ⁇ HBV inhibitors: agents that inhibit viral DNA polymerase or is an HBV vaccine.
- combination therapy is contemplated wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof, is co-administered with at least one additional agent selected from: an antiviral agent, an immunomodulatory agent, another inhibitor of HCV NS3 protease, an inhibitor of HCV polymerase, an inhibitor of another target in the HCV life cycle, an HIV inhibitor, an HAV inhibitor • and an HBV inhibitor.
- additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
- treatment means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the hepatitis C disease and/or to reduce viral load in a patient.
- prevention means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease.
- B is preferably selected from (C 2 . 8 )alkyl, (C 3-7 )cycloalkyI and (C 1-3 )alkyl- (C 3 . 7 )cycloalkyl, a) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri- substituted with (C t .
- alkyl, cycloalkyl and alkyl-cycloalkyl may be mono- or di-substituted with substituents selected from hydroxy and O-(C 1-4 )alkyl; and c) wherein each of said alkyl groups may be mono-, di- or tri-substituted with fluorine or mono-substituted with chlorine or bromine; and d) wherein in each of said cycloalkyl groups being 5-, 6- or 7-membered, one or two -CH 2 -groups not being directly linked to each other may be replaced by -O- such that the O-atom is linked to the group X via at least two C-atoms.
- B is selected from ethyl, n-propyl, i-propyl, n-butyl, 1-methylpropyl, 2-methylpropyI, ferf-butyl, cyclopropyl, cycl ⁇ butyl, cyclopentyl and cyclohexyl, a) wherein each of said groups is optionally substituted with 1 to 3 substituents selected from methyl and ethyl; b) wherein each of said groups is optionally mono- or di-substituted with substituents selected from hydroxy, methoxy and ethoxy; and c) wherein each of said alkyl groups may be mono-, di- or tri-substituted with fluorine or mono-substituted with chlorine or bromine; and d) wherein in each of said cycloalkyl groups being 5-, 6- or 7-membered, one or two -CH 2 -groups not being directly linked to each other may be replaced by -O
- B is even more preferably selected from ethyl, 1-methylethyl, ,1-dimethylethyl, propyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2- dimethylpropyl, 1,1,2-trirnethylpropyl, 1,2,2-trimethylpropyl, 1-ethylpropyl, 1 -ethyl-2- methyipropyl, 1-(1-methylethyl)-2-methylpropyl, 1-ethyl-2,2-dimethylpropyl, butyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, 1 ,2-dimethylbutyl, 1, -dimethylbutyl, 1,3- dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1,2,2- trimethylbutyl, 1 ,2,3
- B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl or is selected from the following formulas, wherein one or two CH 2 - groups of a cycloalkyl group is replaced by oxygen:
- cycloalkyl and alkyl-cycloalkyl groups optionally comprising 1 or 2 O-atoms are optionally substituted with 1 , 2 or 3 methyl-groups.
- cycloalkyl groups, optionally comprising 1 or 2 O-atoms are preferred, wherein the -C-atom is substituted with methyl.
- B is selected from ethyl, n-propyl, terf-butyl, 2-methylpropyl, 1,2- dimethylpropyl, 1 ,2,2-trimethylpropyl, 2-fluoroethyl, 3-fluoropropyl, 3,3,3- trifluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl and 1 -methylcyclohexyl, and a group selected from:
- B is selected from ethyl, n-propyl, terf-butyl, cyclopentyl, 1-methylcyclopentyl, 2-fluoroethyl or 3-fluoropropyl.
- X is O.
- X is NH
- R 3 is preferably (C 2-6 )alkyl, (C 3 . 7 )cycloalkyl or (C ⁇ -3 )alkyl-(C 3 . 7 )cycloalkyl, each of which being optionally substituted with 1 to 3 substituents selected from (C 1- )alkyl.
- R 3 is more preferably selected from ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, each of which optionally being substituted with 1 or 2 substituents selected from methyl, ethyl and propyl.
- R 3 is selected from 1-methylethyl, 1 ,1-dimethyiethyl, 1-methylpropyl, 2-methyl propyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl, 1- methylcyclohexyl, cyclopentylmethyl, cyclohexylmethyl, (l-methylcyclopentyl)methyl and ( -methylcyclohexyl)methyl.
- R 3 is most preferably selected from 1,1-dimethylethyl, cyclopentyl, cyclohexyl and 1 -methylcyclohexyl.
- R is most preferably selected from 1,1-dimethylethyl and cyclohexyl.
- L° is preferably selected from H, halogen, CH 3 , -OH, -OCH 3 , -OC 2 H 5 , -OC 3 H 7) -OCH(CH 3 ) 2 , -NHCH 3l -NHC 2 H 5 , -NHC 3 H 7 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -N(CH 3 )C 2 H 5 , N(CH 3 )C 3 H 7 and -N(CH 3 )CH(CH 3 ) 2 .
- L u is selected from H, -OH, -OCH 3 , halogen and -N(CH 3 ) 2 .
- L° is H, -OH or-OCH 3 .
- L° is H or -OCH 3 .
- L 1 and L 2 are preferably each independently selected from: halogen, -CH 3 , -C 2 H 5 , -OCH3, -OC 2 H 5 , -OC 3 H 7 , -OCH(CH 3 ) 2 , CF 3 , -SMe, -SOMe, and SO 2 Me whereby either L 1 or L 2 may be H.
- L 1 and L 2 are -CH 3 , -F, -Cl, -Br, -OMe, -SMe, or -SO 2 Me and the other of L 1 and L 2 is H.
- L 1 is CH 3 , -F, -Cl, -Br, -OMe, -SMe, or -SO 2 Me and L 2 is H.
- L° is selected from: H, -OH and -OCH 3 ; and either one of L 1 and L 2 is CH 3 , -F, -Cl, -Br, -OMe, -SMe, or -SO 2 Me and the other of L 1 and L 2 is H.
- L° is selected from H, -OH and -OCH 3 ;
- L 1 is - CH 3 , -F, -Cl, -Br, -OMe, -SMe, or -SO 2 Me; and
- L 2 is H.
- L° is H or -OCH 3 ;
- L 1 is -CH 3 , Ci or Br; and
- L 2 is H.
- this ring system is preferably selected from:
- X a , X b are independently selected from CH 2) O and NR a ; most preferably O;
- R a is each independently H or (C 1- )alkyl
- R is each independently (Chal y!;
- L 2 is as defined; preferably H or methyl, particularly H.
- this ring system is preferably selected from:
- X a , X b are independently selected from CH 2 , O and NR a ; most preferably O;
- R a is each independently H or (C 1- )alkyl
- R b is each independently (C 1-4 )alkyl
- L 1 is as defined; preferably H or methyl, particularly H.
- L° and L 1 are covalently bonded to form, together with the quinoline residue to Which they are linked, a ring system which is selected from:
- each R is independently (C 1-4 )alkyl and L 2 is as defined; preferably H or methyl, particularly H. Most preferably, L° and L are covalently bonded to form together with the quinoline residue to which they are linked a ring system selected from
- L 2 is H or -CH 3 , preferably H
- R 2 is preferably R 20 , -NHCOR 20 , -NHCOOR 20 , -NHR 21 and -NHCONR 21 R 23 , wherein R 20 is selected from (Chalky!, (C 3-7 )cycloalkyl, (C ⁇ . 3 )alkyl-(C 3-7 )cycloalkyl, wherein said cycloalkyl and alkyl-cycloalkyl may be mono-, di- or tri-substituted with
- R 21 is H or R 20 as defined above;
- R 23 is H or methyl; most preferably H.
- R 2 is R 20 , NHCOR 20 , -NHCOOR 20 , -NHR 21 -and -NHCONR 21 R 23 , wherein
- R 20 is selected from methyl, ethyl, n-propyl, /-propyl, n-butyl, 1-methylpropyl, 2- methylpropyl, tert-butyl, 2,2-dimethylpropyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl- methyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl, each of said cycloalkyl and alkyl-cycloalkyl groups being optionally substituted with 1 to 3 substituents selected from methyl and ethyl, in particular methyl; and
- R 21 is H or R 20 as defined above; and R 23 is H or methyl; most preferably H.
- R 2 is selected from: a) amino, ⁇ /-methylamino, ⁇ /-ethy!amino, N-propylamino, ⁇ /-(1-methylethyl)amino, A/-( ,1-dimethylethy[)amino, /V-(2-methylpropyl)amino, ⁇ /-(1-methylpropyl)amino, N-(2,2-dimethyIpropyl)amino, A/-(1,2-dimethylpropyl)amino, ⁇ /-(1,1- dimethylpropyl)amino, ⁇ /-cyclopropylamino, ⁇ /-cyclobuty!amino-, ⁇ /-cyclopentylamino ⁇ , ⁇ /-cyclohexylamino-, ⁇ /-(cyclopropylmethyl)amino, ⁇ /-(cyclobutylmethyl)amino, ⁇ /-(
- R 2 is -NHCOR 20 , -NHCOOR 20 , or -NHR 21 , wherein R 20 and R 21 are as defined herein.
- R 20 and R 21 are independently selected from: methyl, ethyl, n-propyl, / ' - propyl, n-butyl, 1-methylpropyl, 2-methylpropyl, fe/f-butyl, 2,2-dimethylpropyl, 1,1- dimethylpropyl, 1 ,2-dimethylpropyl, 1,2,2-trimethylpropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, each of said cycloalkyl or alkyl-cycloalkyl groups optionally being mono- or di-substituted with methyl or ethyl.
- R 20 and R 21 are independently selected from: methyl, ethyl, n- propyl, /-propyl, 2,2-dimethylpropyl, cyclopentyl and cyclopentylmethyl.
- R 1 is vinyl
- the asymmetric carbon atoms in the cyclopropyl group take the R,S configuration according to the subformula:
- R 1 is preferably vinyl.
- R c is preferably selected from hydroxy or NHSO 2 R s wherein R s is methyl, ethyl, n-propyl, /-propyl, n-butyl, 1-methylpropyl, 2- methylpropyl, ferf-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, naphthyl, pyridinyl, phenylmethyl (benzyl), naphthylmethyl or pyridinylmethyl; a) each of which optionally being mono-, di- or tri-substituted with substituents selected from fluorine and methyl; and b) each of which optionally being mono- or disubstituted with substituents selected from hydroxy, trifluoromethyl, methoxy and triflu
- R c is NHSO 2 R s , wherein R s is -N(R N2 )R N1 ), wherein R N1 and R N2 are independently selected from H, (C 1-4 )alkyl, (C 3-7 )cycloalkyl, (C ⁇ . 3 )alkyl-
- (C 3-7 )cycloalkyl, (C ⁇ -3 )alkyl-(C 3 . 7 )cycloaIkyl, phenyl and (C 1-3 )alkyl-phenyl are optionally substituted with one, two or three substituents independently selected from halogen, (C ⁇ alkyl, hydroxy, cyano, O-(C ⁇ -6 )alkyl, -NH 2 , -NH(C 1- )alkyl, -N((C 1-4 )alkyl) 2 , -CO-NH 2 , -CO-NH(C )alkyl, -CO-N((C ⁇ )alkyl) 2 , -COOH, and - COO(C 1-6 )alkyl; or
- R N2 and R N1 are linked, together with the nitrogen to which they are bonded, to form a 5 or 6-membered monocyclic heterocycle which may be saturated or. unsaturated, optionally containing from one to three further heteroatoms independently selected from N, S and O, and optionally substituted with one, two or three substituents independently selected from halogen, (C ⁇ -6 )alkyl, hydroxy, cyano, O-(C 1-6 )alkyl, - .
- the group R c is hydroxy, NHSO 2 -methyl, NHSO 2 -ethyl, NHSO 2 -(1- methyl)ethyl, NHSO 2 -propyl, NHSO 2 -cyclopropyl, NHSO 2 -CH 2 -cyclopropyl, NHSO 2 - cyclobutyl, NHSO 2 -cyclopentyl, or NHSO 2 -phenyl.
- R c is hydroxy, or NHSO 2 -cyclopropyl.
- the group R c is hydroxy. According to an alternative most preferred embodiment, the group R c is NHSO 2 -cyclopropyl. According to another alternative most preferred embodiment, the group R c is NHSO 2 N(CH 3 ) 2 .
- B is (C ⁇ . 10 )alkyl, (C 3-7 )cycloalkyl, or (C 1 ⁇ )alkyl-(C 3-7 )cycloalkyl, a) wherein said cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri-
- alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di- substituted with substituents selected from hydroxy and O-(C 1-4 )alkyl; and c) wherein all said alkyl-groups may be mono-, di- or tri-substituted with ' halogen; and d) wherein all said cycloalkyl-groups being 4-, 5-, 6- or 7-membered having optionally one (for the 4-, 5, 6, or 7-membered) or two (for the 5-, 6- or 7- membered) -CH 2 -groups not directly linked to each other replaced by -O- such that the O-atom is linked to the group X via at least two C-atoms; X is O or NH;
- R 3 is (C 2-8 )alkyl, (C 3-7 )cycloalkyl or (C -3 )alkyl-(C 3-7 )cycloalkyl, wherein said cycloalkyl groups may be mono-, di- or tri-substituted with (C 1-4 )alkyl;
- L° is H, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(C ⁇ )alkyl or -N((C 1-4 )alkyl) 2 ;
- L 1 , L 2 are each independently halogen, (C 1-4 )alkyl, -O-(C 1-4 )alkyl or -S-(C M )alkyl (in any oxidized state such as SO or SO 2 ); and either L or L z (but not both at the same time) may also be H; or
- L° and L 2 may be covalently bonded to form, together with the two C-atoms to which they are linked, a 5- or 6-membered carbocyclic ring wherein one or two
- -CH 2 -groups not being directly linked to each other may be replaced each independently by -O- or NR a wherein R a is H or (C ⁇ alkyl, and wherein said carbo- or heterocyclic ring is optionally mono- or di-substituted with (C 1-4 )alkyl;
- R 2 is R 20 , -NR 22 COR 20 , -NR 22 COOR 20 -NR 22 R 21 and -NR 22 CONR 21 R 23 , wherein R 20 is selected from (C 1-a )alkyl, (C 3-7 )cycloalkyl and (C 1- )alkyl- (C 3- )cycloalkyl, wherein said cycloalkyl and alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C ⁇ -3 )alkyl; R 2 is H or has one of the meanings, of R 20 as defined above,
- R 22 and R 23 are independently selected from H and methyl
- R 1 is ethyl or vinyl
- R c is hydroxy or NHSO 2 R s wherein R s is (C 1 . 6 )alkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkyl- (C 3-7 )cycloalkyl, phenyl, naphthyl, pyridinyl, (C 1-4 )alkyl- naphthyl or (C 1-4 )alkyl-pyridinyl; all of which optionally being mono-, di- or tri- substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 )alkyl, O-(C 1-6 )alkyl, -CO-NH 2 , -CO-NH(C 1-4 )alkyl, -CO-N((C 1-4 )alkyl) 2 , -NH 2 , -NH(C 1-4 )alkyl and -N((Ci -4 )aikyl) 2 ; and all of which
- B is (C 2-8 )alkyl, (C 3-7 )cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl, a) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono-, di- or tri- substituted with (C 1-3 )alkyl; and b) wherein said alkyl, cycloalkyl, and alkyl-cycloalkyl may be mono- or di- substituted with substituents selected from hydroxy and ⁇ -(C t ⁇ alkyl; and c) wherein each of said alkyl groups may be mono-, di- or tri-substituted with fluorine or mono-substituted with chlorine or bromine; and d) wherein in each of said cycloalkyl groups being 5-, 6- or 7-membered, one or two -CH 2 -groups not being directly linked to each other may be replaced by -O
- X ⁇ is O or NH;
- R 3 is (C 2 . 6 )alkyl or (C 3-7 )cycloalkyl, both of which being optionally substituted with 1 to 3 substituents selected from
- L° is H, -OH, -OCH 3 , halogen or -N(CH 3 ) 2 ;
- L 1 and L 2 are each independently selected from: halogen, -CH 3 , -C 2 H 5 , -OCH 3 ,
- L 1 or L 2 may be H;
- R 2 is R 20 , -NHCOR 20 , -NHCOOR 20 , -NHR 21 and -NHCONR 21 R 23 , wherein
- R 20 is selected from (C ⁇ alkyl, (C 3- )cycloalkyl, (C ⁇ . 3 )alkyl-(C 3-7 )cycloalkyl, wherein each of said cycloalkyl and alkyl-cycloalkyl groups may be mono-, di- or tri-substituted with (C 1-3 )alkyl; and
- R 21 is H or R 20 as defined above;
- R 23 is H or methyl
- R 1 is ethyl or vinyl; and R c is hydroxy, NHSO 2 -methyl, NHSO 2 -ethyl, NHSO 2 -(1-methyl)ethyl, NHSO 2 - propyl, NHSO 2 -cyclopropyl, NHSO 2 -CH 2 -cyclopropyl, NHSO 2 -cyclobutyl, NHSO 2 - cyclopentyl or NHSO 2 -phenyl.
- B is selected from: ethyl, n-propyl, tetf-butyl, 2-methylpropyl, 1 ,2- dimethylpropyl, 1,2,2-trimethylpropyl, 2-fluoroethyl, 3-fluoropropyl, 3,3,3- trifluoropropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopentyl and 1 -methylcyclohexyl, and a group selected from:
- R 3 is selected from 1,1-dimethylethyl, cyclopentyl, cyclohexyl and 1- methylcyclohexyl;
- L° is H, -OH or-OCH 3 ;
- L 1 is CH 3 , -F, -Cl, -Br, -OMe, -SMe, or
- R 2 is -NHCOR 20 , -NHCOOR 20 or -NHR 21 , wherein R 20 and R 21 are independently selected from methyl, ethyl, n-propyl, /-propyl, 2,2-dimethylpropyl, cyclopentyl and cyclopentylmethyl;
- R 1 is vinyl; and R c is hydroxy or NHSO 2 -cyclopropyl.
- B is selected from ethyl, n-propyl, .erf-butyl, cyclopentyl, 1-methylcyclopentyl, 2-fluoroethyl and 3-fluoropropyl;
- R 3 is selected from 1,1- dimethylethyl and cyclohexyl;
- L° is H or -OCH 3 ;
- L is -CH 3 , -Cl, or -Br;
- L 2 is H; and
- R c is hydroxy.
- Examples of preferred embodiments according to this invention is each single compound listed in the following Tables 1, 2, 3, 4, 5 and 6.
- the pharmaceutical composition of this invention may additionally comprise at least one other anti-HCV agent.
- anti-HCV agents include, ⁇ - (alpha), ⁇ - (beta), ⁇ - (delta), ⁇ - (gamma), ⁇ - (omega) or ⁇ - (tau) interferon, pegylated -interferon, ribavirin and amantadine.
- the pharmaceutical composition of this invention may additionally comprise at least one other inhibitor of HCV NS3 protease.
- the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of HCV polymerase.
- the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of other targets in the HCV life cycle, including but not limited to, helicase, NS2/3 protease or internal ribosome entry site (IRES).
- at least one inhibitor of other targets in the HCV life cycle including but not limited to, helicase, NS2/3 protease or internal ribosome entry site (IRES).
- the pharmaceutical composition of this invention may be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred.
- the pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
- the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
- This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents.
- the pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
- carriers which are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried corn starch.
- aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
- Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 50 mg/kg body weight per day of the protease inhibitor compound described herein are useful in a monotherapy for the prevention and treatment of HCV mediated disease.
- the pharmaceutical composition of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w).
- such preparations contain from about 20% to about 80% active compound.
- composition of this invention comprises a combination of a compound of formula I and one or more additional therapeutic or prophylactic agent
- both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
- compositions may be administered in vivo to mammals, such as man, to inhibit HCV NS3 protease or to treat or prevent HCV virus infection. Such treatment may also be achieved using a compound of this invention in combination with another antiviral agent.
- Preferred other antiviral agents are described within the Definitions section and the section of preferred pharmaceutical compositions according to this invention and include, but are not limited to: ⁇ , ⁇ -, ⁇ -, ⁇ -, ⁇ - or ⁇ - interferon, ribavirin, amantadine; other inhibitors of HCV NS3 protease; inhibitors of HCV polymerase; inhibitors of other targets in the HCV life cycle, which include but are not limited to, helicase, NS2/3 protease, or internal ribosome entry site (IRES); or combinations thereof.
- the additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form. .
- another embodiment of this invention provides a method of inhibiting HCV NS3 protease activity in a mammal by administering a compound of the formula I, including a pharmaceutically acceptable salt or ester thereof.
- this method is useful in decreasing the NS3 protease activity of the hepatitis C virus infecting a mammal.
- combination therapy is contemplated wherein a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, is co-administered with at least one additional antiviral agent.
- additional antiviral agents are described hereinbefore and examples of such agents are provided in the Definitions section.
- These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
- a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, set forth herein may also be used as a laboratory reagent.
- a compound of this invention, including a pharmaceutically acceptable salt or ester thereof may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials (e.g. blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection apparatuses and materials).
- a compound of formula (I), including a pharmaceutically acceptable salt or ester thereof, set forth herein may also be used as a research reagent.
- a compound of formula (I), including a pharmaceutically acceptable salt or ester thereof, may also be used as positive control to validate surrogate cell-based assays or in vitro or in vivo viral replication assays.
- dipeptide 3 is carried out by coupling the P1 residue to the properly protected .rans-hydroxy proline under standard conditions.
- the stereochemistry of the hydroxyl group is inverted by the well known Mitsunobu reaction using para-nitrobenzoic acid.
- Coupling of dipeptide with the P3 moiety yielded tripeptide 6.
- Introduction of the quinoline moiety to the hydroxyl group of the tripeptide 7 with inversion of stereochemistry can be carried out using either a Mitsunobu reaction or by converting the free hydroxyl group into a good leaving group (such as a brosylate) and displacing it with the hydroxyl quinoline derivative 9.
- the quinoline used contains a 2-carbomethoxy group as shown in 9. Conversion of the carboxylate group to the aminothiazole derivative is carried out by well known synthetic methodology and is described and exemplified in WO 00/09543 and WO 00/09598. Finally the C-terminal ester is hydrolyzed under basic aqueous conditions.
- Scheme 2 describes another reaction sequence for making compounds of Formula I.
- the quinoline moiety is introduced to the dipeptide in a similar way as described in Scheme 1.
- the P3 moiety is coupled under standard conditions to the dipeptide 21. Conversion of the resulting tripeptide to the final compound is carried out as described in Scheme 1.
- P1 moieties of compounds of Formula (I) were prepared using the protocols outlined in WO 00/59929, published October 12, 2000, and WO 00/09543, published on February 24, 2000. In particular, reference is made to pages 33-35, Example 1 of WOOO/59929 and Pages 56-69 , Example 9 - 20 of WOOO/09543 for the preparation of 1-aminocyclopropanecarboxylic acid P1 moieties.
- properly substituted anilines at the 2, 3 and/or 4 position are allowed to react with dimethyl acetylene dicarboxylate and the resulting enamine is heated at high , temperatures to effect the cyclization.
- the corresponding anilines are commercially available or may require some well known chemical transformation.
- the nitro is commercially available and is then converted to the corresponding amine by using a reducing agent.
- the carboxylic acid when commercially available, it can be transformed into the corresponding amine via a Curtius rearrangement.
- the reaction was rendered basic by the addition of 1 N NaOH (25 mL - final pH >10).
- the solution was washed with EtOAc (2x 200 mL) and the aqueous phase acidified with 1 N HCI (ca. 70 mL - final pH ⁇ 2).
- the turbid solution was extracted with EtOAc (200 + 150 mL).
- the extract was dried (MgSO 4 ) and evaporated to give carbamate 4a as a white solid (8.68 g).
- the reaction mixture was diluted with EtOAc, washed with 10% citric acid (2x), water (2x), saturated NaHCO 3 (2x), water (2x) and brine (1x), dried (MgSO 4 ), filtered and evaporated to obtain the crude compound as a nearly colorless oil (3.73 g; >100%; assume 9.89 mmol).
- the crude product (1.01 g; 2.97 mmol) was dissolved in DMSO (6.5 mL) and cyclopentylamine was added dropwise. The reaction mixture was stirred at R.T. for 45 min and then diluted with EtOAc.
- the organic phase was washed with 10% citric acid (2x), water (2x), saturated NaHCO 3 (2x), water (2x) and brine (1x), dried (MgSO 4 ), filtered and evaporated to give the crude cyclopentyl urea -Tbg-OBn product as a nearly colorless oil.
- the crude material was purified by flash column chromatography with silica using hexane:EtOAc 9:1 to remove the less polar impurities and 7:3 to elute the purified product as a thick colorless oil (936 mg; 95%o).
- the benzyl ester product (936 mg; 2.82 mmol) was deprotected under a hydrogen filled balloon at R.T.
- the diester A4 (6.5 g, 23.27 mmol) was dissolved in diphenyl ether (12 mL) and the reaction mixture placed into a pre-heated sand bath at a bath temperature of 350- 400 ° C. Once the reaction mixture attained an internal temperature of 240 ° C (observe MeOH evolution at 230-240 ° C) a count of six minutes was begun before the bath (temperature end point: 262 ° C) was removed and the reaction allowed to cool to room temperature. A solid formed upon cooling which was diluted with ether, filtered and dried to give a tan brown solid (3.48 g crude).
- Step A 2-Amino-3-nitrophenol B1 (5 g; 32.4 mmol) was dissolved in H 2 O (29.5 mL) and 1,4- dioxane (14.7 mL). The mixture was heated to reflux and hydrobromic acid (48%; 16.7 mL; 147 mmol) was added dropwise over a period of 20 min. Upon completion of the addition, the reflux was maintained an additional 15 min. The reaction was cooled to 0 ° C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H 2 O (20 mL) was added over a period of 30 min.
- Step B The nitrophenol starting material B2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1x 200 mL), washed with water (1x 200 mL), brine (4x 00 mL), dried (MgSO 4 ), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole B3 (94%; 3.1 g) as an orange solid.
- Step A 2-Amino-3-nitrophenol B1 (5 g; 32.4 mmol) was dissolved in concentrated HCl (75 mL) and 1 ,4-dioxane (14.7 mL). The mixture was heated to 70 ° C until most of the solids were in solution. The reaction mixture was cooled to 0 ° C (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H 2 O (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained below 10 ° C during the addition and the stirring was continued for an additional 15 min at 0 ° C.
- This diazonium intermediate was poured into a solution of Cu(l)CI (3.8 g; 38.9 mmol) in H 2 O (18.5 mL) and cone. HCl (18.5 mL) at 0 ° C. The reaction was stirred for 15 min at 0 ° C, warmed to 60 ° C, and stirred for an additional 15 min The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3X 150 mL). The organic layers were combined, washed with brine (1X), dried (Na 2 SO 4 ), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil.
- Step B The nitrophenol starting material C2 (1.3 g; 7.49 mmol) was dissolved in DMF (10 mL) and to this solution was added ground cesium carbonate (2.92 g; 8.96 mmol), followed by Mel (1.4 mL; 22.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated in vac ⁇ o and the residue taken up in ether (150 mL), washed with water (150 mL), brine (4x 100 mL), and then dried over (MgSO 4 >. The organic phase was filtered and evaporated to afford the crude 2- chloro-3-nitroanisole 03 (98%; 1.38 g) as an orange solid. Homogeneity by HPLC (TFA) @ 220 nm: 93%.
- Step C 2-Chloro-3-nitroanisole C3 (1.38 g; 7.36 mmol) was dissolved in a mixture of glacial acetic acid (19 mL)/ethanol (19 mL). To this solution was added iron powder (1.64 g; 29.4 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (70 mL), neutralized with solid Na 2 CO 3 and the product extracted with CH 2 CI 2 (3X 150 mL).
- Step B Compound D2 (2.28 g, 9.45 mmol) was treated with 4N HCI/dioxane solution (from Aldrich) (10 mL, 40 mmol) for 60 min and HPLC analysis showed that the starting material was fully consumed.
- the reaction mixture was concentrated in vacuo, re- dissolved in EtOAc and washed with water, saturated NaHCO 3 (aq), and saturated brine.
- the organic phase was dried (MgSO ), filtered and concentrated to give. 1.18 g (88%) of D3 as a brown oil, which was used as is in the following step.
- Step C Aniline D3 (1.18 g, 8.36 mmol) was combined with dimethylacetylene dicarboxylate A3 (1.45 mL, 10.0 mmol) in methanol (25 mL). The reaction was refluxed for 2 hours before being concentrated to dryness. The crude material was purified by flash chromatography eluting with 9/1 (hexane/EtOAc) to give the Michael adduct D4 as a yellow oil, (1.27 g, 54%).
- the Michael adduct D4 was dissolved in warm diphenyl ether (6 mL) and placed in a sand bath previously heated to ⁇ 350°C. The internal temperature of the reaction was monitored and maintained at ⁇ 245°C for about 5 minutes (solution turns brown). After cooling to R.T., the desired 4-hydroxy ' quinoline crashed out of solution. The brown solid was filtered and washed several times with diethyl ether to give, after drying, quinoline D5 as a brown solid (0.51 g, 45%). MS: 252 (M + H) + , 249.9 (M - H)-.
- Step C Sulfuric acid (18 mL) was added to the solution of aniline E3 (4.20 g, 25.27 mmol) in water (36 mL) at 0°C followed by the addition of sodium nitrite (2.3 g, 33.33 mmol in water (6 mL).
- sodium nitrite 2.3 g, 33.33 mmol in water (6 mL).
- This solution was brought to reflux and then the initial solution was added dropwise while maintaining a boil. After the addition was complete, boiling was continued for 5 ' min and the mixture then poured onto ice/sodium carbonate mixture while cooling in an ice bath.
- the product was extracted with aq. EtOAc and concentrated to yield a dark brown viscous liquid E4 (2.00 g, 47 %) which was employed in subsequent reaction without further purification.
- MS ES " 210.9.
- the Michael adduct E7 was dissolved in warm diphenyl ether (10 mL) and placed in a sand bath previously heated to ⁇ 350°C. The, internal temperature of the reaction was monitored, maintained at ⁇ 245°C for about 5 minutes (solution turns brown) and cooled to R.T. at which time the desired 4-hydroxyquinoline precipitated out of solution. The brown solid was filtered and washed several times with diethyl ether to give quinoline E8 as a yellow-brown solid after drying (1.10 g, 88 %).
- the diester F3 (1.8 g, 6.44 mmol) was dissolved in diphenyl ether (5 mL) and the reaction mixture placed into a pre-heated sand bath at a bath temperature of 350- 400 ° C. Once the reaction mixture attained an internal temperature of 240 ° C, a count of five minutes was begun before the bath was removed and the reaction allowed to cool to room temperature overnight. A solid formed upon cooling which was diluted with ether, filtered and dried to give a brown solid (0.97 g crude) containing both regioisomers in almost equal proportions. The crude material was triturated with MeOH and EtOAc, filtered and dried to provide the correct regioisomer of the methylquinoline product F4 as a yellow solid (245 mg, 15% yield).
- the Boc starting material G2 (257 mg; 1.08 mmol) was dissolved in 4M HCI/dioxane (5.0 mL) and stirred at room temperature for 1 hr. The solvent was evaporated and the residue diluted with saturated sodium bicarbonate (few mL) and 1 M NaOH (1 mL), extracted with EtOAc (2x), dried (MgSO 4 ), filtered and evaporated to dryness to provide the crude 2,3-methylene dioxyaniline G3 (158 mg; 106%,).
- the diester G4 (180 mg, 0.645 mmol) was dissolved in diphenyl ether (2.5 mL) and the reaction mixture placed into a pre-heated sand bath at a bath temperature of 350-400 ° C. Once the reaction mixture attained an internal temperature of 250 ° C (observe MeOH evolution at 220-230°C) a count of six minutes was begun before the bath (temperature end point :262 ° C) was removed and the reaction allowed to cool to room temperature. A solid formed upon cooling which was diluted with ether, filtered and dried to give the crude dioxyquinoline G5 (125 mg; 78 %). Purification was not required and the material was used as such in the following reactions. MS (M + H) + ; 246, and (M - H) " ; 248.1. Homogeneity by HPLC (TFA) @ 220 nm :88%.
- Triethylamine (5.0 mL, 35.6 mmol) was added to a flask containing the amine H1 (2.0 mL, 17.8 mmol) and dichioromethane (100 mL) under an atmosphere of nitrogen. The contents were cooled in an ice bath and trimethylacetylchloride (3.3 mL, 26.7 mmol) was added dropwise. The reaction was allowed to warm slowly to R.T. and stirred for 14 h. at this temperature. The reaction was quenched with NaHCO 3 saturated solution and extracted with EtOAc. The combined organic layers were dried, filtered and concentrated followed by flash column chromatography (4:1 to 1:1 hexane:EtOAc) to yield the desired product H2 as an off-white solid (3.7 g, 97 % yield).
- n-BuLi (15.9 mL, 1.6M, 25.5 mmol) was added dropwise to a flame dried flask containing a solution of the starting amide H2 (1.6 g, 7.72 mmol) in THF at 0 ° C under argon. Solution turned slight yellow/orange color when n-BuLi was added. The solution was allowed to warm slowly to R.T. and stirred for 24 h. The solution was again cooled to 0°C and ethylene oxide (0.46 mL, 9.26 mmol) was added dropwise.
- H4 H5 HCl (4.0 mL, 6.0M) was added to a solution of amide H4 (0.27 g, 1.22 mmol) in MeOH (4.0 mL) at 23 ° C. The reaction was then heated to reflux for 48 h, NaHCO 3 (saturated, aq) was added and was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated to obtain the desired aniline H5 which was of sufficient purity to employ in further transformations.
- the diester J2 (10.53 g, 37.43 mmol) was dissolved in diphenyl ether (35 mL) and the reaction mixture placed into a pre-heated sand bath at a bath temperature of 350-400 ° C. Once the reaction mixture attained an internal temperature of 245 ° C, a count of six minutes was begun before the bath was removed and the reaction allowed to cool to room temperature. A precipitate formed, which was suspended in ether, filtered and washed again with ether to provide the C8-SMe quinoline product J3 (6.15 g; 66%). MS (M + H) + ; 250 Homogeneity by HPLC (TFA) @ 220 nm: 99%.
- Step 1
- the diester K5 (1.13 g, 3.52 mmol) was dissolved in diphenyl ether (3.0 mL) and the reaction mixture placed into a pre-heated sand bath at a bath temperature of 400- 440°C. Once the reaction mixture attained an internal temperature of 230°C (observe MeOH evolution at 220°C) a count of six minutes was begun before the bath (temperature end point : 242°C) was removed and the reaction allowed to cool to room temperature.
- This quinoline moiety was used for the synthesis of compounds 1032 and 1033 of table 1.
- quinoline K6 was used for the synthesis of compounds 1034, 1035, 1057 and 1058, also of table 1 .
- Conversion of the C7-fen!-butyl-ether group to an hydroxyl group was done by treatment of the final compound with 50% TFA in dichloromethane for 30 min. at 0°C then for 30 min. at R.T. , evaporated to dryness, diluted with water and lyophilized.
- the diester L2 (10 g, 37.70 mmol) was dissolved in diphenyl ether (15 mL) and the reaction mixture placed into a pre-heated sand bath at a bath temperature of 350- 400 ° C. Once the reaction mixture attained an internal temperature of 240 ° C, a count of six minutes was begun before the bath was removed and the reaction allowed to cool to room temperature. No solid formed upon cooling, therefore, the crude mixture was flash column purified with hexane : EtOAc (6 : 4 to 5 : 5 to remove impurities, then, 2 : 8 to complete elution) to provide the C8-OMe quinoline product L3 (4.56 g; 52 %). MS (M - H) " ; 231.9 Homogeneity by HPLC (TFA) @ 220 nm: 99%.
- Dipeptide 1 (72.0 g, 203 mmol), triphenylphosphine (63.94 g, 243.8 mmol, 1.2 equiv.) and 4-nitrobenzoic acid (41.08 g, 245.8 mmol, 1.2 equiv) were dissolved in dry THF (1.4 L) The stirred solution was cooled to 0°C under a nitrogen atmosphere. Diethyl azodicarboxylate (38.4 mL, 244 mmol, 1.2 equiv.) was then added dropwise over 45 min and the reaction allowed to warm to R.T. After 4 h, the solvent was evaporated. The residue was divided into four portions.
- Boc-dipeptide ester 2 was obtained as an amorphous white solid after evaporation of the solvents and drying of the residues under high vacuum at 70°C for 1 h (108.1 g, quantitative).
- a solution of 4N hydrogen chloride in dioxane was added to the Boc-dipeptide ester 2 (108 g, 243 mmol) resulting in a colorless solution. The solution was stirred at R.T. for 1 h. The solvent was evaporated and the residue placed under high vacuum for 3 h affording the hydrochloride salt of compound 3 as an amorphous solid. The solid was used as such.
- the tripeptide 6a (15.68 g) was dissolved in THF (200 mL) and water (30 mL) was added. The resulting solution was cooled to 0 ° C and a solution of lithium hydroxide monohydrate (1.18 g, 28.12 mmol) was added over 3 min with vigorous stirring. After 3 h at 0 ° C, the excess base was neutralized with 1 N HCl (final pH ca. 6) and the THF evaporated, resulting in an aqueous suspension (yellow gum). The mixture was extracted with EtOAc (2x 200 mL) and washed with saturated NaHCO 3 (2x 300 mL). The combined extracts were dried over MgSO 4 and evaporated to yield a pale yellow foam. Flash chromatography of the foam over silica gel using EtOAc as eluent afforded 7a as a white amorphous solid (9.77 g, 91%).
- brosylate 7aBrs 0.5 g; 0.71 mmol
- bromoquinoline B6 (234 mg; 0.75 mmol)
- ground cesium carbonate 56 mg; 0.78 mmol
- the reaction mixture was poured into EtOAc, washed with H 2 O (1X), NaHCO 3 (saturated; 2X), brine (5X), dried, filtered and concentrated to afford the crude product (0.565 g) as an off white solid.
- Tripeptide 10b (149 mg, 0.210 mmol), in 5 mL of a 1:1 mixture of THF-MeOH, was cooled to ' 0 ° C for the addition of a 1 N NaOH aqueous solution (0.24 mL, 0.240 mmol). The resulting solution was stirred.15 min at 0 ° C, 1.5 h at R.T. and found to be incomplete by analytical HPLC. Additional 1 N NaOH (0.05 mL, 0.05 mmol) was added and the reaction stirred for an additional hour. The mixture was quenched with 1 M HCl, evaporated to near dryness, diluted with water, frozen and lyophilized to provide the acid 11b (crude material used for next step; assume 0.210 mmol). Reverse Phase HPLC Homogeneity (0.06% TFA; CH 3 CN : H 2 O) : 89%. Step 2 : Synthesis of diazoketone 12b:
- ⁇ -Bromoketone 13b 49 mg, 0.0635 mmol
- ⁇ /-neopentylthiourea 8a (12 mg; 0.0688 mmol) were dissolved in isopropanol (3 mL) and the yellow solution was heated at 75 ° C for 1 hour. The solution was allowed to cool to R.T. and evaporated to dryness. This crude material 14b was used for next step (assume 0.0635 mmol).
- M.S.(electrospray) 845.5 (M-H) " 847.5 (M+H) + .
- Step 2 The conversion of the 2-carbomethoxy group of 10d into the 2-(1-oxo-2-bromo)ethyl group of 13d was done using the reaction sequence described in Example 7, steps 1, 2 and 3.
- Step 3 The conversion of the 2-carbomethoxy group of 10d into the 2-(1-oxo-2-bromo)ethyl group of 13d was done using the reaction sequence described in Example 7, steps 1, 2 and 3.
- E11-1 Potassium cyanide (1.43 g, 22.0 mmol) was added to a stirred solution of methylcyclopentanol (2.00 g, 20.0 mmol) in glacial acetic acid (1.00 mL) resulting in a thick slurry. To this was added, dropwise, sulfuric acid (3 mL, caution: exothermic) at a rate at which the temperature was maintained at ca. 30-35°C. Additional acetic acid (1 mL) was added to facilitate stirring of the thick paste. The mixture was then heated to 55-60°C for 30 min followed by stirring at ambient temperature for 16 h.
- E11-4 The E11-3 (6.80 g, 21.2 mmol) was dissolved in dioxane (4 mL) and a solution of 4N HCl in dioxane (30 mL, 120 mmol) added. After stirring at ambient temperature for 2 h, the solvent was evaporated and the residue allowed to stand under a stream of nitrogen resulting in slow solidification. This material was then triturated with hexane (2x 50 mL), filtered, air dried for 30 min then placed under high vacuum for 5 days to afford the hydrochloride salt as a white solid (4.86 g, 89%).
- E11-5 To a stirred, ice cold solution of E11-4 (4.85 g, 18.8 mmol) in tetrahydrofuran (75 mL) was added diisopropylethylamine (8.20 mL, 47.0 mmol) followed by the dropwise addition of phenylchloroformate (2.60 mL, 20.7 mmol) under an argon atmosphere. A thick precipitate formed which, upon vigorous stirring, became a fine suspension. After 4.5 h, the mixture was concentrated to.
- E11-6 To a solution of E11 -5 (1.00 g, 2.93 mmol) in DMSO (2.00 mL) containing acetonitrile (1.00 mL) was added diisopropylethylamine (817 ⁇ L) followed by the amine E11-2 (477 mg, 3.52 mmol). The reaction was stirred at ambient temperature for 2 h and then heated to 70°C for 45 min The solution was then diluted with ethyl acetate (30 mL), washed with 5% aq K 2 CO 3 (4x 50 mL) and brine (50 L).
- E 1-7 To solution of urea E11-6 (780 mg, 2.25 mmol) in absolute ethanol (10 mL) under an argon atmosphere was added 10% Pd-C. catalyst (100 mg). The system was purged three times with H 2 and then stirred vigorously under a hydrogen- balloon. After 3 h, the catalyst was filtered over Celite and the filtrate evaporated. The residue was then dissolved in methanol (ca. 10 mL), filtered through a Millipore Millex 0.45 uM filter and then evaporated to yield the acid E11 -7 as a white solid (539 mg, 93%).
- E11-8 The urea E11-7 (239 mg, 0.932 mmol) and TBTU (3.06 mg, 0.979 mmol) were dissolved/suspended in anhydrous dichloromethane (4 mL) and diisopropylethylamine (157 ⁇ L, 0.900 mmol) added. The reaction was stirred at ambient temperature under a nitrogen atmosphere until the solution became nearly homogeneous (ca. 5 min).
- E11-9 The ester E11-8 (645 mg, 0.894 mmol) was dissolved in tetrahydrofuran (16 mL) containing methanol (8 mL) and 1.0N aqueous sodium hydroxide solution (900 mL, 0.900 mmol) then added dropwise with vigorous stirring at ambient temperature. After 5 h, the solution was evaporated (keeping the bath temperature below 30°C) and then placed under high vacuum overnight to afford the carboxylate salt as a pale yellow solid (725 mg, quantitative) which was used without further purification (ca. 10 % of diacid present).
- E11-1Q To a stirred, ice cold suspension of sodium salt E11-9 (0.894 mmol) in tetrahydrofuran (10 L) under an argon atmosphere was added triethylamine (240 ⁇ L, 1.72 mmol) followed by the dropwise addition of isobutyl chloroformate (174 ⁇ L, .34 mmol). The resulting suspension was stirred at 0 C C for 3 h and a solution of diazomethane in ethyl ether (0.7M, 10 mL, 7 mmol) then added. The yellow suspension was stirred for 30 min at 0°C and then allowed to warm to ambient temperature. After 1 h, nitrogen was bubbled through the suspension for 5 min.
- E11-12 To a solution of bromoketone E11-11 (75 mg, 0.10 mmol) in isopropanol (0.30 mL) was added diisopropylethylamine (87 ⁇ L, 0.50 mmol) and N- acetylthiourea (18 mg, 0.15 mmol). The stirred mixture was heated to 70°C for 1 h and then extracted with ethyl acetate (30 mL) and washed with 5% aqueous
- tripeptide ester E13-2 The urea-P3 acid was coupled with the P1-P2 fragment 15b as described in Example 11.
- E14-2 The urea-P3 acid E14-2 was prepared from E11-5 and amine E14-1 by the same sequence of reactions as described in Example 11.
- E14-3 The urea-P3 acid was coupled with the P1-P2 fragment 15b as described in Example 11.
- the final inhibitor was prepared from E14-3 by a sequence of steps identical to that described on Example 11.
- the product of the final saponification was isolated as an amorphous yellow powder (trifluoroacetate salt, 10 mg, 21 %).
- a series of 8-mL vials were disposed in a reaction block from an ACT496 synthesizer (from Advanced Chemtech).
- ACT496 synthesizer from Advanced Chemtech
- each vial was added the thio-derivative (8) of interest (0.0688 mmole), the bromoketone (0.0625 mmole) and isopropanol (500 ⁇ L).
- the closed vials were heated at 70°C for 1 h.
- the solvent was then evaporated using a vacuum centrifuge (SpeedVac) and was co-evaporated with 1 ,2- dichloroethane.
- the crude products were dried under high vacuum overnight.
- HATU (20 mg, 0.05 mmol) was added to a solution of compound 17A1 (Compound 3004, Table 3; 20 mg, 0.03 mmol) and DIPEA (0.03 mL, 0.16 mmol) in DMF (1.5 mL) at RT.
- the solution was stirred for 1h followed by the addition of DMAP (16 mg, 0.13 mmol) and cyclopropanesulfonamide (7.0 mg, 0.06 mmol). After addition was complete, the mixture was allowed to stir for 15 min and DBU (0.02 mL, 0.14 mmol) was added dropwise.
- Example 17A Using the procedure of Example 17A but starting with compound 17B1 (Compound 6016, Table 6), compound 17B2 (Compound 7002, Table 7) was prepared as a light yellow solid (5.4 mg, 16% yield).
- Huh7 cells that stably maintain a subgenomic HCV replicon were established as previously described (Lohman et al., 1999. Science 285: 110-113) and designated as the S22.3 cell-line.
- S22.3 cells are maintained in Dulbecco's Modified Earle Medium (DMEM) supplemented with 10% FBS and 1 mg/mL neomycin (Standard Medium). During the assay, DMEM medium supplemented with 10% FBS, containing 0.5% DMSO and lacking neomycin was used (Assay Medium). 16 hours prior to compound addition, S22.3 cells are trypsinized and diluted to 50 000 cells/mL in Standard Medium. 200 ⁇ L (10 000 cells) are distributed into each well of a 96-well plate. The plate was then incubated at 37°C with 5% CO 2 until the next day.
- test compound 10 ⁇ L was added to 2 mL of Assay Medium for a final DMSO concentration of 0.5% and the solution was sonicated for 15 min and filtered through a 0.22 ⁇ M Millipore Filter Unit. 900 ⁇ L was transferred into row A of a Polypropylene Deep-Well Titer Plate. Rows B to H contain 400 ⁇ L aliquots of Assay Medium (containing 0.5% DMSO), and are used to prepare serial dilutions (1/2) by transferring 400 ⁇ L from row to row (no compound was included in row H).
- Cell culture medium was aspirated from the 96-well plate containing the S22.3 cells. 175 ⁇ L of assay medium with the appropriate dilution of test compound was transferred from each well of the compound plate to the corresponding well of the cell culture plate (row H was used as the "No inhibition control"). The cell culture plate was incubated at 37°C with 5% CO 2 for 72 h.
- RNeasy 96 plate was sealed with tape and the Square-Well Block with the RNeasy 96 plate was loaded into the holder and placed in a rotor bucket of a 4K15C centrifuge. The sample was centrifuged at 6000 rpm (-5600 x g) for 4 min at room temperature. The tape was removed from the plate and 0.8 mL of Buffer RW1 (Qiagen® RNeasy 96 kit) was added to each well of the RNeasy 96 plate. The RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 4 min at room temperature.
- the RNeasy 96 plate was placed on top of another clean Square-Well Block, the tape removed and 0.8 mL of Buffer RPE (Qiagen® RNeasy 96 kit) was added to each well of the RNeasy 96 plate.
- the RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 4 min at room temperature.
- the tape was removed and another 0.8 mL of Buffer RPE (Qiagen® RNeasy 96 kit) was added to each well of the RNeasy 96 plate.
- the RNeasy 96 plate was sealed with a new piece of tape and centrifuged at 6000 rpm for 10 min at room temperature.
- RNA was quantified on the STORM® system (Molecular Dynamics®) using the RiboGreen® RNA Quantification Kit (Molecular Probes®). Briefly, the RiboGreen reagent was diluted 200-fold in TE (10 mM Tris-HCI pH 7.5, 1 mM EDTA). Generally, 50 ⁇ L of reagent was diluted in 10 mL TE. A Standard Curve of ribosomal RNA was diluted in TE to 2 ⁇ g/mL and pre-determined amounts (100, 50, 40, 20, 10, 5, 2 and 0 ⁇ L) of the ribosomal RNA solution are then transferred in a new 96- well plate (COSTAR # 3997) and the volume was completed to 100 ⁇ L with TE.
- column 1 of the 96-well plate was used for the standard curve and the other wells are used for the RNA samples to be quantified.
- 10 ⁇ L of each RNA sample that was to be quantified was transferred to the corresponding well of the 96-well plate and 90 ⁇ L of TE was added.
- One volume (100 ⁇ L) of diluted RiboGreen reagent was added to each well of the 96-well plate and incubated for 2 to 5 minutes at room temperature, protected from light (a 10 ⁇ L RNA sample in a 200 ⁇ L final volume generates a 20X dilution).
- the fluorescence intensity of each well was measured on the STORM® system (Molecular Dynamics®).
- a standard curve was created on the basis of the known quantities of the ribosomal RNA and the resulting fluorescent intensities.
- the RNA concentration in the experimental samples was determined from the standard curve and corrected for the 20X dilution.
- R.T.-PCR was optimized for the quantification of the 5' IRES of HCV RNA by using the Taqman technology (Roche Molecular Diagnostics Systems) similar to the technique previously described (Martell et al., 1999. J. Clin. Microbiol. 37: 327-332).
- the system exploits the 5'-3' nucleolytic activity of AmpliTaq DNA polymerase. Briefly, the method utilizes a dual-labeled fluorogenic hybridization probe (PUTR Probe) that specifically anneals to the template between the PCR primers (primers 8125 and 7028).
- PUTR Probe dual-labeled fluorogenic hybridization probe
- the 5' end of the probe contains a fluorescent reporter (6-carboxyfluorescein [FAM]) and the 3' end contains a fluorescent quencher (6-carboxytetramethylrhodamine [TAMRA]).
- FAM reporter's emission spectrum was suppressed by the quencher on the intact hybridization probe. Nuclease degradation of the hybridization probe releases the reporter, resulting in an increase in fluorescence emission.
- the ABI Prism 7700 sequence detector measures the increase in fluorescence emission continuously during the PCR amplification such that the amplified product was directly proportion to the signal. The amplification plot was analysed early in the reaction at a point that represents the logarithmic phase of product accumulation.
- C ⁇ A point representing a defined detection threshold of the increase inthe fluorescent signal associated with the exponential growth of the PCR product for the sequence detector was defined as the cycle threshold (C ⁇ ).
- C r values are inversely proportional to the quantity of input HCV RNA; such that under identical PCR conditions, the larger the starting concentration of HCV RNA, the lower the C ⁇ .
- a standard curve was created automatically by the ABI Prism 7700 detection system by plotting the C ⁇ against each standard dilution of known HCV RNA concentration.
- the Real-Time R.T.-PCR reaction was set-up for the experimental samples that were purified on RNeasy 96 -well plates by combining 5 ⁇ L of each total cellular RNA sample with 45 ⁇ L of Reagent Mix.
- Those primers amplify a region of 256-nt present within the 5' untranslated region of HCV.
- NTC No Template Controls
- RNA copy number was normalized (based on the RiboGreen RNA quantification of the total RNA extracted from the cell culture well) and expressed as genome equivalents / ⁇ g of total RNA [g.e./ ⁇ g].
- RNA copy number [g.e./ ⁇ g] from each well of the cell culture plate was a measure of the amount of replicating HCV RNA in the presence of various concentrations of inhibitor.
- the % inhibition was calculated with the following equation:
- the compounds of this invention are evaluated in the preceding enzymatic and cell based assays, the compounds are found to be highly active.
- the compounds of formula 1 were found to be selective in that they do not show significant inhibition (no measurable activity at concentrations up to 30 ⁇ M) in the Human Leukocyte Elastase and Cathepsin B assays.
- the present invention comprises compounds that show pharmacokinetic properties such as detectable plasma levels in the rat at 1 hour and 2 h after an oral dose of 5 mg/kg.
- an in vivo oral absorption screen is used to determine plasma levels of test compounds in a rat after oral administration:
- Each "cassette” contains 3-4 compounds at 5 or 4 mg/kg for each compound.
- the cassettes were prepared as an oral suspension in 0.5% aqueous methylcellulose and 0.3%) of polyoxyethylene (20) sorbitan monooleate (Tween-80).
- the dosing volume was 10 mL/kg via oral gavage.
- Plasma samples at 1 and 2 h, blank plasma, blank plasma spiked with all the compounds at 0.5 ⁇ M of each, are extracted by the solid phase extraction method. Samples were analyzed by HPLC and HPLC/MS for comparison purpose. Plasma concentrations are estimated based on the single concentration of 0.5 ⁇ M standard.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Zoology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE602004010137T DE602004010137T2 (de) | 2003-05-21 | 2004-05-19 | Verbindungen als hepatitis c inhibitoren |
KR1020057022088A KR101115294B1 (ko) | 2003-05-21 | 2004-05-19 | C형 간염 억제제 화합물 |
MEP-2008-583A ME00382B (me) | 2003-05-21 | 2004-05-19 | Inhibitorna jedinjenja za hepatitis c |
YUP-2005/0871A RS51294B (sr) | 2003-05-21 | 2004-05-19 | Inhibitorna jedinjenja za hepatitis c |
SI200430588T SI1654261T1 (sl) | 2003-05-21 | 2004-05-19 | Inhibitorske spojine hepatitisa C |
EP04733750A EP1654261B1 (en) | 2003-05-21 | 2004-05-19 | Hepatitis c inhibitor compounds |
AU2004240704A AU2004240704B9 (en) | 2003-05-21 | 2004-05-19 | Hepatitis C inhibitor compounds |
NZ544076A NZ544076A (en) | 2003-05-21 | 2004-05-19 | Hepatitis C inhibitor compounds |
DK04733750T DK1654261T3 (da) | 2003-05-21 | 2004-05-19 | Hepatitis C-inhibitorforbindelser |
JP2006529495A JP4447603B2 (ja) | 2003-05-21 | 2004-05-19 | C型肝炎インヒビター化合物 |
MXPA05012545A MXPA05012545A (es) | 2003-05-21 | 2004-05-19 | Compuestos inhibidores de la hepatitis c. |
CA2522577A CA2522577C (en) | 2003-05-21 | 2004-05-19 | Hepatitis c inhibitor compounds |
PL04733750T PL1654261T3 (pl) | 2003-05-21 | 2004-05-19 | Związki hamujące aktywność wirusa zapalenia wątroby typu C |
BRPI0410456A BRPI0410456B8 (pt) | 2003-05-21 | 2004-05-19 | compostos inibidores de hepatite c, composição farmacêutica, uso dos mesmos, bem como artigo de fabricação |
EA200501689A EA009295B1 (ru) | 2003-05-21 | 2004-05-19 | Соединения в качестве ингибиторов вируса гепатита с |
IL172013A IL172013A (en) | 2003-05-21 | 2005-11-17 | Hepatitis C-inhibiting compounds and pharmaceutical preparations containing them |
NO20056047A NO332056B1 (no) | 2003-05-21 | 2005-12-19 | Hepatitt C inhibitor-forbindelser, farmasoytisk preparat inneholdende slike samt slike forbindelser for behandling av sykdom |
HR20080014T HRP20080014T3 (en) | 2003-05-21 | 2008-01-11 | Hepatitis c inhibitor compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US47270903P | 2003-05-21 | 2003-05-21 | |
US60/472,709 | 2003-05-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004103996A1 true WO2004103996A1 (en) | 2004-12-02 |
Family
ID=33476973
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CA2004/000750 WO2004103996A1 (en) | 2003-05-21 | 2004-05-19 | Hepatitis c inhibitor compounds |
Country Status (33)
Cited By (109)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005080388A1 (en) | 2004-02-20 | 2005-09-01 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2005116054A1 (en) * | 2004-05-25 | 2005-12-08 | Boehringer Ingelheim International, Gmbh | Process for preparing acyclic hcv protease inhibitors |
WO2006007700A1 (en) * | 2004-07-20 | 2006-01-26 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor dipeptide analogs |
WO2007005838A2 (en) | 2005-06-30 | 2007-01-11 | Virobay, Inc. | Hcv inhibitors |
WO2007019674A1 (en) | 2005-08-12 | 2007-02-22 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
EP1763531A1 (en) * | 2004-06-28 | 2007-03-21 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
WO2007009109A3 (en) * | 2005-07-14 | 2007-06-07 | Gilead Sciences Inc | Antiviral compounds |
US7323447B2 (en) | 2005-02-08 | 2008-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7368452B2 (en) | 2003-04-18 | 2008-05-06 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
WO2008057209A1 (en) * | 2006-10-27 | 2008-05-15 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
WO2008070358A2 (en) * | 2006-11-16 | 2008-06-12 | Phenomix Corporation | N-cyclopropyl-hydroxyproline-based tripeptidic hepatitis c serine protease inhibitors containing an isoindole, pyrrolopyridine, pyrrolopyrimidine or pyrrolopyrazine heterocycle in the side chain |
US7449479B2 (en) | 2002-05-20 | 2008-11-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2009076173A2 (en) | 2007-12-05 | 2009-06-18 | Enanta Pharmaceuticals, Inc. | Fluorinated tripeptide hcv serine protease inhibitors |
WO2009076747A1 (en) | 2007-12-19 | 2009-06-25 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
EP2079480A2 (en) * | 2006-10-24 | 2009-07-22 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
US7592336B2 (en) | 2005-05-10 | 2009-09-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7601686B2 (en) | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7608590B2 (en) | 2004-01-30 | 2009-10-27 | Medivir Ab | HCV NS-3 serine protease inhibitors |
WO2010033444A1 (en) * | 2008-09-16 | 2010-03-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of a 2-thiazolyl- 4-quinolinyl-oxy derivative, a potent hcv inhibitor |
WO2010033443A1 (en) * | 2008-09-17 | 2010-03-25 | Boehringer Ingelheim International Gmbh | Combination of hcv ns3 protease inhibitor with interferon and ribavirin |
US7696242B2 (en) | 2004-07-20 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor peptide analogs |
US7718612B2 (en) * | 2007-08-02 | 2010-05-18 | Enanta Pharmaceuticals, Inc. | Pyridazinonyl macrocyclic hepatitis C serine protease inhibitors |
WO2010059667A1 (en) * | 2008-11-21 | 2010-05-27 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition of a potent hcv inhibitor for oral administration |
US7741281B2 (en) | 2005-11-03 | 2010-06-22 | 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 |
US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7767660B2 (en) | 2006-12-20 | 2010-08-03 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7772183B2 (en) | 2005-10-12 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7772180B2 (en) | 2006-11-09 | 2010-08-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7781422B2 (en) | 2006-12-20 | 2010-08-24 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7816348B2 (en) | 2006-02-03 | 2010-10-19 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2010132163A1 (en) | 2009-05-13 | 2010-11-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis c virus inhibitors |
US7879797B2 (en) | 2005-05-02 | 2011-02-01 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7897622B2 (en) | 2006-08-17 | 2011-03-01 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US7906619B2 (en) | 2006-07-13 | 2011-03-15 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
US7935670B2 (en) | 2006-07-11 | 2011-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7939667B2 (en) | 2003-05-21 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7973040B2 (en) | 2008-07-22 | 2011-07-05 | Merck Sharp & Dohme Corp. | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
US7989438B2 (en) | 2007-07-17 | 2011-08-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Therapeutic compounds |
US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2361925A1 (en) * | 2003-10-10 | 2011-08-31 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
EP2364984A1 (en) | 2005-08-26 | 2011-09-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044087B2 (en) | 2008-09-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2399575A2 (en) | 2006-08-11 | 2011-12-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for treatment of an infection by a virus of the family of flaviviridae through the farnesoid X receptor (FXR) inhibition |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
US20120059033A1 (en) * | 2010-03-11 | 2012-03-08 | Boehringer Ingelheim International Gmbh | Crystalline Salts of a Potent HCV Inhibitor |
US8138164B2 (en) | 2006-10-24 | 2012-03-20 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8148399B2 (en) | 2005-07-29 | 2012-04-03 | Tibotec Pharmaceuticals Ltd. | Macrocyclic inhibitors of hepatitis C virus |
US8163693B2 (en) | 2007-09-24 | 2012-04-24 | Achillion Pharmaceuticals, Inc. | Urea-containing peptides as inhibitors of viral replication |
US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8178491B2 (en) | 2007-06-29 | 2012-05-15 | Gilead Sciences, Inc. | Antiviral compounds |
US8178520B2 (en) | 2006-05-15 | 2012-05-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
KR20120059481A (ko) * | 2009-07-07 | 2012-06-08 | 베링거 인겔하임 인터내셔날 게엠베하 | C형 간염 바이러스 프로테아제 억제제를 위한 약제학적 조성물 |
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 |
US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
US8216999B2 (en) | 2005-07-20 | 2012-07-10 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8242140B2 (en) | 2007-08-03 | 2012-08-14 | Boehringer Ingelheim International Gmbh | Viral polymerase 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 |
US8278322B2 (en) | 2005-08-01 | 2012-10-02 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8283310B2 (en) | 2008-12-15 | 2012-10-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2512477A1 (en) * | 2009-12-18 | 2012-10-24 | Boehringer Ingelheim International GmbH | Hcv combination therapy |
US8314062B2 (en) | 2006-06-23 | 2012-11-20 | Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
US8314141B2 (en) | 1996-10-18 | 2012-11-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
US8324417B2 (en) | 2009-08-19 | 2012-12-04 | Virobay, Inc. | Process for the preparation of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid and alkyl esters and acid salts thereof |
US8343477B2 (en) | 2006-11-01 | 2013-01-01 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
US8377874B2 (en) | 2006-10-27 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8420596B2 (en) | 2008-09-11 | 2013-04-16 | Abbott Laboratories | Macrocyclic hepatitis C serine protease inhibitors |
US8435984B2 (en) | 2007-02-26 | 2013-05-07 | Achillion Pharmaceuticals, Inc. | Tertiary amine substituted peptides useful as inhibitors of HCV replication |
US8461107B2 (en) | 2008-04-28 | 2013-06-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8513186B2 (en) | 2007-06-29 | 2013-08-20 | Gilead Sciences, Inc. | Antiviral compounds |
EP2631238A1 (en) | 2007-02-27 | 2013-08-28 | Vertex Pharmaceuticals Incorporated | Spirocyclic inhibitors of serine proteases for the treatment of hcv infections |
US8563505B2 (en) | 2008-09-29 | 2013-10-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8591878B2 (en) | 2008-02-25 | 2013-11-26 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
US8614180B2 (en) | 2008-12-10 | 2013-12-24 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
US8691757B2 (en) | 2011-06-15 | 2014-04-08 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8778877B2 (en) | 2007-12-21 | 2014-07-15 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
TWI449711B (zh) * | 2005-06-30 | 2014-08-21 | Virobay Inc | C型肝炎病毒(hcv)抑制劑 |
US8822496B2 (en) | 2009-10-30 | 2014-09-02 | Boehringer Ingelheim International Gmbh | Dosage regimens for HCV combination therapy |
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
US8927569B2 (en) | 2007-07-19 | 2015-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as antiviral agents |
US8937041B2 (en) | 2010-12-30 | 2015-01-20 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US8951964B2 (en) | 2010-12-30 | 2015-02-10 | Abbvie Inc. | Phenanthridine macrocyclic hepatitis C serine protease inhibitors |
US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8993595B2 (en) | 2009-04-08 | 2015-03-31 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
US9006423B2 (en) | 2013-03-15 | 2015-04-14 | Achillion Pharmaceuticals Inc. | Process for making a 4-amino-4-oxobutanoyl peptide cyclic analogue, an inhibitor of viral replication, and intermediates thereof |
US9085607B2 (en) | 2013-03-15 | 2015-07-21 | Achillion Pharmaceuticals, Inc. | ACH-0142684 sodium salt polymorph, composition including the same, and method of manufacture thereof |
KR20150095903A (ko) * | 2012-12-21 | 2015-08-21 | 길리애드 사이언시즈, 인코포레이티드 | 아폽토시스 신호-조절 키나제 억제제로서의 치환된 피리딘-2-카르복스아미드 화합물 |
US9115175B2 (en) | 2013-03-14 | 2015-08-25 | Achillion Pharmaceuticals, Inc. | Processes for Producing sovaprevir |
US9163061B2 (en) | 2007-12-21 | 2015-10-20 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
WO2015192077A1 (en) * | 2014-06-12 | 2015-12-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Heterocyclic compounds and methods of use thereof |
US9227952B2 (en) | 2013-03-15 | 2016-01-05 | Achillion Pharmaceuticals, Inc. | Sovaprevir polymorphs and methods of manufacture thereof |
US9284307B2 (en) | 2009-08-05 | 2016-03-15 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors |
US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
EP3020723A1 (en) | 2010-09-21 | 2016-05-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived hcv serine protease inhibitors |
US9353100B2 (en) | 2011-02-10 | 2016-05-31 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections |
US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9499550B2 (en) | 2012-10-19 | 2016-11-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9580463B2 (en) | 2013-03-07 | 2017-02-28 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9598433B2 (en) | 2012-11-02 | 2017-03-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9694086B2 (en) | 2007-12-21 | 2017-07-04 | Celgene Car Llc | HCV protease inhibitors and uses thereof |
US9732076B2 (en) | 2013-03-15 | 2017-08-15 | Boehringer Ingelheim International Gmbh | Solid oral dosage formulation of HCV inhibitor in the amorphous state |
CN108610301A (zh) * | 2016-12-12 | 2018-10-02 | 中山大学 | 一类手性芳杂胺类衍生物及其合成方法和应用 |
US10201541B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
Families Citing this family (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SV2003000617A (es) | 2000-08-31 | 2003-01-13 | Lilly Co Eli | Inhibidores de la proteasa peptidomimetica ref. x-14912m |
US7119072B2 (en) * | 2002-01-30 | 2006-10-10 | Boehringer Ingelheim (Canada) Ltd. | Macrocyclic peptides active against the hepatitis C virus |
US20050075279A1 (en) * | 2002-10-25 | 2005-04-07 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
TWI359147B (en) | 2003-09-05 | 2012-03-01 | Vertex Pharma | Inhibitors of serine proteases, particularly hcv n |
KR20060094083A (ko) * | 2003-09-22 | 2006-08-28 | 베링거 인겔하임 인터내셔날 게엠베하 | C형 간염 바이러스에 대해 활성인 마크로사이클릭펩타이드 |
US7132504B2 (en) * | 2003-11-12 | 2006-11-07 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
ES2358333T3 (es) * | 2004-01-21 | 2011-05-09 | Boehringer Ingelheim International Gmbh | Péptidos macrocíclicos con acción contra el virus de la hepatitis c. |
JP4654239B2 (ja) | 2004-03-15 | 2011-03-16 | 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 | C型肝炎ウィルス感染症の治療に適した大環状ジペプチドの調製方法 |
CN102160891A (zh) * | 2004-10-01 | 2011-08-24 | 威特克斯医药股份有限公司 | Hcv ns3-ns4a蛋白酶抑制 |
MY141025A (en) | 2004-10-29 | 2010-02-25 | Vertex Pharma | Dose forms |
KR101514953B1 (ko) * | 2005-03-08 | 2015-04-24 | 베링거 인겔하임 인터내셔날 게엠베하 | 매크로사이클릭 화합물의 제조방법 |
US20070105781A1 (en) * | 2005-08-02 | 2007-05-10 | Steve Lyons | Inhibitors of serine proteases |
WO2007053755A1 (en) * | 2005-11-03 | 2007-05-10 | Boehringer Ingelheim International Gmbh | Process for preparing substituted anisidines |
WO2007130704A1 (en) * | 2006-01-25 | 2007-11-15 | Boehringer Ingelheim International Gmbh | A two step process for preparing substituted anisidines |
WO2007098270A2 (en) | 2006-02-27 | 2007-08-30 | Vertex Pharmaceuticals Incorporated | Co-crystals comprising vx-950 and pharmaceutical compositions comprising the same |
BRPI0709567A2 (pt) | 2006-03-16 | 2011-07-12 | Vertex Pharma | inibidores deuterados de protease de hepatite c |
MX2009009176A (es) * | 2007-02-27 | 2009-09-28 | Vertex Pharma | Inhibidores de serina-proteasas. |
PL2114924T3 (pl) * | 2007-02-27 | 2012-07-31 | Vertex Pharmceuticals Incorporated | Ko-kryształy i kompozycje farmaceutyczne je zawierające |
EP2185546B1 (en) * | 2007-08-30 | 2011-10-26 | Vertex Pharmceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
CA2708042A1 (en) * | 2007-12-05 | 2009-06-11 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl derivatives |
US8293705B2 (en) | 2007-12-21 | 2012-10-23 | Avila Therapeutics, Inc. | HCV protease inhibitors and uses thereof |
CN101977915B (zh) * | 2008-02-04 | 2014-08-13 | 埃迪尼克斯医药公司 | 大环丝氨酸蛋白酶抑制剂 |
AU2014201788B2 (en) * | 2008-09-16 | 2015-09-03 | Boehringer Ingelheim International Gmbh | Crystalline forms of a 2-thiazolyl- 4-quinolinyl-oxy derivative, a potent HCV inhibitor |
JP2012502925A (ja) * | 2008-09-23 | 2012-02-02 | 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 | C型肝炎阻害化合物 |
CA2747636A1 (en) | 2008-12-19 | 2010-07-15 | Gilead Sciences, Inc. | Hcv ns3 protease inhibitors |
JP2012517478A (ja) | 2009-02-12 | 2012-08-02 | 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 | ペグ化インターフェロン、リバビリンおよびテラプレビルを含む、hcv組合せ治療剤 |
US20120142929A1 (en) | 2009-03-19 | 2012-06-07 | Boehringer Ingelheim International Gmbh | Process for preparing sulfonyl quinolines |
CN102365283B (zh) * | 2009-03-26 | 2014-04-09 | 株式会社大熊制药 | 阿德福韦酯的新晶型及其制备方法 |
US8633320B2 (en) | 2009-05-05 | 2014-01-21 | Boehringer Ingelheim International Gmbh | Process for preparing bromo-substituted quinolines |
US8232246B2 (en) * | 2009-06-30 | 2012-07-31 | Abbott Laboratories | Anti-viral compounds |
US9193740B2 (en) * | 2009-10-19 | 2015-11-24 | Enanta Pharmaceuticals, Inc. | Bismacrocyclic compounds as hepatitis C virus inhibitors |
MX2012008652A (es) | 2010-01-29 | 2012-08-23 | Vertex Pharma | Terapias para tratar infeccion por virus de hepatitis c. |
WO2011156545A1 (en) | 2010-06-09 | 2011-12-15 | Vertex Pharmaceuticals Incorporated | Viral dynamic model for hcv combination therapy |
EP2593105A1 (en) | 2010-07-14 | 2013-05-22 | Vertex Pharmaceuticals Incorporated | Palatable pharmaceutical composition comprising vx-950 |
US20120135949A1 (en) | 2010-09-30 | 2012-05-31 | Boehringer Ingelheim International Gmbh | Combination therapy for treating hcv infection |
KR20130120481A (ko) * | 2010-10-08 | 2013-11-04 | 노파르티스 아게 | 술파미드 ns3 억제제의 비타민 e 제제 |
US10873191B2 (en) | 2010-11-19 | 2020-12-22 | Tseng-Lu Chien | Desk top alarm or time or LED lighting device has USB-port(s) |
US10873190B2 (en) | 2010-11-19 | 2020-12-22 | Tseng-Lu Chien | Desktop or floor LED lighting device has USB-port(s) |
WO2012109646A1 (en) | 2011-02-11 | 2012-08-16 | Vertex Pharmaceuticals Incorporated | Treatment of hcv in hiv infection patients |
US8912141B2 (en) | 2011-06-23 | 2014-12-16 | Panmed Ltd. | Treatment of hepatitis C virus |
DK2583677T1 (da) | 2011-10-21 | 2015-01-19 | Abbvie Inc | Fremgangsmåder til behandling af HCV omfattende mindst to direktevirkende antivirale midler, ribavirin, men ikke inteferon |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
DE202012012954U1 (de) | 2011-10-21 | 2014-08-12 | Abbvie Inc. | Eine Kombination aus mindestens zwei direkt wirkenden antiviralen Wirkstoffen (DAAs) für die Verwendung zur Behandlung von HCV |
EP2780026B1 (en) | 2011-11-15 | 2019-10-23 | Merck Sharp & Dohme Corp. | Hcv ns3 protease inhibitors |
AP2014007760A0 (en) | 2012-01-12 | 2014-07-31 | Boehringer Ingelheim Int | Stabilized pharmaceutical formulations of a potentHCV inhibitor |
US20130195797A1 (en) | 2012-01-31 | 2013-08-01 | Vertex Pharmaceuticals Incorporated | High potency formulations of vx-950 |
WO2013137869A1 (en) | 2012-03-14 | 2013-09-19 | Boehringer Ingelheim International Gmbh | Combination therapy for treating hcv infection in an hcv-hiv coinfected patient population |
WO2013147749A1 (en) | 2012-03-27 | 2013-10-03 | Boehringer Ingelheim International Gmbh | Oral combination therapy for treating hcv infection in specific patient subgenotype populations |
WO2013147750A1 (en) | 2012-03-27 | 2013-10-03 | Boehringer Ingelheim International Gmbh | Oral combination therapy for treating hcv infection in specific patient sub-population |
JP2015512900A (ja) | 2012-03-28 | 2015-04-30 | 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 | 特別な患者の遺伝子亜型分集団のhcv感染症を治療するための併用療法 |
UA119315C2 (uk) | 2012-07-03 | 2019-06-10 | Гіліад Фармассет Елелсі | Інгібітори вірусу гепатиту с |
JP5870001B2 (ja) | 2012-09-28 | 2016-02-24 | 株式会社吉野工業所 | ブロー成形装置及び容器の製造方法 |
WO2014138374A1 (en) | 2013-03-08 | 2014-09-12 | Boehringer Ingelheim International Gmbh | Oral combination therapy for treating hcv infection in specific patient sub-population |
BR112015021768A2 (pt) | 2013-03-15 | 2016-02-02 | Gilead Sciences Inc | inibidores do vírus da hepatite c |
EA201892448A1 (ru) | 2016-04-28 | 2019-06-28 | Эмори Юниверсити | Алкинсодержащие нуклеотидные и нуклеозидные терапевтические композиции и связанные с ними способы применения |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000009543A2 (en) * | 1998-08-10 | 2000-02-24 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
Family Cites Families (90)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US684806A (en) * | 1900-03-08 | 1901-10-22 | Filter & Brautechnische Maschinen Fabrik Akt Ges Vorm L A Enzinger | Pressure-regulator for pumps. |
AR205953A1 (es) * | 1975-01-22 | 1976-06-15 | Diamond Shamrock Corp | Produccion de carbonatos de metales a calinos en una celula de membrana |
DE3481913D1 (de) * | 1983-04-27 | 1990-05-17 | Ici America Inc | Prolin-derivate. |
JPH01103993A (ja) | 1987-10-16 | 1989-04-21 | Sumitomo Electric Ind Ltd | ダイヤモンド単結晶成長方法 |
JPH01135478A (ja) | 1987-11-19 | 1989-05-29 | Brother Ind Ltd | 研削工具 |
US5164402A (en) * | 1989-08-16 | 1992-11-17 | Pfizer Inc | Azabicyclo quinolone and naphthyridinone carboxylic acids |
US5290405A (en) * | 1991-05-24 | 1994-03-01 | Ceramatec, Inc. | NaOH production from ceramic electrolytic cell |
JPH05155827A (ja) | 1991-12-09 | 1993-06-22 | Banyu Pharmaceut Co Ltd | cis−2−アミノシクロプロパンカルボン酸誘導体の製造法 |
KR100347285B1 (ko) | 1994-06-02 | 2003-01-15 | 아벤티스 파마슈티칼스 인크. | 신규의엘라스타제저해제 |
DE4430601A1 (de) * | 1994-08-22 | 1996-02-29 | Beiersdorf Ag | Zelladhäsions-Peptide zur Modifikation des Haftungsverhaltens eukaryontischer Zellen untereinander |
US6159938A (en) * | 1994-11-21 | 2000-12-12 | Cortech, Inc. | Serine protease inhibitors comprising α-keto heterocycles |
DE4444893A1 (de) * | 1994-12-16 | 1996-06-20 | Merck Patent Gmbh | Peptide und synthetische Zellmembranen |
GB9517022D0 (en) | 1995-08-19 | 1995-10-25 | Glaxo Group Ltd | Medicaments |
DE19600034C2 (de) | 1996-01-02 | 2003-12-24 | Degussa | 1,1,2-Trisubstituierte Cyclopropanverbindungen, Verfahren zu deren Herstellung und Dihydroxyethyl-substituierte 1-Amino-cyclopropan-1-carbonsäure |
US5633388A (en) * | 1996-03-29 | 1997-05-27 | Viropharma Incorporated | Compounds, compositions and methods for treatment of hepatitis C |
AU2933797A (en) | 1996-05-10 | 1997-12-05 | Schering Corporation | Synthetic inhibitors of hepatitis c virus ns3 protease |
EA001915B1 (ru) | 1996-10-18 | 2001-10-22 | Вертекс Фармасьютикалз Инкорпорейтед | Ингибиторы серин-протеаз, в частности ns3 протеазы вируса гепатита c (hvc) |
GB9623908D0 (en) * | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
AU7127298A (en) | 1997-04-14 | 1998-11-11 | Emory University | Serine protease inhibitors |
GB9707659D0 (en) | 1997-04-16 | 1997-06-04 | Peptide Therapeutics Ltd | Hepatitis C NS3 Protease inhibitors |
JPH10298151A (ja) | 1997-04-30 | 1998-11-10 | Japan Energy Corp | C型肝炎ウイルスプロテアーゼ阻害剤 |
EP1001764A4 (en) | 1997-05-29 | 2005-08-24 | Merck & Co Inc | Heterocyclic amides as cell adhesion inhibitors |
JPH1135478A (ja) | 1997-07-17 | 1999-02-09 | Soyaku Gijutsu Kenkyusho:Kk | キク科植物の有機抽出物を含有する抗c型肝炎ウイルス剤及びプロテアーゼns3の特異的阻害剤 |
US6767991B1 (en) * | 1997-08-11 | 2004-07-27 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C inhibitor peptides |
JP4452401B2 (ja) | 1997-08-11 | 2010-04-21 | ベーリンガー インゲルハイム (カナダ) リミテッド | C型肝炎ウイルス阻害ペプチドアナログ |
EP1003775B1 (en) | 1997-08-11 | 2005-03-16 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor peptides |
JPH11127861A (ja) | 1997-10-29 | 1999-05-18 | Japan Energy Corp | C型肝炎ウイルス由来のセリンプロテアーゼに対する中和抗体部分ペプチド |
JP3612551B2 (ja) | 1997-11-07 | 2005-01-19 | 独立行政法人産業技術総合研究所 | C型肝炎ウイルスのns3プロテアーゼを阻害するrna分子 |
SE9704543D0 (sv) * | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
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 |
GB9806815D0 (en) | 1998-03-30 | 1998-05-27 | Hoffmann La Roche | Amino acid derivatives |
ES2281170T3 (es) | 1998-03-31 | 2007-09-16 | Vertex Pharmaceuticals Incorporated | Inhibidores de serina proteasas, particularmente proteasa ns3 del virus de la hepatitis c. |
JPH11292840A (ja) | 1998-04-06 | 1999-10-26 | Soyaku Gijutsu Kenkyusho:Kk | ノルスタチン誘導体又はその塩 |
US6455571B1 (en) * | 1998-04-23 | 2002-09-24 | Abbott Laboratories | Inhibitors of neuraminidases |
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 |
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. |
AU1099000A (en) | 1998-10-05 | 2000-04-26 | Axys Pharmaceuticals, Inc. | Novel compounds and compositions for treating hepatitis c infections |
US6277830B1 (en) * | 1998-10-16 | 2001-08-21 | Schering Corporation | 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon |
GB9825946D0 (en) | 1998-11-26 | 1999-01-20 | Angeletti P Ist Richerche Bio | Pharmaceutical compounds for the inhibition of hepatitis C virus NS3 protease |
US6608027B1 (en) * | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
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 |
EP1196436A2 (en) | 1999-07-07 | 2002-04-17 | Bristol-Myers Squibb Pharma Company | Peptide boronic acid inhibitors of hepatitis c virus protease |
AU6371900A (en) | 1999-07-26 | 2001-02-13 | Du Pont Pharmaceuticals Company | Lactam inhibitors of hepatitis c virus ns3 protease |
EP1206568A2 (en) | 1999-08-30 | 2002-05-22 | K.U. Leuven Research & Development | Target for antiparasitic agents and inhibitors thereof |
JP2001103993A (ja) | 1999-10-05 | 2001-04-17 | Japan Energy Corp | 環状ペプチド及びセリンプロテアーゼ阻害剤 |
US6222241B1 (en) * | 1999-10-29 | 2001-04-24 | Advanced Micro Devices, Inc. | Method and system for reducing ARC layer removal by providing a capping layer for the ARC layer |
GB9925955D0 (en) | 1999-11-02 | 1999-12-29 | Angeletti P Ist Richerche Bio | Hcv n33 protease inhibitors |
EP1252178A1 (en) | 1999-12-03 | 2002-10-30 | Bristol-Myers Squibb Pharma Company | Alpha-ketoamide inhibitors of hepatitis c virus ns3 protease |
US6624290B2 (en) | 2000-02-08 | 2003-09-23 | Schering Corporation | Azapeptides useful in the treatment of Hepatitis C |
WO2001064678A2 (en) | 2000-02-29 | 2001-09-07 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
AU2001251165A1 (en) | 2000-04-03 | 2001-10-15 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
EP1268525B1 (en) | 2000-04-05 | 2008-12-31 | Schering Corporation | Macrocyclic ns3-serine protease inhibitors of hepatitis c virus comprising n-cyclic p2 moieties |
AR030558A1 (es) | 2000-04-19 | 2003-08-27 | Schering Corp | COMPUESTOS MACROCICLICOS, QUE INCLUYEN ENANTIOMEROS, ESTEROISOMEROS, ROTAMEROS Y TAUTOMEROS, SALES Y SOLVATOS FARMACEUTICAMENTE ACEPTABLES, COMPOSICIoN FARMACEUTICA, UN METODO PARA SU PREPARACION Y EL USO DE DICHOS COMPUESTOS PARA LA ELABORACION DE UN MEDICAMENTO, INHIBIDORES DE LA SERINA PROTEASA, |
JP4452441B2 (ja) | 2000-07-21 | 2010-04-21 | シェーリング コーポレイション | C型肝炎ウイルスのns3−セリンプロテアーゼ阻害剤としての新規ペプチド |
AR029851A1 (es) | 2000-07-21 | 2003-07-16 | Dendreon Corp | Nuevos peptidos como inhibidores de ns3-serina proteasa del virus de hepatitis c |
EP1301527A2 (en) | 2000-07-21 | 2003-04-16 | Corvas International, Inc. | Peptides as ns3-serine protease inhibitors of hepatitis c virus |
RU2355700C9 (ru) | 2000-07-21 | 2010-03-20 | Шеринг Корпорейшн | Новые пептиды как ингибиторы ns3-серинпротеазы вируса гепатита с |
AR034127A1 (es) | 2000-07-21 | 2004-02-04 | Schering Corp | Imidazolidinonas como inhibidores de ns3-serina proteasa del virus de hepatitis c, composicion farmaceutica, un metodo para su preparacion, y el uso de las mismas para la manufactura de un medicamento |
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 |
EP1337550B1 (en) | 2000-11-20 | 2006-05-24 | Bristol-Myers Squibb Company | Hepatitis c tripeptide inhibitors |
GB0107924D0 (en) | 2001-03-29 | 2001-05-23 | Angeletti P Ist Richerche Bio | Inhibitor of hepatitis C virus NS3 protease |
US6867185B2 (en) | 2001-12-20 | 2005-03-15 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus |
CA2369711A1 (en) | 2002-01-30 | 2003-07-30 | Boehringer Ingelheim (Canada) Ltd. | Macrocyclic peptides active against the hepatitis c virus |
CA2474156C (en) | 2002-02-01 | 2011-09-20 | Boehringer Ingelheim International Gmbh | Tripeptides having a hydroxyproline ether of a substituted quinoline for the inhibition of ns3 (hepatitis c) |
CA2370396A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
CA2369970A1 (en) | 2002-02-01 | 2003-08-01 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
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 |
MY140680A (en) | 2002-05-20 | 2010-01-15 | Bristol Myers Squibb Co | Hepatitis c virus inhibitors |
US6869964B2 (en) * | 2002-05-20 | 2005-03-22 | Bristol-Myers Squibb Company | Heterocyclicsulfonamide hepatitis C virus inhibitors |
US6878722B2 (en) * | 2002-05-20 | 2005-04-12 | Bristol-Myers Squibb Company | Substituted cycloalkyl P1′ hepatitis C virus inhibitors |
AU2003299519A1 (en) * | 2002-05-20 | 2004-05-04 | Bristol-Myers Squibb Company | Hepatitis c virus inhibitors |
US20040033959A1 (en) * | 2002-07-19 | 2004-02-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical compositions for hepatitis C viral protease inhibitors |
ES2354282T3 (es) * | 2003-03-05 | 2011-03-11 | Boehringer Ingelheim International Gmbh | Análogos peptídicos inhibidores de la hepatitis c. |
EP1601685A1 (en) | 2003-03-05 | 2005-12-07 | Boehringer Ingelheim International GmbH | Hepatitis c inhibiting compounds |
AU2004240704B9 (en) * | 2003-05-21 | 2009-10-22 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
KR20060094083A (ko) | 2003-09-22 | 2006-08-28 | 베링거 인겔하임 인터내셔날 게엠베하 | C형 간염 바이러스에 대해 활성인 마크로사이클릭펩타이드 |
US7132504B2 (en) | 2003-11-12 | 2006-11-07 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7918986B2 (en) * | 2003-12-11 | 2011-04-05 | Ceramatec, Inc. | Electrolytic method to make alkali alcoholates using ceramic ion conducting solid membranes |
PT1713823E (pt) * | 2004-01-30 | 2010-02-02 | Medivir Ab | Inibidores da protease ns-3 da serina do hcv |
US7514557B2 (en) * | 2004-05-25 | 2009-04-07 | Boehringer Ingelheim International Gmbh | Process for preparing acyclic HCV protease inhibitors |
RU2004119195A (ru) | 2004-06-24 | 2005-12-10 | Дмитрий Александрович Гертнер (RU) | Способ бесконтактной, гарантированной доставки товаров до конечного потребителя и система для его реализации |
JP4914348B2 (ja) * | 2004-06-28 | 2012-04-11 | 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 | C型肝炎インヒビターペプチド類似体 |
WO2006007708A1 (en) * | 2004-07-20 | 2006-01-26 | Boehringer Engelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
UY29016A1 (es) * | 2004-07-20 | 2006-02-24 | Boehringer Ingelheim Int | Analogos de dipeptidos inhibidores de la hepatitis c |
WO2008124047A1 (en) * | 2007-04-03 | 2008-10-16 | Ceramatec, Inc. | Electrochemical process to recycle aqueous alkali chemicals using ceramic ion conducting solid membranes |
US20090090638A1 (en) * | 2007-10-05 | 2009-04-09 | Kelly Michael T | Processes and reactors for alkali metal production |
US8246863B2 (en) * | 2009-06-26 | 2012-08-21 | Ceramatec, Inc. | Alkali metal super ionic conducting ceramic |
-
2004
- 2004-05-19 AU AU2004240704A patent/AU2004240704B9/en not_active Ceased
- 2004-05-19 ME MEP-2008-583A patent/ME00382B/me unknown
- 2004-05-19 EA EA200501689A patent/EA009295B1/ru not_active IP Right Cessation
- 2004-05-19 AT AT04733750T patent/ATE378334T1/de active
- 2004-05-19 UA UAA200512307A patent/UA83046C2/ru unknown
- 2004-05-19 PT PT04733750T patent/PT1654261E/pt unknown
- 2004-05-19 ES ES04733750T patent/ES2297424T3/es not_active Expired - Lifetime
- 2004-05-19 EP EP04733750A patent/EP1654261B1/en not_active Expired - Lifetime
- 2004-05-19 WO PCT/CA2004/000750 patent/WO2004103996A1/en active IP Right Grant
- 2004-05-19 MY MYPI20041902A patent/MY143076A/en unknown
- 2004-05-19 DE DE602004010137T patent/DE602004010137T2/de not_active Expired - Lifetime
- 2004-05-19 CL CL200401161A patent/CL2004001161A1/es unknown
- 2004-05-19 KR KR1020057022088A patent/KR101115294B1/ko active IP Right Grant
- 2004-05-19 CN CN201310097223XA patent/CN103203010A/zh active Pending
- 2004-05-19 PL PL04733750T patent/PL1654261T3/pl unknown
- 2004-05-19 JP JP2006529495A patent/JP4447603B2/ja not_active Expired - Fee Related
- 2004-05-19 PE PE2004000512A patent/PE20050204A1/es active IP Right Grant
- 2004-05-19 DK DK04733750T patent/DK1654261T3/da active
- 2004-05-19 NZ NZ544076A patent/NZ544076A/en not_active IP Right Cessation
- 2004-05-19 MX MXPA05012545A patent/MXPA05012545A/es active IP Right Grant
- 2004-05-19 UY UY28323A patent/UY28323A1/es not_active Application Discontinuation
- 2004-05-19 BR BRPI0410456A patent/BRPI0410456B8/pt not_active IP Right Cessation
- 2004-05-19 CN CNA2004800137831A patent/CN1791599A/zh active Pending
- 2004-05-19 CA CA2522577A patent/CA2522577C/en not_active Expired - Fee Related
- 2004-05-19 RS YUP-2005/0871A patent/RS51294B/sr unknown
- 2004-05-19 CN CN2013100935669A patent/CN103204903A/zh active Pending
- 2004-05-20 US US10/850,101 patent/US7585845B2/en active Active
- 2004-05-20 TW TW093114272A patent/TWI327145B/zh not_active IP Right Cessation
-
2005
- 2005-10-11 ZA ZA200508201A patent/ZA200508201B/en unknown
- 2005-11-17 IL IL172013A patent/IL172013A/en active IP Right Grant
- 2005-11-18 CO CO05117348A patent/CO5630024A2/es active IP Right Grant
- 2005-11-21 EC EC2005006181A patent/ECSP056181A/es unknown
- 2005-12-19 NO NO20056047A patent/NO332056B1/no not_active IP Right Cessation
-
2007
- 2007-06-21 US US11/766,171 patent/US7939667B2/en active Active
-
2008
- 2008-01-11 HR HR20080014T patent/HRP20080014T3/xx unknown
- 2008-02-14 CY CY20081100184T patent/CY1107200T1/el unknown
-
2009
- 2009-11-24 JP JP2009266291A patent/JP2010043129A/ja not_active Withdrawn
-
2011
- 2011-04-01 US US13/078,225 patent/US8067438B2/en not_active Expired - Lifetime
- 2011-10-21 US US13/278,532 patent/US20120034187A1/en not_active Abandoned
-
2012
- 2012-07-03 US US13/540,859 patent/US20120269769A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000009543A2 (en) * | 1998-08-10 | 2000-02-24 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor tri-peptides |
Cited By (201)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8314141B2 (en) | 1996-10-18 | 2012-11-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis C virus NS3 protease |
US7449479B2 (en) | 2002-05-20 | 2008-11-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7915291B2 (en) | 2002-05-20 | 2011-03-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8299094B2 (en) | 2002-05-20 | 2012-10-30 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9636375B2 (en) | 2002-05-20 | 2017-05-02 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9227940B2 (en) | 2002-05-20 | 2016-01-05 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8889871B2 (en) | 2002-05-20 | 2014-11-18 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8710229B2 (en) | 2002-05-20 | 2014-04-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8507722B2 (en) | 2002-05-20 | 2013-08-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7368452B2 (en) | 2003-04-18 | 2008-05-06 | Enanta Pharmaceuticals, Inc. | Quinoxalinyl macrocyclic hepatitis C serine protease inhibitors |
US8067438B2 (en) | 2003-05-21 | 2011-11-29 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
US7939667B2 (en) | 2003-05-21 | 2011-05-10 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor compounds |
EP2361925A1 (en) * | 2003-10-10 | 2011-08-31 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US8039623B2 (en) | 2003-10-10 | 2011-10-18 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly HCV NS3-NS4A protease |
US7608590B2 (en) | 2004-01-30 | 2009-10-27 | Medivir Ab | HCV NS-3 serine protease inhibitors |
US10172846B2 (en) | 2004-01-30 | 2019-01-08 | Medivir Ab | HCV NS-3 serine protease inhibitors |
US7671032B2 (en) | 2004-01-30 | 2010-03-02 | Medivir Ab | HCV NS-3 serine protease inhibitors |
EP2626354A1 (en) | 2004-02-20 | 2013-08-14 | Boehringer Ingelheim International GmbH | Viral polymerase inhibitors |
WO2005080388A1 (en) | 2004-02-20 | 2005-09-01 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2005116054A1 (en) * | 2004-05-25 | 2005-12-08 | Boehringer Ingelheim International, Gmbh | Process for preparing acyclic hcv protease inhibitors |
US7514557B2 (en) | 2004-05-25 | 2009-04-07 | Boehringer Ingelheim International Gmbh | Process for preparing acyclic HCV protease inhibitors |
US8101765B2 (en) | 2004-05-25 | 2012-01-24 | Boehringer Ingelheim International Gmbh | Process for preparing acyclic HCV protease inhibitors |
US8017771B2 (en) | 2004-05-25 | 2011-09-13 | Boehringer Ingelheim International Gmbh | Process for preparing acyclic HCV protease inhibitors |
EP1763531A1 (en) * | 2004-06-28 | 2007-03-21 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor peptide analogs |
JP4914348B2 (ja) * | 2004-06-28 | 2012-04-11 | 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 | C型肝炎インヒビターペプチド類似体 |
JP2008504240A (ja) * | 2004-06-28 | 2008-02-14 | 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 | C型肝炎インヒビターペプチド類似体 |
US7705146B2 (en) | 2004-06-28 | 2010-04-27 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor peptide analogs |
EP1763531A4 (en) * | 2004-06-28 | 2009-07-01 | Boehringer Ingelheim Int | ANALOGUE OF HEPATITIS-C INHIBITING PEPTIDES |
US7767818B2 (en) | 2004-07-20 | 2010-08-03 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor dipeptide analogs |
US7696242B2 (en) | 2004-07-20 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Hepatitis C inhibitor peptide analogs |
WO2006007700A1 (en) * | 2004-07-20 | 2006-01-26 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor dipeptide analogs |
US7323447B2 (en) | 2005-02-08 | 2008-01-29 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7879797B2 (en) | 2005-05-02 | 2011-02-01 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US7592336B2 (en) | 2005-05-10 | 2009-09-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2007005838A2 (en) | 2005-06-30 | 2007-01-11 | Virobay, Inc. | Hcv inhibitors |
US8518874B2 (en) | 2005-06-30 | 2013-08-27 | Virobay, Inc. | HCV inhibitors |
TWI449711B (zh) * | 2005-06-30 | 2014-08-21 | Virobay Inc | C型肝炎病毒(hcv)抑制劑 |
JP2009500353A (ja) * | 2005-06-30 | 2009-01-08 | ビロベイ,インコーポレイティド | Hcvインヒビター |
EP1906945B1 (en) * | 2005-06-30 | 2015-08-05 | Virobay, Inc. | Hcv inhibitors |
JP2012176973A (ja) * | 2005-06-30 | 2012-09-13 | Virobay Inc | Hcvインヒビター |
US7601686B2 (en) | 2005-07-11 | 2009-10-13 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
WO2007009109A3 (en) * | 2005-07-14 | 2007-06-07 | Gilead Sciences Inc | Antiviral compounds |
KR101345008B1 (ko) | 2005-07-14 | 2013-12-31 | 길리애드 사이언시즈, 인코포레이티드 | 항바이러스 화합물 |
US8216999B2 (en) | 2005-07-20 | 2012-07-10 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US9856265B2 (en) | 2005-07-29 | 2018-01-02 | Janssen Sciences Ireland Uc | Macrocyclic inhibitors of hepatitis C virus |
US8148399B2 (en) | 2005-07-29 | 2012-04-03 | Tibotec Pharmaceuticals Ltd. | Macrocyclic inhibitors of hepatitis C virus |
US8153800B2 (en) | 2005-07-29 | 2012-04-10 | Tibotec Pharmaceuticals Ltd. | Macrocyclic inhibitors of hepatitis C virus |
US9040562B2 (en) | 2005-07-29 | 2015-05-26 | Janssen R&D Ireland | Macrocyclic inhibitors of hepatitis C virus |
US9623022B2 (en) | 2005-07-29 | 2017-04-18 | Janssen Sciences Ireland Uc | Macrocyclic inhibitors of hepatitis C virus |
US8741926B2 (en) | 2005-07-29 | 2014-06-03 | Janssen R&D Ireland | Macrocyclic inhibitors of hepatitis C virus |
US8754106B2 (en) | 2005-07-29 | 2014-06-17 | Janssen R&D Ireland | Macrocyclic inhibitors of hepatitis C virus |
US9353103B2 (en) | 2005-07-29 | 2016-05-31 | Janssen Sciences Ireland Uc | Macrocyclic inhibitors of hepatitis C virus |
US8349869B2 (en) | 2005-07-29 | 2013-01-08 | Tibotec Pharmaceuticals Ltd. | Macrocylic inhibitors of hepatitis C virus |
US8278322B2 (en) | 2005-08-01 | 2012-10-02 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
WO2007019674A1 (en) | 2005-08-12 | 2007-02-22 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
EP2364984A1 (en) | 2005-08-26 | 2011-09-14 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
EP2366704A1 (en) | 2005-08-26 | 2011-09-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
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 |
US7816348B2 (en) | 2006-02-03 | 2010-10-19 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US8178520B2 (en) | 2006-05-15 | 2012-05-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Macrocyclic compounds as antiviral agents |
US8314062B2 (en) | 2006-06-23 | 2012-11-20 | Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | Macrocyclic compounds as antiviral agents |
US7935670B2 (en) | 2006-07-11 | 2011-05-03 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9610317B2 (en) | 2006-07-13 | 2017-04-04 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
US9233136B2 (en) | 2006-07-13 | 2016-01-12 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
US7906619B2 (en) | 2006-07-13 | 2011-03-15 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
US8785378B2 (en) | 2006-07-13 | 2014-07-22 | Achillion Pharmaceuticals, Inc. | Macrocyclic peptides as inhibitors of viral replication |
EP2399575A2 (en) | 2006-08-11 | 2011-12-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods, uses and compositions for treatment of an infection by a virus of the family of flaviviridae through the farnesoid X receptor (FXR) inhibition |
EP2399988A2 (en) | 2006-08-11 | 2011-12-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Cell culture system for replication of HCV through the farnesoid X receptor (FXR) activation or inhibition and diagnostic method for HCV infection |
US7897622B2 (en) | 2006-08-17 | 2011-03-01 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US8377873B2 (en) | 2006-10-24 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8309540B2 (en) | 2006-10-24 | 2012-11-13 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8138164B2 (en) | 2006-10-24 | 2012-03-20 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
EP2079480A4 (en) * | 2006-10-24 | 2011-06-15 | Merck Sharp & Dohme | INHIBITORS OF HCV NS3 PROTEASE |
EP2079480A2 (en) * | 2006-10-24 | 2009-07-22 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
US9738661B2 (en) | 2006-10-27 | 2017-08-22 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US8377874B2 (en) | 2006-10-27 | 2013-02-19 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
RU2468029C2 (ru) * | 2006-10-27 | 2012-11-27 | Иституто Ди Ричерке Ди Биолоджиа Молеколаре П.Анджелетти С.П.А. | Ингибиторы hcv ns3 протеазы |
KR101615500B1 (ko) | 2006-10-27 | 2016-04-27 | 머크 샤프 앤드 돔 코포레이션 | Hcv ns3 프로테아제 억제제 |
KR20090075874A (ko) * | 2006-10-27 | 2009-07-09 | 머크 앤드 캄파니 인코포레이티드 | Hcv ns3 프로테아제 억제제 |
WO2008057209A1 (en) * | 2006-10-27 | 2008-05-15 | Merck & Co., Inc. | Hcv ns3 protease inhibitors |
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 |
WO2008070358A3 (en) * | 2006-11-16 | 2008-11-06 | Phenomix Corp | N-cyclopropyl-hydroxyproline-based tripeptidic hepatitis c serine protease inhibitors containing an isoindole, pyrrolopyridine, pyrrolopyrimidine or pyrrolopyrazine heterocycle in the side chain |
WO2008070358A2 (en) * | 2006-11-16 | 2008-06-12 | Phenomix Corporation | N-cyclopropyl-hydroxyproline-based tripeptidic hepatitis c serine protease inhibitors containing an isoindole, pyrrolopyridine, pyrrolopyrimidine or pyrrolopyrazine heterocycle in the side chain |
US8003604B2 (en) | 2006-11-16 | 2011-08-23 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7763584B2 (en) | 2006-11-16 | 2010-07-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7888464B2 (en) | 2006-11-16 | 2011-02-15 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7767660B2 (en) | 2006-12-20 | 2010-08-03 | Istituto Di Richerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US7781422B2 (en) | 2006-12-20 | 2010-08-24 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Antiviral indoles |
US8101595B2 (en) | 2006-12-20 | 2012-01-24 | Istituto di Ricerche di Biologia Molecolare P. Angletti SpA | Antiviral indoles |
US8435984B2 (en) | 2007-02-26 | 2013-05-07 | Achillion Pharmaceuticals, Inc. | Tertiary amine substituted peptides useful as inhibitors of HCV replication |
EP2631238A1 (en) | 2007-02-27 | 2013-08-28 | Vertex Pharmaceuticals Incorporated | Spirocyclic inhibitors of serine proteases for the treatment of hcv infections |
US8178491B2 (en) | 2007-06-29 | 2012-05-15 | Gilead Sciences, Inc. | Antiviral compounds |
US8513186B2 (en) | 2007-06-29 | 2013-08-20 | Gilead Sciences, Inc. | Antiviral compounds |
US8809266B2 (en) | 2007-06-29 | 2014-08-19 | Gilead Sciences, Inc. | Antiviral compounds |
US8809267B2 (en) | 2007-06-29 | 2014-08-19 | Gilead Sciences, Inc. | Antiviral compounds |
US7989438B2 (en) | 2007-07-17 | 2011-08-02 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Therapeutic compounds |
US8927569B2 (en) | 2007-07-19 | 2015-01-06 | Merck Sharp & Dohme Corp. | Macrocyclic compounds as antiviral agents |
US7718612B2 (en) * | 2007-08-02 | 2010-05-18 | Enanta Pharmaceuticals, Inc. | Pyridazinonyl macrocyclic hepatitis C serine protease inhibitors |
US8242140B2 (en) | 2007-08-03 | 2012-08-14 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US8163693B2 (en) | 2007-09-24 | 2012-04-24 | Achillion Pharmaceuticals, Inc. | Urea-containing peptides as inhibitors of viral replication |
WO2009076173A2 (en) | 2007-12-05 | 2009-06-18 | Enanta Pharmaceuticals, Inc. | Fluorinated tripeptide hcv serine protease inhibitors |
US8476257B2 (en) | 2007-12-19 | 2013-07-02 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US8541402B2 (en) | 2007-12-19 | 2013-09-24 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2009076747A1 (en) | 2007-12-19 | 2009-06-25 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US8912182B2 (en) | 2007-12-19 | 2014-12-16 | 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 |
US8778877B2 (en) | 2007-12-21 | 2014-07-15 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
US9676785B2 (en) | 2007-12-21 | 2017-06-13 | Celgene Car Llc | HCV protease inhibitors and uses thereof |
US8338606B2 (en) | 2007-12-21 | 2012-12-25 | 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 |
US9163061B2 (en) | 2007-12-21 | 2015-10-20 | Celgene Avilomics Research, Inc. | HCV protease inhibitors and uses thereof |
US9694086B2 (en) | 2007-12-21 | 2017-07-04 | Celgene Car Llc | HCV protease inhibitors and uses thereof |
US8591878B2 (en) | 2008-02-25 | 2013-11-26 | Merck Sharp & Dohme Corp. | Therapeutic compounds |
US8163921B2 (en) | 2008-04-16 | 2012-04-24 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8461107B2 (en) | 2008-04-28 | 2013-06-11 | Merck Sharp & Dohme Corp. | HCV NS3 protease inhibitors |
US7964560B2 (en) | 2008-05-29 | 2011-06-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8044023B2 (en) | 2008-05-29 | 2011-10-25 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8080654B2 (en) | 2008-07-22 | 2011-12-20 | Insituto di Ricerche di Biologia Molecolare P. Angeletti SpA | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
US7973040B2 (en) | 2008-07-22 | 2011-07-05 | Merck Sharp & Dohme Corp. | Macrocyclic quinoxaline compounds as HCV NS3 protease inhibitors |
US8357806B2 (en) | 2008-09-04 | 2013-01-22 | Bristol-Myers Squibb Company | Process for synthesizing substituted isoquinolines |
US8877929B2 (en) | 2008-09-04 | 2014-11-04 | Bristol-Myers Squibb Company | Process for synthesizing substituted isoquinolines |
US8207341B2 (en) | 2008-09-04 | 2012-06-26 | Bristol-Myers Squibb Company | Process or synthesizing substituted isoquinolines |
US9309279B2 (en) | 2008-09-11 | 2016-04-12 | Abbvie Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US8642538B2 (en) | 2008-09-11 | 2014-02-04 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US8420596B2 (en) | 2008-09-11 | 2013-04-16 | Abbott Laboratories | Macrocyclic hepatitis C serine protease inhibitors |
EA018603B1 (ru) * | 2008-09-16 | 2013-09-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Кристаллические формы 2-тиазолил-4-хинолинилоксипроизводного, активного ингибитора hcv |
US8232293B2 (en) | 2008-09-16 | 2012-07-31 | Boehringer Ingelheim International Gmbh | Crystalline forms of a potent HCV inhibitor |
KR20110059841A (ko) * | 2008-09-16 | 2011-06-07 | 베링거 인겔하임 인터내셔날 게엠베하 | 강력한 hcv 억제제인 2-티아졸릴-4-퀴놀리닐-옥시 유도체의 결정 형태 |
WO2010033444A1 (en) * | 2008-09-16 | 2010-03-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of a 2-thiazolyl- 4-quinolinyl-oxy derivative, a potent hcv inhibitor |
TWI471323B (zh) * | 2008-09-16 | 2015-02-01 | Boehringer Ingelheim Int | 有效hcv抑制劑之結晶型式 |
KR101653550B1 (ko) * | 2008-09-16 | 2016-09-02 | 베링거 인겔하임 인터내셔날 게엠베하 | 강력한 hcv 억제제인 2-티아졸릴-4-퀴놀리닐-옥시 유도체의 결정 형태 |
AU2009293494B2 (en) * | 2008-09-16 | 2014-04-24 | Boehringer Ingelheim International Gmbh | Crystalline forms of a 2-thiazolyl- 4-quinolinyl-oxy derivative, a potent HCV inhibitor |
EP2687526A1 (en) * | 2008-09-16 | 2014-01-22 | Boehringer Ingelheim International Gmbh | Crystalline forms of a 2-thiazolyl- 4-quinolinyl-oxy derivative, a potent HCV inhibitor |
US8362035B2 (en) | 2008-09-16 | 2013-01-29 | Boehringer Ingelheim International Gmbh | Crystalline forms of a potent HCV inhibitor |
CN102159571A (zh) * | 2008-09-16 | 2011-08-17 | 贝林格尔.英格海姆国际有限公司 | 强效hcv抑制剂2-噻唑基-4-喹啉基-氧基衍生物的结晶形式 |
CN102159571B (zh) * | 2008-09-16 | 2014-10-01 | 贝林格尔.英格海姆国际有限公司 | 强效hcv抑制剂2-噻唑基-4-喹啉基-氧基衍生物的结晶形式 |
AU2009293493B2 (en) * | 2008-09-17 | 2014-09-18 | Boehringer Ingelheim International Gmbh | Combination of HCV NS3 protease inhibitor with interferon and ribavirin |
US8399484B2 (en) | 2008-09-17 | 2013-03-19 | Boehringer Ingelheim International Gmbh | Combination therapy for treating HCV infection |
WO2010033443A1 (en) * | 2008-09-17 | 2010-03-25 | Boehringer Ingelheim International Gmbh | Combination of hcv ns3 protease inhibitor with interferon and ribavirin |
EA019965B1 (ru) * | 2008-09-17 | 2014-07-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Комбинация ингибитора протеазы ns3 hcv с интерфероном и рибавирином |
CN102159245B (zh) * | 2008-09-17 | 2013-07-24 | 贝林格尔.英格海姆国际有限公司 | Hcv ns3蛋白酶抑制剂与干扰素和利巴韦林的组合 |
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 |
WO2010059667A1 (en) * | 2008-11-21 | 2010-05-27 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition of a potent hcv inhibitor for oral administration |
EA022272B1 (ru) * | 2008-11-21 | 2015-12-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Фармацевтическая композиция эффективного ингибитора всг для перорального введения |
CN102223875A (zh) * | 2008-11-21 | 2011-10-19 | 贝林格尔.英格海姆国际有限公司 | 口服给药的强效hcv抑制剂的药物组合物 |
AU2009316755B2 (en) * | 2008-11-21 | 2015-10-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition of a potent HCV inhibitor for oral administration |
US8614180B2 (en) | 2008-12-10 | 2013-12-24 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
US9133115B2 (en) | 2008-12-10 | 2015-09-15 | Achillion Pharmaceuticals, Inc. | 4-amino-4-oxobutanoyl peptides as inhibitors of viral replication |
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 |
US8993595B2 (en) | 2009-04-08 | 2015-03-31 | Idenix Pharmaceuticals, Inc. | Macrocyclic serine protease inhibitors |
WO2010132163A1 (en) | 2009-05-13 | 2010-11-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic compounds as hepatitis c virus inhibitors |
KR20120059481A (ko) * | 2009-07-07 | 2012-06-08 | 베링거 인겔하임 인터내셔날 게엠베하 | C형 간염 바이러스 프로테아제 억제제를 위한 약제학적 조성물 |
US9034831B2 (en) | 2009-07-07 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition for a hepatitis C viral protease inhibitor |
KR101685941B1 (ko) | 2009-07-07 | 2016-12-13 | 베링거 인겔하임 인터내셔날 게엠베하 | C형 간염 바이러스 프로테아제 억제제를 위한 약제학적 조성물 |
US8828930B2 (en) | 2009-07-30 | 2014-09-09 | Merck Sharp & Dohme Corp. | Hepatitis C virus NS3 protease inhibitors |
US9284307B2 (en) | 2009-08-05 | 2016-03-15 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors |
US8324417B2 (en) | 2009-08-19 | 2012-12-04 | Virobay, Inc. | Process for the preparation of (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid and alkyl esters and acid salts thereof |
US8822496B2 (en) | 2009-10-30 | 2014-09-02 | Boehringer Ingelheim International Gmbh | Dosage regimens for HCV combination therapy |
AU2010333656B2 (en) * | 2009-12-18 | 2015-08-27 | Boehringer Ingelheim International Gmbh | HCV combination therapy |
EP2512477A4 (en) * | 2009-12-18 | 2013-07-10 | Boehringer Ingelheim Int | HCV POLYTHERAPY |
EP2512477A1 (en) * | 2009-12-18 | 2012-10-24 | Boehringer Ingelheim International GmbH | Hcv combination therapy |
CN102844315B (zh) * | 2010-03-11 | 2015-05-20 | 贝林格尔.英格海姆国际有限公司 | 强效hcv抑制剂的结晶盐 |
CN102844315A (zh) * | 2010-03-11 | 2012-12-26 | 贝林格尔.英格海姆国际有限公司 | 强效hcv抑制剂的结晶盐 |
US9382240B2 (en) | 2010-03-11 | 2016-07-05 | Boehringer Ingelheim International Gmbh | Crystalline salts of a potent HCV inhibitor |
US20120059033A1 (en) * | 2010-03-11 | 2012-03-08 | Boehringer Ingelheim International Gmbh | Crystalline Salts of a Potent HCV Inhibitor |
US8530497B2 (en) | 2010-03-11 | 2013-09-10 | Boehringer Ingelheim International Gmbh | Crystalline salts of a potent HCV inhibitor |
EP3020723A1 (en) | 2010-09-21 | 2016-05-18 | Enanta Pharmaceuticals, Inc. | Macrocyclic proline derived hcv serine protease inhibitors |
US8951964B2 (en) | 2010-12-30 | 2015-02-10 | Abbvie Inc. | Phenanthridine macrocyclic hepatitis C serine protease inhibitors |
US8937041B2 (en) | 2010-12-30 | 2015-01-20 | Abbvie, Inc. | Macrocyclic hepatitis C serine protease inhibitors |
US9353100B2 (en) | 2011-02-10 | 2016-05-31 | Idenix Pharmaceuticals Llc | Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections |
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 |
US9527885B2 (en) | 2011-05-05 | 2016-12-27 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US8957203B2 (en) | 2011-05-05 | 2015-02-17 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US10201541B1 (en) | 2011-05-17 | 2019-02-12 | Abbvie Inc. | Compositions and methods for treating HCV |
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 |
US9499550B2 (en) | 2012-10-19 | 2016-11-22 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9598433B2 (en) | 2012-11-02 | 2017-03-21 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9643999B2 (en) | 2012-11-02 | 2017-05-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9334279B2 (en) | 2012-11-02 | 2016-05-10 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9409943B2 (en) | 2012-11-05 | 2016-08-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
KR101712758B1 (ko) | 2012-12-21 | 2017-03-06 | 길리애드 사이언시즈, 인코포레이티드 | 아폽토시스 신호-조절 키나제 억제제로서의 치환된 피리딘-2-카르복스아미드 화합물 |
KR20150095903A (ko) * | 2012-12-21 | 2015-08-21 | 길리애드 사이언시즈, 인코포레이티드 | 아폽토시스 신호-조절 키나제 억제제로서의 치환된 피리딘-2-카르복스아미드 화합물 |
US9580463B2 (en) | 2013-03-07 | 2017-02-28 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US9115175B2 (en) | 2013-03-14 | 2015-08-25 | Achillion Pharmaceuticals, Inc. | Processes for Producing sovaprevir |
US9481708B2 (en) | 2013-03-14 | 2016-11-01 | Achillion Pharmaceuticals, Inc. | Process for producing Sovaprevir |
US9732076B2 (en) | 2013-03-15 | 2017-08-15 | Boehringer Ingelheim International Gmbh | Solid oral dosage formulation of HCV inhibitor in the amorphous state |
US9540346B2 (en) | 2013-03-15 | 2017-01-10 | Achillion Pharmaceuticals, Inc. | Sovaprevir polymorphs and methods of manufacture thereof |
US9227952B2 (en) | 2013-03-15 | 2016-01-05 | Achillion Pharmaceuticals, Inc. | Sovaprevir polymorphs and methods of manufacture thereof |
US9085607B2 (en) | 2013-03-15 | 2015-07-21 | Achillion Pharmaceuticals, Inc. | ACH-0142684 sodium salt polymorph, composition including the same, and method of manufacture thereof |
US9006423B2 (en) | 2013-03-15 | 2015-04-14 | Achillion Pharmaceuticals Inc. | Process for making a 4-amino-4-oxobutanoyl peptide cyclic analogue, an inhibitor of viral replication, and intermediates thereof |
US9744170B2 (en) | 2014-01-03 | 2017-08-29 | Abbvie Inc. | Solid antiviral dosage forms |
US10105365B2 (en) | 2014-01-03 | 2018-10-23 | Abbvie Inc. | Solid antiviral dosage forms |
US9333204B2 (en) | 2014-01-03 | 2016-05-10 | Abbvie Inc. | Solid antiviral dosage forms |
WO2015192077A1 (en) * | 2014-06-12 | 2015-12-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Heterocyclic compounds and methods of use thereof |
US10202367B2 (en) | 2014-06-12 | 2019-02-12 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Heterocyclic compounds and methods of use thereof |
CN108610301A (zh) * | 2016-12-12 | 2018-10-02 | 中山大学 | 一类手性芳杂胺类衍生物及其合成方法和应用 |
CN108610301B (zh) * | 2016-12-12 | 2021-08-31 | 中山大学 | 一类手性芳杂胺类衍生物及其合成方法和应用 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1654261B1 (en) | Hepatitis c inhibitor compounds | |
EP1474423B1 (en) | Heterocyclic tripeptides as hepatitis c inhibitors | |
US7091184B2 (en) | Hepatitis C inhibitor tri-peptides | |
US7642235B2 (en) | Macrocyclic peptides active against the hepatitis C virus | |
EP1474441B1 (en) | Tripeptides having a hydroxyproline ether of a substituted quinoline for the inhibition of ns3 (hepatitis c) | |
US6642204B2 (en) | Hepatitis C inhibitor tri-peptides | |
US7119072B2 (en) | Macrocyclic peptides active against the hepatitis C virus | |
AU2003202348A1 (en) | Heterocyclic tripeptides as hepatitis c inhibitors | |
WO2004101605A1 (en) | Hepatitis c inhibiting compounds | |
CA2474031C (en) | Heterocyclic tripeptides as hepatitis c inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 1200501881 Country of ref document: VN Ref document number: P-2005/0871 Country of ref document: YU |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DPEN | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2004733750 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005/08201 Country of ref document: ZA Ref document number: 200508201 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2522577 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 172013 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006529495 Country of ref document: JP Ref document number: 1020057022088 Country of ref document: KR Ref document number: 12005502087 Country of ref document: PH Ref document number: 05117348 Country of ref document: CO |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2005/012545 Country of ref document: MX Ref document number: 20048137831 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200501689 Country of ref document: EA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004240704 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 544076 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 02624/KOLNP/2005 Country of ref document: IN Ref document number: 2624/KOLNP/2005 Country of ref document: IN |
|
WWP | Wipo information: published in national office |
Ref document number: 2004240704 Country of ref document: AU |
|
WWP | Wipo information: published in national office |
Ref document number: 1020057022088 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2004733750 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0410456 Country of ref document: BR |
|
WWG | Wipo information: grant in national office |
Ref document number: 2004733750 Country of ref document: EP |