WO2009137500A1 - Composés de benzofurane substitués en 6 pour traiter l’infection par le virus de l’hépatite c - Google Patents

Composés de benzofurane substitués en 6 pour traiter l’infection par le virus de l’hépatite c Download PDF

Info

Publication number
WO2009137500A1
WO2009137500A1 PCT/US2009/042870 US2009042870W WO2009137500A1 WO 2009137500 A1 WO2009137500 A1 WO 2009137500A1 US 2009042870 W US2009042870 W US 2009042870W WO 2009137500 A1 WO2009137500 A1 WO 2009137500A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
group
alkoxy
amino
Prior art date
Application number
PCT/US2009/042870
Other languages
English (en)
Inventor
Jonathan D. Bloom
Tarek Mansour
Jeremy Levin
Christoph Zapf
Original Assignee
Wyeth
Viropharma Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wyeth, Viropharma Incorporated filed Critical Wyeth
Publication of WO2009137500A1 publication Critical patent/WO2009137500A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to a series of benzofuran compounds which are effective pharmaceuticals for the treatment and prophylaxis of viral infections and diseases associated with viral infections, especially hepatitis C virus infection, as well as to pharmaceutical compositions containing them and their use in therapy.
  • Hepatitis C is a common viral infection that can lead to chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma. Infection with hepatitis C virus (HCV) leads to chronic hepatitis in at least 85% of cases, is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States. Hepatology, 26(Suppl. l):2S-10S (1997). [0003] There is no effective vaccine to prevent HCV infection. The only therapies currently available are treatment with interferon- ⁇ (INF- ⁇ ) or combination treatment with INF- ⁇ and the nucleoside analog ribavirin. Antiviral Chemistry & Chemotherapy, 8:281-301 (1997).
  • INF- ⁇ interferon- ⁇
  • ribavirin Antiviral Chemistry & Chemotherapy, 8:281-301 (1997).
  • HCV is a member of the Flaviviridae family, and its genome is a single- stranded linear RNA of positive sense. Hepatology, 26(Suppl. 1):11S-14S (1997). HCV displays extensive genetic heterogeneity, with at least six genotypes and more than 50 subtypes identified to date. [0005] Following infection with HCV, the viral RNA is translated into a polyprotein. This approximately 3,000 residue polyprotein is subsequently cleaved into individual proteins. The HCV genome encodes both structural proteins, which are required for virus assembly, and non- structural proteins, which are required for virus replication. These non-structural proteins include: NS2, NS3, NS4A, NS4B, NS5A, and NS5B. J. Gen. Virol, 81:1631-1648 (2000).
  • RNA In positive-stranded RNA viruses, such as HCV, RNA is the sole genetic material. Because mammalian host cells ordinarily lack RNA-dependent RNA polymerase activity, the positive-stranded RNA viruses must encode their own replicative polymerase. These polymerases are necessary for viral replication and, thus, are essential for the production of virion progeny. In the case of HCV, this polymerase is NS5B. The inhibition of NS5B activity is, therefore, an attractive target for the development of new anti-HCV therapeutic agents.
  • R 1 is selected from the group consisting of hydrogen, alkyl, halogen, and cyano
  • R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, cycloalkyl, cycloalkyloxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amino, monoalkylamino, dialkylamino, cyano, thiazolyl-CH 2 -O-, optionally substituted benzyloxy, and optionally substituted heterocyclyl;
  • R 5 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl;
  • Re is optionally substituted aryl
  • R 12 is independently selected from the groups consisting of hydrogen, alkyl and aryloxy
  • Ri 3 is (Ci-C 4 )alkyl
  • Ri 6 is hydrogen, (Ci-C 4 )alkyl, or (Ci-C 4 )alkoxy; G is optionally substituted aryl or optionally substituted heteroaryl; R w is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, each of which may be optionally substituted;
  • Rz is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, each of which may be optionally substituted; wherein substituents for the groups of R w and R z are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, hydroxy, halogen, aryl, heteroaryl, formyl, acyl, alkylthio, arylthio, amidino, carboxamido, sulfonamido, N-alkyl sulfonamido, N,N-dialkyl sulfonamide, N-sulfonylamido, N-alkyl-N- sulfonylamido, guanidino, heteroarylthio, alkylsulfinyl, arylsulfinyl, azido,
  • R 5 is methyl
  • Re is a substituted phenyl.
  • the phenyl ring is substituted with a halogen, an alkylsulfinyl, or an alkylthio.
  • the halogen is fluorine
  • the alkylsulfinyl is methanesulfinyl
  • the alkylthio is methylsulfanyl.
  • Re is 4-fluorophenyl.
  • R 1 and R 4 are hydrogen.
  • R 3 is -NR 1O SO 2 R 11 .
  • R 1O is a substituted alkyl and R 11 is methyl.
  • R 3 is -
  • R w is hydrogen or an alkyl and R z is methyl.
  • R 10 is not hydrogen
  • R 3 is a heterocyclic group that is substituted at a position that is adjacent to the position of attachment to the benzofuran ring.
  • R 3 is a substituted oxazolyl, pyridyl, or pyrimidyl group.
  • R 2 is alkoxy or cycloalkyl.
  • R 2 is methoxy or cyclopropyl.
  • R 5 is methyl
  • Re is 4-fluorophenyl, R 2 is methoxy and R 3 is 3-hydroxymethyl-5-methyloxazol-
  • R 5 is methyl
  • Re is 4-fluorophenyl
  • R 2 is methoxy
  • R 3 is 4-hydroxymethyloxazol-5-yl.
  • R 5 is methyl
  • Preferred compounds of the present invention include:
  • the invention is further directed to pharmaceutical compositions containing the compounds of formula (I) and the corresponding methods of use for treating and preventing viral infections, especially HCV infection, as well as diseases associated with viral infections.
  • This invention relates to a series of benzofuran derivatives, pharmaceutical compositions containing them, and their use in therapy.
  • the inventive compounds are believed to be useful in the treatment of hepatitis C by virtue of their ability to inhibit hepatitis C polymerase (NS5B).
  • a first embodiment of the invention is directed to compounds of formula (I):
  • R 1 is selected from the group consisting of hydrogen, alkyl, halogen, and cyano
  • R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, cycloalkyl, cycloalkyloxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amino, monoalkylamino, dialkylamino, cyano, thiazolyl-CH 2 -O-, optionally substituted benzyloxy, and optionally substituted heterocyclyl;
  • R 4 is selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy;
  • R 5 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl;
  • Re is optionally substituted aryl
  • R 12 is independently selected from the groups consisting of hydrogen, alkyl and aryloxy
  • Ri 3 is (Ci-C 4 )alkyl
  • Ri 6 is hydrogen, (Ci-C 4 )alkyl, or (Ci-C 4 )alkoxy;
  • G is optionally substituted aryl or optionally substituted heteroaryl
  • R w is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, each of which may be optionally substituted;
  • Rz is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl, each of which may be optionally substituted; wherein substituents for the groups of Rw and Rz are selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, hydroxy, halogen, aryl, heteroaryl, formyl, acyl, alkylthio, arylthio, amidino, carboxamido, sulfonamido, N-alkyl sulfonamido, N,N-dialkyl sulfonamide, N-sulfonylamido, N-alkyl-N- sulfonylamido, guanidino, heteroarylthio, alkylsulfinyl, arylsulfinyl, azido, acy
  • Alkyl refers to straight or branched chain aliphatic hydrocarbon radicals of up to 12 carbon atoms, preferably up to 10 carbon atoms and more preferably 1 to 6 carbon atoms.
  • alkenyl refers to straight or branched chain aliphatic hydrocarbon radicals of 2 to 10 carbon atoms containing at least one double bond. Such alkenyl moieties may exist in the E or Z configurations; the compounds of this invention include both configurations.
  • Alkynyl refers to straight or branched chain aliphatic hydrocarbon radicals containing 2 to 10 carbon atoms having at least one triple bond.
  • Cyclo alkenyl refers to cyclic chain aliphatic hydrocarbon radicals of 2 to 10 carbon atoms containing at least one double bond.
  • alkenyl moieties may exist in the E or Z configurations; the compounds of this invention include both configurations.
  • Aryl when used as such, or in combination form (for example “aralkyl”), refers to an aromatic carbocyclic group, preferably having 6 to 10 carbon atoms and at least one aromatic ring, which may be mono-, bi- or tricyclic.
  • Aryl groups may be selected from, but not limited to, phenyl, ⁇ -naphthyl, ⁇ -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and phenanthrenyl.
  • Heteroaryl refers to (1) an aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moieties are selected from, for example, furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4- triazole, 1 -methyl- 1,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N- methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quino
  • Cycloalkyl refers to non-aromatic carbocylic groups, having 3 to 12, more preferably 3 to 7 carbon atoms, as for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl and the like.
  • Cycloalkyloxy refers to a radical or substituent of the formula -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • Polyfluoroalkyl refers to an alkyl radical or substituent having one or more fluoro substituents and includes perfluoroalkyl groups. Examples include trifluoromethyl and trifluoroethyl.
  • Polyfluoroalkoxy refers to an alkoxy radical or substituent having one or more fluoro substituents and includes perfluoroalkoxy groups. Examples include trifluoromethoxy and trifluoroethoxy.
  • Heterocyclyl refers to an aromatic or non-aromatic cyclic group having in the ring at least one carbon atom and one to four heteroatoms independently selected from oxygen, nitrogen or sulfur atoms.
  • heterocyclic radicals can either be through a carbon atom or a heteroatom.
  • Heterocyclic radicals preferably have 3 to 10 members, and more preferably 4, 5, or 6 members in the ring.
  • heterocyclic radicals include azetidinyl, furyl, tetrahydrofuranyl, thienyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl, isoxazolyl, isothiazolyl, morpholinyl, thiomorpholinyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,3-triazo
  • aminoalkyl refers to a radical or substituent of the formula -alkyl-
  • R alkyl, and alkoxy are as previously defined.
  • substituted sulfonamido refers to a radical or substituent of the formula -
  • Heterocyclosulfonyl refers to a radical or substituent of the formula -
  • heterocyclic group as defined above.
  • Preferred heterocyclosulfonyl groups include pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, and thiomorpholinylsulfonyl.
  • Arylamino refers to a radical or substituent of the formula-N(R")-aryl, wherein R" and aryl are as previously defined.
  • a “substituted arylamino” refers to an arylamino radical or substituent in which the aryl group is further substituted with the indicated substituents.
  • Heteroarylamino refers to a radical or substituent of the formula -
  • substituted heteroarylamino refers to a heteroarylamino radical or substituent in which the heteroaryl group is further substituted with the indicated substituents.
  • “Monoalkylamino” and “dialkylamino” refer to moieties with one or two alkyl groups, respectively, bonded to a nitrogen atom, wherein the alkyl chain is from 1 to 8 carbon atoms.
  • the groups may be the same or different.
  • “monoalkylaminoalkyl” and “dialkylaminoalkyl” refer to monoalkylamino and dialkylamino moieties wherein the nitrogen atom is further attached to an alkyl having 1 to 8 carbon atoms.
  • a “substituted monoalkylamino” or “substituted dialkylamino” refers to a radical or substituent of the formula -NH-alkyl or -NH- alkyl-alkyl, respectively, in which an alkyl group is further substituted with the indicated substituents.
  • “cycloalkyl-alkylamino” refers to a monoalkylamino radical or substituent, as defined above, in which the alkyl group is further substituted with a cycloalkyl group as defined above.
  • Benzyloxy refers to a radical or substituent of the formula -OCH 2 - phenyl.
  • a "substituted benzyloxy” is a benzyloxy in which the phenyl group is further substituted with the indicated substituents.
  • Halogen refers to a radical or substituent selected from the group consisting of chloro, bromo, iodo, and fluoro.
  • Haloalkyl refers to an alkyl group as defined above that is further substituted with a halogen, as defined above.
  • Amino refers to an -NH 2 group.
  • Preferred examples include, but are not limited to, acetyl, propionyl, butyryl, and trifluoroacetyl.
  • Alkylsulfonamido refers to the radical R 5 SO 2 NH-, wherein R' is an alkyl having 1 to 8 carbon atoms.
  • benzyloxy substituents may be independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl.
  • heterocyclyl substituents may be independently selected from the group consisting of alkyl, amino, amido, monoalkylamino, cycloalkyl-alkylamino, dialkylamino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, carboxyl, carboxamide, halogen, haloalkyl, cyano, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, alkylcarbonyl, cycloalkylcarbonyl, alkoxycarbonyl, mercapto, oxo, optionally substituted aryl, arylaklyl, and optionally substituted heteroaryl.
  • monoalkylamino and dialkylamino substituents may be independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and optionally substituted heterocyclyl.
  • heteroaryl substituents may be independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxamido, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo.
  • Arylamino and heteroarylamino substituents may be independently selected from the group consisting of alkyl and alkoxycarbonyl.
  • sulfonamido substituents may be independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamido, optionally substituted aryl, and optionally substituted heterocyclyl.
  • heterocyclosulfonyl substituents may be independently selected from the group consisting of alkoxy and hydroxy.
  • the compounds of this invention may contain asymmetric carbon atoms and one or more asymmetric centers, and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in formula (I), this invention includes all optical isomers and diastereomers, racemic and resolved, enantiomerically pure R and S stereoisomers, and other mixtures of the R and S stereoisomers, as well as pharmaceutically acceptable salts thereof.
  • Pharmaceutically acceptable salts of the compounds of formula (I) having acidic moieties may be formed from both organic and inorganic bases.
  • salts may be formed from organic and inorganic acids.
  • salts can be formed from acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
  • R 5 is methyl
  • Re is a substituted phenyl.
  • the phenyl ring is substituted with a halogen, an alkylsulfinyl, or an alkylthio.
  • the halogen is fluorine
  • the alkylsulfinyl is methanesulfinyl
  • the alkylthio is methylsulfanyl.
  • Re is 4-fluorophenyl.
  • R 1 and R 4 are hydrogen.
  • R 3 is -NR 1O SO 2 R 11 .
  • R 1O is a substituted alkyl and R 11 is methyl.
  • R 3 is -
  • R w is hydrogen or an alkyl and R z is methyl.
  • R 10 is not hydrogen
  • R 3 is a heterocyclic group that is substituted at a position that is adjacent to the position of attachment to the benzofuran ring.
  • R 3 is a substituted oxazolyl, pyridyl, or pyrimidyl group.
  • R 2 is alkoxy or cycloalkyl.
  • R 2 is methoxy or cyclopropyl.
  • R 5 is methyl
  • Re is 4-fluorophenyl, R 2 is methoxy and R 3 is 3-hydroxymethyl-5-methyloxazol-
  • R 5 is methyl
  • Re is 4-fluorophenyl
  • R 2 is methoxy
  • R 3 is 4-hydroxymethyloxazol-5-yl.
  • R 5 is methyl
  • Preferred compounds of the present invention include:
  • a second embodiment of the present invention is directed to a pharmaceutical composition that comprises at least one compound of formula (I) in combination or association with a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions can be prepared in various forms for administration including, but not limited to, tablets, caplets, pills and dragees and may also fill suitable containers such as capsules or bottles.
  • the compositions may be formulated with conventional excipients, such as fillers, disintegrating agents, binders, lubricants, flavoring agents, and the like.
  • the active agent may be present in an amount of at least 0.5%, and generally not more than 90% by weight, based on the total weight of the composition, including any carriers and/or excipients.
  • the proportion of active agent is about 5% to about 50% by weight of the composition.
  • the compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of antiviral agent that is appropriate for the subject to be treated.
  • the compounds of formula (I) will be administered in dosage units containing from about 2 mg to about 7000 mg of active agent, preferably from about 10 mg to about 2000 mg.
  • the compounds may be administered 1 to 6 times a day, more usually 1 to 4 times a day.
  • Administration may be oral, rectal, parenteral, such as by intramuscular injection, subcutaneous injection, intravenous infusion or the like, intravaginal, intraperitoneal, by inhalation, or local, such as by ointments, drops, powders or the like.
  • parenteral such as by intramuscular injection, subcutaneous injection, intravenous infusion or the like, intravaginal, intraperitoneal, by inhalation, or local, such as by ointments, drops, powders or the like.
  • parenteral such as by intramuscular injection, subcutaneous injection, intravenous infusion or the like, intravaginal, intraperitoneal, by inhalation, or local, such as by ointments, drops, powders or the like.
  • the compounds of formula (I) are also useful in treating and preventing HCV infections and diseases associated with such infections when used in combination with other active agents including, but not limited to, interferons, ribavirin, protease inhibitors, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, anti-infectious agents, and the like.
  • pharmaceutical compositions of the present invention may also comprise other active agents such as those noted above.
  • the active agents may be incorporated into the same formulation as that of the compounds of formula (I), or may be administered as a separate formulation. Therefore, the administration of the compounds of formula (I) along with other active agents may be in combination, serially, or simultaneously.
  • inventions are directed to methods for the treatment and/or prophylaxis of HCV infections and diseases associated with such infections comprising the step of administering a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition thereof to a subject in need of such treatment or prophylaxis.
  • the subject is a living host that is capable of being infected with a virus such as HCV.
  • the subject is a mammal, and more preferably is a human.
  • therapeutically effective amount refers to a nontoxic but sufficient amount of a compound to provide the desired treatment and/or prophylaxis of viral infection. The exact amount required will vary from subject to subject, depending upon the species, age and general condition of the subject, the severity of the infection, the particular compound, the mode of administration, and the like.
  • Yet another embodiment of the present invention is directed to a method for the inhibition of the hepatitis C RNA polymerase NS5B comprising the step of contacting a cell with a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition thereof.
  • HCV replicon is a sub genomic viral RNA that expresses the HCV proteins required for its own replication.
  • the replicon also contains a foreign gene encoding a drug- selectable marker (neomycin phosphotransferase) to allow for G418 (neomycin) selection of cells that contain the replicon.
  • a drug- selectable marker neomycin phosphotransferase
  • ELISA enzyme-linked immunosorbant assay
  • the glutaraldehyde is washed off using phosphate -buffered saline (PBS) and the cells are blocked for non-specific antibody binding using a blocking buffer such as SUPERB LOCK® reagent in PBS.
  • PBS phosphate -buffered saline
  • the blocking agent is rinsed from the cells with PBS and primary monoclonal antibody is added to each well containing compound.
  • the primary antibody is incubated for 1 hour at 37 0 C and then rinsed 3 times with PBS containing 0.02% TWEEN®-20.
  • Horseradish peroxidase (HRP)-conjugated secondary antibody is then added and incubated for 1 hour at 37 0 C.
  • HRP horseradish peroxidase
  • TMB 3,3',5,5'-tetramethylbenzidine
  • Compound dose response was measured in an 8-point dose curve diluted serially to determine the inhibitory concentration at 50% (IC 50 value) for representative compounds of the invention as listed in Table 1.
  • Preferred compounds have an IC 50 at about 30 ⁇ M or less; more preferred compounds have an IC 50 at about 10 ⁇ M or less; and most preferred compounds have an IC 50 at about 1 ⁇ M or less.

Abstract

La présente invention concerne des composés de formule (I) suivante ; dans laquelle R1, R2, R3, R4, R5, et R6 sont tels que définis, y compris toutes leurs formes cristallines et tous leurs sels pharmaceutiquement acceptables, qui sont utiles dans des préparations pharmaceutiques pour le traitement ou la prévention des infections par le virus de l’hépatite C et des maladies associées à de telles infections.
PCT/US2009/042870 2008-05-05 2009-05-05 Composés de benzofurane substitués en 6 pour traiter l’infection par le virus de l’hépatite c WO2009137500A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5030008P 2008-05-05 2008-05-05
US61/050,300 2008-05-05

Publications (1)

Publication Number Publication Date
WO2009137500A1 true WO2009137500A1 (fr) 2009-11-12

Family

ID=40766062

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/042870 WO2009137500A1 (fr) 2008-05-05 2009-05-05 Composés de benzofurane substitués en 6 pour traiter l’infection par le virus de l’hépatite c

Country Status (1)

Country Link
WO (1) WO2009137500A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7994171B2 (en) 2008-09-11 2011-08-09 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2011103063A1 (fr) * 2010-02-19 2011-08-25 Glaxo Group Limited Composés thérapeutiques
WO2011112769A1 (fr) * 2010-03-11 2011-09-15 Bristol-Myers Squibb Company Composés utilisables dans le cadre du traitement de l'hépatite c
WO2011131709A1 (fr) * 2010-04-21 2011-10-27 Novartis Ag Composés de furopyridine et ses utilisations
US8048887B2 (en) 2008-09-11 2011-11-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2012058125A1 (fr) 2010-10-26 2012-05-03 Presidio Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
WO2012067663A1 (fr) * 2010-11-18 2012-05-24 Glaxo Group Limited Composés
US8198449B2 (en) 2008-09-11 2012-06-12 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2012078545A1 (fr) * 2010-12-09 2012-06-14 Bristol-Myers Squibb Company Dérivés de benzofurane pour le traitement de l'hépatite c
US8293909B2 (en) 2008-09-11 2012-10-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8324212B2 (en) 2010-02-25 2012-12-04 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2013025992A1 (fr) 2011-08-17 2013-02-21 Glaxosmithkline Llc Procédés thérapeutiques
US8445497B2 (en) 2010-06-30 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2013125732A1 (fr) 2012-02-24 2013-08-29 Takeda Pharmaceutical Company Limited Composé à noyau aromatique
JP2014527529A (ja) * 2011-08-19 2014-10-16 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ Ｃ型肝炎ウイルス感染の治療のためのベンゾフラン化合物
WO2014205592A1 (fr) * 2013-06-24 2014-12-31 Merck Sharp & Dohme Corp. Composés hétérocycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9303020B2 (en) 2012-02-08 2016-04-05 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2016154241A1 (fr) * 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibiteurs de polymérase du virus de l'hépatite c
WO2021021706A1 (fr) * 2019-07-29 2021-02-04 The Brigham And Women's Hospital, Inc. Inhibiteurs du facteur d'inhibition de la migration des macrophages

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041201A2 (fr) * 2002-11-01 2004-05-21 Viropharma Incorporated Composes de benzofurane, compositions et methodes utilisees pour le traitement et la prophylaxie des infections virales induites par l'hepatite c et des maladies associees
WO2007059422A2 (fr) * 2005-11-10 2007-05-24 Wyeth Formulations pharmaceutiques contenant le 5-cyclopropyl-2(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-n-methyl-1-benzofuran-3-carboxamide et procede de preparation de celles-ci
WO2008024843A2 (fr) * 2006-08-25 2008-02-28 Viropharma Incorporated Méthode de thérapie combinatoire pour le traitement d'une infection par le virus de l'hépatite c et compositions pharmaceutiques correspondantes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041201A2 (fr) * 2002-11-01 2004-05-21 Viropharma Incorporated Composes de benzofurane, compositions et methodes utilisees pour le traitement et la prophylaxie des infections virales induites par l'hepatite c et des maladies associees
WO2007059422A2 (fr) * 2005-11-10 2007-05-24 Wyeth Formulations pharmaceutiques contenant le 5-cyclopropyl-2(4-fluorophenyl)-6-[(2-hydroxyethyl)(methylsulfonyl)amino]-n-methyl-1-benzofuran-3-carboxamide et procede de preparation de celles-ci
WO2008024843A2 (fr) * 2006-08-25 2008-02-28 Viropharma Incorporated Méthode de thérapie combinatoire pour le traitement d'une infection par le virus de l'hépatite c et compositions pharmaceutiques correspondantes

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8293909B2 (en) 2008-09-11 2012-10-23 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US7994171B2 (en) 2008-09-11 2011-08-09 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8309558B2 (en) 2008-09-11 2012-11-13 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8198449B2 (en) 2008-09-11 2012-06-12 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8048887B2 (en) 2008-09-11 2011-11-01 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8148382B2 (en) 2008-09-11 2012-04-03 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8536338B2 (en) 2008-09-11 2013-09-17 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US8722688B2 (en) 2008-09-11 2014-05-13 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2011103063A1 (fr) * 2010-02-19 2011-08-25 Glaxo Group Limited Composés thérapeutiques
US8324212B2 (en) 2010-02-25 2012-12-04 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
JP2013522224A (ja) * 2010-03-11 2013-06-13 ブリストル−マイヤーズ スクイブ カンパニー Ｃ型肝炎の処置のための化合物
US8354410B2 (en) 2010-03-11 2013-01-15 Bristol-Meyers Squibb Company Compounds for the treatment of hepatitis C
WO2011112769A1 (fr) * 2010-03-11 2011-09-15 Bristol-Myers Squibb Company Composés utilisables dans le cadre du traitement de l'hépatite c
CN102892767A (zh) * 2010-03-11 2013-01-23 百时美施贵宝公司 治疗丙型肝炎的化合物
CN103025738A (zh) * 2010-04-21 2013-04-03 诺瓦提斯公司 呋喃并吡啶化合物及其用途
US8324239B2 (en) 2010-04-21 2012-12-04 Novartis Ag Furopyridine compounds and uses thereof
JP2013527842A (ja) * 2010-04-21 2013-07-04 ノバルティス アーゲー フロピリジン化合物およびその使用
CN103025738B (zh) * 2010-04-21 2015-08-19 诺华股份有限公司 呋喃并吡啶化合物及其用途
WO2011131709A1 (fr) * 2010-04-21 2011-10-27 Novartis Ag Composés de furopyridine et ses utilisations
US8445497B2 (en) 2010-06-30 2013-05-21 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
EP2632261A1 (fr) * 2010-10-26 2013-09-04 Presidio Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
CN103269586A (zh) * 2010-10-26 2013-08-28 普雷西迪奥制药公司 丙型肝炎病毒抑制剂
US9085587B2 (en) 2010-10-26 2015-07-21 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
CN103269586B (zh) * 2010-10-26 2015-07-15 普雷西迪奥制药公司 丙型肝炎病毒抑制剂
WO2012058125A1 (fr) 2010-10-26 2012-05-03 Presidio Pharmaceuticals, Inc. Inhibiteurs du virus de l'hépatite c
EP2632261A4 (fr) * 2010-10-26 2013-11-27 Presidio Pharmaceuticals Inc Inhibiteurs du virus de l'hépatite c
US9309260B2 (en) 2010-10-26 2016-04-12 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
WO2012067663A1 (fr) * 2010-11-18 2012-05-24 Glaxo Group Limited Composés
US8507683B2 (en) 2010-12-09 2013-08-13 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
WO2012078545A1 (fr) * 2010-12-09 2012-06-14 Bristol-Myers Squibb Company Dérivés de benzofurane pour le traitement de l'hépatite c
US9453007B2 (en) 2010-12-22 2016-09-27 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9567355B2 (en) 2010-12-22 2017-02-14 Abbvie Inc. Hepatitis C inhibitors and uses thereof
CN106109479A (zh) * 2011-08-17 2016-11-16 葛兰素史克有限责任公司 治疗方法
JP2014524446A (ja) * 2011-08-17 2014-09-22 グラクソスミスクライン エルエルシー 治療方法
WO2013025992A1 (fr) 2011-08-17 2013-02-21 Glaxosmithkline Llc Procédés thérapeutiques
KR20180129973A (ko) * 2011-08-17 2018-12-05 글락소스미스클라인 엘엘씨 치료 방법
KR101975233B1 (ko) 2011-08-17 2019-05-07 글락소스미스클라인 엘엘씨 치료 방법
US9119868B2 (en) 2011-08-17 2015-09-01 Glaxosmithkline Llc Therapeutic methods
AU2012296446B2 (en) * 2011-08-17 2015-07-09 Glaxosmithkline Llc Therapeutic methods
EA024357B1 (ru) * 2011-08-17 2016-09-30 ГЛАКСОСМИТКЛАЙН ЭлЭлСи 6-(N-(7-ХЛОР-1-ГИДРОКСИ-1,3-ДИГИДРОБЕНЗО[c][1,2]ОКСАБОРОЛ-5-ИЛ)МЕТИЛСУЛЬФОНАМИДО)-5-ЦИКЛОПРОПИЛ-2-(4-ФТОРФЕНИЛ)-N-МЕТИЛБЕНЗОФУРАН-3-КАРБОКСАМИД
US10238678B2 (en) 2011-08-17 2019-03-26 Glaxosmithkline Llc Therapeutic methods
JP2017165732A (ja) * 2011-08-17 2017-09-21 グラクソスミスクライン エルエルシー 治療方法
CN103929965B (zh) * 2011-08-17 2016-08-17 葛兰素史克有限责任公司 治疗方法
CN103929965A (zh) * 2011-08-17 2014-07-16 葛兰素史克有限责任公司 治疗方法
JP2014527529A (ja) * 2011-08-19 2014-10-16 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ Ｃ型肝炎ウイルス感染の治療のためのベンゾフラン化合物
US8927593B2 (en) 2011-08-19 2015-01-06 Glaxo Group Limited Benzofuran compounds for the treatment of hepatitis C virus infections
US9682999B2 (en) 2011-08-19 2017-06-20 Glaxo Group Limited Benzofuran compounds for the treatment of hepatitis C virus infections
JP2017125010A (ja) * 2011-08-19 2017-07-20 グラクソ グループ リミテッドＧｌａｘｏ Ｇｒｏｕｐ Ｌｉｍｉｔｅｄ Ｃ型肝炎ウイルス感染の治療のためのベンゾフラン化合物
US9303020B2 (en) 2012-02-08 2016-04-05 Bristol-Myers Squibb Company Compounds for the treatment of hepatitis C
US9238639B2 (en) 2012-02-24 2016-01-19 Takeda Pharmaceutical Company Limited Aromatic ring compound
WO2013125732A1 (fr) 2012-02-24 2013-08-29 Takeda Pharmaceutical Company Limited Composé à noyau aromatique
JP2015508051A (ja) * 2012-02-24 2015-03-16 武田薬品工業株式会社 芳香環化合物
EP3013333A4 (fr) * 2013-06-24 2017-01-11 Merck Sharp & Dohme Corp. Composés hétérocycliques et leurs méthodes d'utilisation pour le traitement de l'hépatite c
US9549921B2 (en) 2013-06-24 2017-01-24 Merck Sharp & Dohme Corp. Heterocyclic compounds and methods of use thereof for the treatment of hepatitis C
WO2014205592A1 (fr) * 2013-06-24 2014-12-31 Merck Sharp & Dohme Corp. Composés hétérocycliques et leurs procédés d'utilisation pour le traitement de l'hépatite c
CN107567442A (zh) * 2015-03-23 2018-01-09 共晶制药公司 C型肝炎病毒聚合酶的抑制剂
JP2018512453A (ja) * 2015-03-23 2018-05-17 コクリスタル ファーマ, インコーポレイテッドCocrystal Pharma, Inc. Ｃ型肝炎ウイルスポリメラーゼの阻害剤
WO2016154241A1 (fr) * 2015-03-23 2016-09-29 Cocrystal Pharma, Inc. Inhibiteurs de polymérase du virus de l'hépatite c
US10464914B2 (en) 2015-03-23 2019-11-05 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
EA033622B1 (ru) * 2015-03-23 2019-11-11 Cocrystal Pharma Inc Ингибиторы полимеразы вируса гепатита c
AU2016235246B2 (en) * 2015-03-23 2020-12-10 Cocrystal Pharma, Inc. Inhibitors of hepatitis C virus polymerase
US10947210B2 (en) 2015-03-23 2021-03-16 Cocrystal Pharma, Inc. Inhibitors of Hepatitis C virus polymerase
TWI731854B (zh) * 2015-03-23 2021-07-01 美商共結晶製藥公司 Ｃ型肝炎病毒聚合酶之抑制劑
WO2021021706A1 (fr) * 2019-07-29 2021-02-04 The Brigham And Women's Hospital, Inc. Inhibiteurs du facteur d'inhibition de la migration des macrophages

Similar Documents

Publication Publication Date Title
WO2009137500A1 (fr) Composés de benzofurane substitués en 6 pour traiter l’infection par le virus de l’hépatite c
WO2009137493A1 (fr) Composés benzofurane substitués en position 2 pour traiter une infection par le virus de l'hépatite c
US7705146B2 (en) Hepatitis C inhibitor peptide analogs
CA3173964A1 (fr) Peptides fonctionnalises en tant qu'agents antiviraux
JP5377290B2 (ja) 抗ウイルス剤としての大環状化合物
US8178531B2 (en) Antiviral agents
EP2410844B1 (fr) Inhibiteurs de la réplication du virus de l'hépatite c
US20100074863A1 (en) Anti-infective pyrrolidine derivatives and analogs
JP2009541293A (ja) 抗ウイルス剤としての大環状化合物
US20070060565A1 (en) Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors
US20090060874A1 (en) Bicyclic pyrrolidine derivatives
WO2009003009A1 (fr) Pyrrolidine substituée utilisée en tant qu'agent anti-infectieux
BRPI0918174A2 (pt) composto que apresenta atividade contra o vírus da hepatite c (hcv), sua composição e seu uso
ES2292126T3 (es) Derivados de 4-carboxipirazol utiles como agentes antivirales.
OA12961A (en) Substituted aryl thioureas and related compounds, inhibitors of viral replication.
KR20080075909A (ko) Ｎ-(6-원 방향족 환)-아미도 항-바이러스 화합물
WO2006133326A1 (fr) Inhibiteurs de replication du virus de l'hepatite c (hcv)
NZ539727A (en) Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases
MXPA06013374A (es) Aril-acil-tioureas sustituidas y compuestos relacionados, inhibidores de la replica viral.
KR20110028665A (ko) 세린 프로테아제, 특히 ｃ형 간염 바이러스 ｎｓ3-ｎｓ4 프로테아제의 억제제
WO2003037893A1 (fr) Derives d'acyl-dihydro-pyrrole utilises comme inhibiteurs du vhc
JP2014534206A (ja) Ｃ型肝炎ウイルス阻害剤
US20220048944A1 (en) Functionalized peptides as antiviral agents
US20090233972A1 (en) Substituted heterocycles as anti-infectives
US20070225344A1 (en) Sulfonamide derivatives to treat infection with hepatitis C virus

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09743486

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09743486

Country of ref document: EP

Kind code of ref document: A1