WO2005112640A2 - Composes, compositions et methodes de traitement et de prophylaxie des infections provoquees par le virus de l'hepatite c et des maladies associees - Google Patents

Composes, compositions et methodes de traitement et de prophylaxie des infections provoquees par le virus de l'hepatite c et des maladies associees Download PDF

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WO2005112640A2
WO2005112640A2 PCT/US2005/016867 US2005016867W WO2005112640A2 WO 2005112640 A2 WO2005112640 A2 WO 2005112640A2 US 2005016867 W US2005016867 W US 2005016867W WO 2005112640 A2 WO2005112640 A2 WO 2005112640A2
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substituted
amino
radical
hydroxy
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WO2005112640A3 (fr
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Thomas R. Bailey
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Wyeth LLC
Viropharma Biologics LLC
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Wyeth LLC
Viropharma Inc
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    • 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
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to novel benzofuran, naphthalene, benzimidazole, benzothiophene, isoindole, and indole derivatives and analogs thereof, as well as compositions containing the same and to the use thereof for the treatment or prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases caused by the hepatitis C virus.
  • Hepatitis C is a common infection that can lead to chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma.
  • Infection with the hepatitis C virus (HCV) leads to chronic hepatitis in at least 85% of cases. It is the leading reason for liver transplantation, and is responsible for at least 10,000 deaths annually in the United States (Hepatology, 1997, 26 (Suppl. 1), 2S-10S).
  • Interferon and interferon in combination with ribavirin are used in the U.S. for hepatitis due to HCV. These treatments are associated with improved serum enzyme response in some patients. The remainder are non-responsive to treatment.
  • hepatitis C virus is a member of the Flaviviridae family.
  • the genome of HCV is positive strand, single stranded linear RNA (Hepatology, 1997, 26 (Suppl. 1), 11S-14S). HCV displays extensive genetic heterogeneity; at least six genotypes and more than 50 subtypes have been identified. Following infection by HCV, the viral RNA is translated into a polyprotein.
  • RNA is the sole genetic material.
  • RNA-dependent RNA polymerase activity Since mammalian host cells ordinarily lack RNA-dependent RNA polymerase activity, the positive stranded RNA viruses encode their own replicative polymerase (NS5B in the case of HCV), which is essential for the production of virion progeny. The inhibition of NS5B activity, therefore, provides an attractive target for HCV drug design.
  • the present invention provides compounds and compositions for the treatment and prophylaxis of viral infections, as well as diseases associated with viral infections in living hosts.
  • the compounds of the invention are of the following general formulas:
  • R lls R 21 , R 31 , Ru, R 51 , R ⁇ i, and R 1 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano
  • Ri2, R22, R32, 42, R52, R62, and R 2 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, hydroxy, cycloalkyl, cycloalkyloxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amino, monoalkylamino, dialkylamino, cyano, a substituted or unsubstituted benzyloxy group, and a substituted or unsubstituted heterocyclic radical; Ri3 > R23, R33, R43, R 5 3, ⁇ 3 5 and R 3 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted
  • the invention also relates to pharmaceutical compositions containing the antiviral compounds of formulas I- VII and the corresponding methods of use for treating and preventing infections caused by hepatitis C virus, as well as the intermediate compounds and related methods of preparing the antiviral compounds described herein.
  • the instant invention provides compounds of formulas I- VII:
  • R 36 R 1 , R 4 2, R43, 44, R4 5 , 46, R 5 1, R 5 2, R 5 3, R 5 4, R 55 , R 5 6, R ⁇ l, R ⁇ 2, R ⁇ 3 5 R ⁇ 4 5 R ⁇ 5 , R ⁇ ,
  • R7 1 , R72, R73, R74, R7 5 and R 6 are as defined above.
  • the instant invention provides compounds of formulas Ia-
  • R ⁇ , R 21 , R 31 , Ru, R51, R ⁇ i, and R 1 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano
  • the instant invention provides compounds of the formulas Ib- Vllb:
  • R 74 Vllb wherein: R ⁇ , R 2 ⁇ , R 31 , Rn, R 51 , Rei, and R 71 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; R12, R22, 32, t2 5 R 5 2, R ⁇ 2, and R 72 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, hydroxy, cycloalkyl, cycloalkyloxy, polyfluoroalkyl, polyfluoroalkoxy, halogen, amino, monoalkylamino, dialkylamino, cyano, a substituted or unsubstituted benzyloxy group, and a substituted or unsubstituted heterocyclic radical; Ri3, R23, R33, R43, R 5 3, R ⁇ 3, and R 3 represent a radical selected from the group consisting of hydrogen, a
  • R ⁇ , R 21 , R 31 , R 41 , R 5 ⁇ , R ⁇ i, and R 71 represent a radical selected from the group consisting of hydrogen, methyl, and chloro
  • R12, 22, R32, R42, R 5 2, R ⁇ 2, and R 7 2 represent a radical selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, hydroxy, hydroxymethyl, methoxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyclopropylmethoxy, carboxymethoxy, cyanomethoxy, cyano-methyl-methoxy, 1- hydroxymethyl-cyclopropylmethoxy, carbamoylmethoxy, methylcarbamoylmethoxy, diethylcarbamoylmethoxy, (4-ethoxycarbonyl-phenylcarbamoyl)-methoxy, tert- butoxycarbon
  • Preferred compounds of formulas I- VII include the compounds wherein Rn, R 22 , R 32 , R42, R 5 2, R ⁇ 2, and R 72 are -OCH 3 or -O(CH)(CH 3 ) 2 , -CH 2 CH 3 , and Other preferred compounds of formulas I- VII include the compounds wherein Ri5, R2 5 , R35, R4 5 , R5S, Res, and R 75 are methyl.
  • a preferred aspect of the invention includes the compound of formula I- VII, la- Vila, Ib-VIIb or Ic-VIIc wherein the aryl group, represented by R 16 , R 26 , R3 6 , Rw, R 56 , Re 6 , and R 6 , is a substituted phenyl, said phenyl substituents being one or more radical(s) independently selected from the group consisting of fluoro, chloro, bromo, methoxy, and cyano.
  • the present invention provides pharmaceutical compositions comprising one or more compounds of formulas I- VII, la- Vila, Ib-VIIb or Ic-VIIc in combination with a pharmaceutically acceptable carrier medium.
  • Preferred pharmaceutical compositions comprise one or more compounds listed in Table 1 below, and pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier medium.
  • the present invention provides methods for the prophylaxis or treatment of hepatitis C infections and diseases associated with such infections in a living host, for example, a mammal including a human, comprising the step of administering a therapeutically effective amount of the compounds formulas I- VII, Ia-VIIa, Ib-VIIb or Ic-VIIc to a host susceptible to, or suffering from such infection.
  • Another aspect of the invention provides methods for the prophylaxis or treatment of hepatitis C infections and diseases associated with such infections in a living host, for example, a mammal including a human.
  • This method comprises administering a therapeutically effective amount of a compound selected from the group consisting of 5 -methoxy-2-phenyl-benzofuran-3 -carboxylic acid methylamide and 5-hydroxy-2-phenyl-benzofuran-3-carboxylic acid methylamide to a host susceptible to, or suffering from such infection.
  • a compound selected from the group consisting of 5 -methoxy-2-phenyl-benzofuran-3 -carboxylic acid methylamide and 5-hydroxy-2-phenyl-benzofuran-3-carboxylic acid methylamide to a host susceptible to, or suffering from such infection.
  • the compounds of formulas I- VII, Ia-VIIa, Ib-VIIb or Ic-VIIc above, their isomers and pharmaceutically acceptable salts exhibit antiviral activity.
  • the compounds of the invention are particularly effective against hepatitis C virus and are useful in the prophylaxis and/or treatment of infections and diseases associated with this virus in living hosts.
  • the term "compounds of the invention” means, collectively, the compounds of formulas I- VII, Ia-VIIa, Ib-VIIb or Ic-VIIc, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the compounds of the invention are identified herein by their chemical structure and/or chemical name. Where a compound is referred to by both a chemical structure and a chemical name, and that chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • alkyl refers to straight or branched chain aliphatic hydrocarbon radicals of up to 10 carbon atoms, preferably up to 6 carbon atoms and more preferably 1 to 4 carbon atoms.
  • alk in a structural formula herein denotes an alkyl group, unless divalency is indicated, in which case the “alk” denotes the corresponding alkylene group(s). Additionally, the term “alkyl (C C ⁇ )” denotes an alkyl group having one to six carbon atoms.
  • alkenyl refers to straight or branched chain aliphatic hydrocarbon radicals of 2 to 7 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 as used herein refers to straight or branched chain aliphatic hydrocarbon radicals containing 2 to 7 carbon atoms having at least one triple bond.
  • phenyl refers to a group.
  • a "substituted phenyl” refers to a phenyl group that is substituted with the indicated substituents.
  • aryl when used as such, or in combination form, for example “aralkyl,” refers to an aromatic carbocyclic group, having 6 to 10 carbon atoms including, without limitation, phenyl and napthyl.
  • heteroaryl refers to a 5- or 6-membered aromatic cyclic group having at least one carbon atom and one or more oxygen, nitrogen or sulfur atoms in the ring, as for example furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3 -oxadiazolyl, 1,2,4- oxadiazolyl, 1,2,3 -triazolyl, 1,2,4-triazolyl, 1-3-oxathiolanly, thiadiazolyl, tetrazolyl, and the like.
  • cycloalkyl refers to non-aromatic carbocylic groups, having 3 to 7 carbon atoms, as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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.
  • heterocyclic 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. The point of attachment of 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 mclude 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- triazolyl, 1,2,4-triazolyl, 1-3-oxathiolanly, thiadiazolyl, tetrazolyl, and the like.
  • R" and R' independently represent hydrogen, alkyl, or cycloalkyl.
  • sulfonamide refers to a radical or substituent of the formula -SO 2 NR"R'" or-NR"SO 2 R'", wherein R" and R'" are as previously defined.
  • a substituted sulfonamide refers to a radical or substituent of the formula -N(alkyl)-SO 2 (alkyl) in which at least one alkyl group is further substituted with the indicated substituents.
  • heterocyclosulfonyl refers to a radical or substituent of the formula -SO 2 -HET, wherein HET is a 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 -N(R")-heteroaryl, wherein R" and heteroaryl are as previously defined.
  • a substituted heteroarylamino refers to a heteroarylamino radical or substituent in which the heteroaryl group is further substituted with the indicated substituents.
  • a substituted monoalkylamino refers to a radical or substituent of the formula -NH-alkyl in which the 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.
  • mercapto refers to a radical or substituent of the formula -SH.
  • benzyloxy refers to a radical or substituent of the formula
  • a substituted benzyloxy is a benzyloxy in which the phenyl group is further substituted with the indicated substituents.
  • hexanes refers to a solvent mixture of straight and branched chain hexane hydrocarbons, wherein the solvent mixture contains mostly n- hexane and some minor amounts of branched hexanes.
  • 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.
  • psig refers to pounds per square inch gauge.
  • HPLC high-performance liquid chromatography.
  • TLC thin layer chromatography.
  • tautomeric form refers two or more isomeric structures formed by migration of a hydrogen atom.
  • amino refers to an -NH 2 group.
  • 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl refers to
  • living host refers to an organism that is living and capable of being infected with a virus, such as the hepatitis C virus; for example, a mammal, which includes a human.
  • the compounds of the present invention and their isomeric forms and pharmaceutically acceptable salts thereof are also useful in treating and preventing viral infections, in particular hepatitis C infection, and diseases in living hosts when used in combination with each other or with other biologically active agents, including but not limited to the group consisting of interferon, a pegylated interferon, ribavirin, protease inhibitors, polymerase inhibitors, small interfering RNA compounds, anti-sense compounds, nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antivirals, and anti-infective compounds.
  • interferon a pegylated interferon
  • ribavirin protease inhibitors
  • polymerase inhibitors small interfering RNA compounds
  • anti-sense compounds nucleotide analogs, nucleoside analogs, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory
  • Such combination therapy may also comprise providing a compound of the invention either concurrently or sequentially with other medicinal agents or potentiators, such as acyclovir, famicyclovir, valgancyclovir and related compounds, ribavirin and related compounds, amantadine and related compounds, various interferons such as, for example, interferon-alpha, interferon-beta, interferon-gamma and the like, as well as alternative forms of interferons such as pegylated interferons. Additionally, combinations of, for example ribavirin and interferon, may be administered as an additional combination for a multiple combination therapy with at least one of the compounds of the present invention.
  • other medicinal agents or potentiators such as acyclovir, famicyclovir, valgancyclovir and related compounds, ribavirin and related compounds, amantadine and related compounds, various interferons such as, for example, interferon-alpha, interferon-beta, interfer
  • the combination therapy can be sequential, that is the treatment with one agent first and then the second agent (for example, where each treatment comprises a different compound of the invention or where one treatment comprises a compound of the invention and the other comprises one or more biologically active agent), or it can be treatment with both agents at the same time (concurrently).
  • the sequential therapy can be within a reasonable time after the completion of the first therapy before beginning the second therapy.
  • the treatment with both agents at the same time can be in the same daily dose or in separate doses.
  • the dosages for both concurrent and sequential combination therapy will depend on absorption, distribution, metabolism, and excretion rates of the components of the combination therapy as well as other factors known to one of skill in the art. Dosage values will also vary with the severity of the condition to be alleviated.
  • the compounds of the invention may be used for the treatment of HCV in humans in combination therapy mode with other inhibitors of the HCV polymerase.
  • the compounds of the present invention may be used for the treatment of HCV in humans in combination therapy mode with other inhibitors of the HCV life cycle such as, for example, inhibitors of HCV cell attachment or virus entry, HCV translation, HCV RNA transcription or replication, HCV maturation, assembly or virus release, or inhibitors of HCV enzyme activities such as the HCV nucleotidyl transferase, helicase, protease or polymerase.
  • combination therapies of the present invention include any chemically compatible combination of a compound of this inventive group with other compounds of the inventive group or other compounds outside of the inventive group, as long as the combination does not eliminate the anti- viral activity of the compound of this inventive group or the anti- viral activity of the pharmaceutical composition itself.
  • interferon-alpha means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response.
  • suitable interferon-alphas include, but are not limited to, recombinant interferon alpha-2b such as INTRON-A INTERFERON available from Schering Corporation, Kenil worth, NJ, recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, NJ, a recombinant interferon alpha-2C, such as BEROFOR ALPHA 2 INTERFERON available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-nl, a purified blend of natural alpha interferons such as SUMIFERON available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from Glaxo-Wellcome Ltd., London, Great Britain, or a consensus alpha interferon
  • Patent Nos. 4,897,471 and 4,695,623 (the contents of which are hereby incorporated by reference in their entireties, specifically examples 7, 8 or 9 thereof) and the specific product available from Amgen, Inc., Newbury Park, Calif, or interferon alpha-n3 a mixture of natural interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the ALFERON trademark.
  • the use of interferon alpha-2a or alpha 2b is preferred. Since interferon alpha 2b, among all interferons, has the broadest approval throughout the world for treating chronic hepatitis C infection, it is most preferred. The manufacture of interferon alpha 2b is described in U.S. Pat. No.
  • pegylated interferon as used herein means polyethylene glycol modified conjugates of interferon, preferably interferon alpha-2a and alpha-2b.
  • the preferred polyethylene-glycol-interferon alpha-2b conjugate is PEG.sub.12000- interferon alpha 2b.
  • PEG.sub.12000-IFN alpha as used herein means conjugates such as are prepared according to the methods of International Application No. WO 95/13090 and containing urethane linkages between the interferon alpha-2a or alpha-2b amino groups and polyethylene glycol having an average molecular weight of 12000.
  • Compounds described herein are also useful in preventing or resolving viral infections in cell, tissue or organ cultures and other in vitro applications.
  • inclusion of compounds of the invention as a supplement in cell or tissue culture growth media and cell or tissue culture components will prevent viral infections or contaminations of cultures not previously infected with viruses.
  • the compounds described above may also be used to eliminate viruses from cultures or other biological materials infected or contaminated with viruses (for example, blood), after a suitable treatment period, under any number of treatment conditions as determined by the skilled artisan.
  • the compounds of the invention can form useful salts with inorganic and organic acids such as hydrochloric, sulfuric, acetic, lactic, or the like and with inorganic or organic bases such as sodium or potassium hydroxide, piperidine, ammonium hydroxide, or the like.
  • the pharmaceutically acceptable salts of the compounds of formula I- VII, Ia-VIIa, Ib-VIIb or Ic-VIIc are prepared following procedures that are familiar to those skilled in the art.
  • sodium and potassium salts can be made by dissolving an appropriate compound of the invention in ethanol and adding about 1.1 equivalents of sodium hydroxide or potassium hydroxide, and allowing salt formation.
  • the isomeric forms of the compounds of the invention include, without limitation, the various isomers of the heterocyclic substituents that may be present therein.
  • the chemical structures depicted herein and therefore the compounds of the invention also encompass all of the corresponding possible tautomeric forms. Such tautomers may, in certain instances, be resolved into individual compounds by methods known to those of skill in the art.
  • the compounds of the present invention are useful for treating HCV in living hosts, for example, mammals including humans. When administered to a living host the compounds can be used alone, or as a pharmaceutical composition.
  • compositions comprising the compounds of the present invention, either alone or in combination with each other, offer a treatment against hepatitis C infection.
  • the antiviral pharmaceutical compositions of the present invention comprise one or more of the compound(s) of formulas I- II, Ia-VIIa, Ib- VIIb or Ic-VIIc above, as the active ingredient in combination with a pharmaceutically acceptable carrier medium or auxiliary agent.
  • the composition may be prepared in various forms for administration, including tablets, caplets, pills or dragees, or can be filled in suitable containers, such as capsules, or, in the case of suspensions, filled into bottles.
  • pharmaceutically acceptable carrier medium includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Twentieth Edition, A. R. Gennaro discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • 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 carrier medium and/or auxiliary agent(s), if any.
  • the proportion of active agent varies between 5 to 50% by weight of the composition.
  • Pharmaceutical organic or inorganic solid or liquid carrier media suitable for enteral or parenteral administration can be used to make up the composition.
  • the compounds of the invention may be administered using any amount and any route of administration effective for attenuating infectivity of the virus.
  • amount effective to attenuate infectivity of virus refers to a nontoxic but sufficient amount of the antiviral agent to provide the desired prophylaxis and/or treatment of viral infection. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular antiviral agent, its mode of administration, and the like.
  • the antiviral compounds 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 appropriate for the patient to be treated.
  • Each dosage should contain the quantity of active material calculated to produce the desired therapeutic effect either as such, or in association with the selected pharmaceutical carrier medium and/or the supplemental active agent(s), if any.
  • the antiviral compounds of the invention will be administered in dosage units containing from about 2 mg to about 7000 mg of the antiviral agent by weight of the composition, with a range of about 10 mg to about 2000 mg being preferred.
  • the compounds may be administered orally, rectally, parenterally, such as by intramuscular injection, subcutaneous injection, intravenous infusion or the like, intracisternally, intravaginally, intraperitoneally, locally, such as by powders, ointments, or drops, or the like, or by inhalation, such as by aerosol or the like, taking into account the nature and severity of the infection being treated.
  • the compounds of the invention may be administered at dosage levels of about 0.05 to about 100 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • the compounds of the invention will typically be administered from 1 to 4 times a day so as to deliver the above-mentioned daily dosage.
  • the exact regimen for administration of the compounds and compositions described herein will necessarily be dependent on the needs of the individual host or patient being treated, the type of treatment administered and the judgment of the attending medical specialist.
  • these compounds will be useful not only for therapeutic treatment of virus infection, but for virus infection prophylaxis, as well.
  • the dosages may be essentially the same, whether for treatment or prophylaxis of virus infection.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux dérivés benzofurane, naphtalène, benzimidazole, benzothiophène, isoindole et indole ainsi que les analogues de ces derniers, de même que des compositions contenant ces derniers, l'utilisation de ces compositions pour le traitement ou la prophylaxie des infections virales et des maladies associées à ces dernières, particulièrement les infections virales et les maladies associées provoquées par le virus de l'hépatite C.
PCT/US2005/016867 2004-05-13 2005-05-13 Composes, compositions et methodes de traitement et de prophylaxie des infections provoquees par le virus de l'hepatite c et des maladies associees Ceased WO2005112640A2 (fr)

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EP05748433A EP1746888A2 (fr) 2004-05-13 2005-05-13 Composes, compositions et methodes de traitement et de prophylaxie des infections provoquees par le virus de l'hepatite c et des maladies associees

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US57145404P 2004-05-13 2004-05-13
US57144804P 2004-05-13 2004-05-13
US60/571,019 2004-05-13
US60/571,448 2004-05-13
US60/571,454 2004-05-13
US60/571,453 2004-05-13
US60/571,130 2004-05-13
US60/571,188 2004-05-13
US57279604P 2004-05-20 2004-05-20
US57281704P 2004-05-20 2004-05-20
US57284004P 2004-05-20 2004-05-20
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US57281404P 2004-05-20 2004-05-20
US57298204P 2004-05-20 2004-05-20
US57280504P 2004-05-20 2004-05-20
US60/572,982 2004-05-20
US60/572,840 2004-05-20
US60/572,817 2004-05-20
US60/572,796 2004-05-20
US60/572,816 2004-05-20
US60/572,805 2004-05-20
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008125874A1 (fr) * 2007-04-12 2008-10-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de benzofurane-carboxamide comme agents antiviraux
WO2008100867A3 (fr) * 2007-02-12 2009-01-08 Intermune Inc Nouveaux inhibiteurs de réplication du virus de l'hépatite c
WO2011106340A1 (fr) * 2010-02-25 2011-09-01 Bristol-Myers Squibb Company Dérivés de pyrazolopyridazine pour le traitement de l'hépatite c
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS60233642A (ja) * 1984-05-07 1985-11-20 Fuji Photo Film Co Ltd 写真画像の形成方法
IL109568A0 (en) * 1993-05-19 1994-08-26 Fujisawa Pharmaceutical Co Urea derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof
CN1832939B (zh) * 2003-05-30 2010-04-28 杰明X医药品加拿大公司 用于治疗癌症或病毒病的三杂环化合物、组合物和方法

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008100867A3 (fr) * 2007-02-12 2009-01-08 Intermune Inc Nouveaux inhibiteurs de réplication du virus de l'hépatite c
JP2010518125A (ja) * 2007-02-12 2010-05-27 インターミューン・インコーポレーテッド Ｃ型肝炎ウイルス複製の新規な阻害剤
WO2008125874A1 (fr) * 2007-04-12 2008-10-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de benzofurane-carboxamide comme agents antiviraux
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
CN102858777B (zh) * 2010-02-25 2015-01-07 百时美施贵宝公司 治疗丙型肝炎的吡唑并哒嗪衍生物
WO2011106340A1 (fr) * 2010-02-25 2011-09-01 Bristol-Myers Squibb Company Dérivés de pyrazolopyridazine pour le traitement de l'hépatite c
CN102858777A (zh) * 2010-02-25 2013-01-02 百时美施贵宝公司 治疗丙型肝炎的吡唑并哒嗪衍生物
US8614207B2 (en) 2010-10-26 2013-12-24 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9085587B2 (en) 2010-10-26 2015-07-21 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9309260B2 (en) 2010-10-26 2016-04-12 Presidio Pharmaceuticals, Inc. Inhibitors of hepatitis C virus
US9173887B2 (en) 2010-12-22 2015-11-03 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9453007B2 (en) 2010-12-22 2016-09-27 Abbvie Inc. Hepatitis C inhibitors and uses thereof
US9567355B2 (en) 2010-12-22 2017-02-14 Abbvie Inc. Hepatitis C inhibitors and uses thereof

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WO2005112640A3 (fr) 2007-03-29

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