EP1746888A2 - Compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases - Google Patents
Compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseasesInfo
- Publication number
- EP1746888A2 EP1746888A2 EP05748433A EP05748433A EP1746888A2 EP 1746888 A2 EP1746888 A2 EP 1746888A2 EP 05748433 A EP05748433 A EP 05748433A EP 05748433 A EP05748433 A EP 05748433A EP 1746888 A2 EP1746888 A2 EP 1746888A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- substituted
- amino
- radical
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 238000011321 prophylaxis Methods 0.000 title claims abstract description 13
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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
- 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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Abstract
Disclosed are novel benzofuran, naphthalene, benzimidazole, benzothiophene, isoindole, and indole derivatives and analogs thereof, as well as compositions containing the same and, the use thereof for the treatment of prophylaxis of viral infections and diseases associated therewith, particularly those viral infections and associated diseases caused by the hepatitis C virus.
Description
COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATMENT AND PROPHYLAXIS OF HEPATITIS C VIRAL INFECTIONS AND ASSOCIATED DISEASES
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Nos. 60/571,453, filed May 13, 2004, 60/571,019, filed May 13, 2004, 60/571,188, filed May 13, 2004, 60/571,448, filed May 13, 2004, 60/571,130, filed May 13, 2004, 60/571,454, filed May 13, 2004, 60/572,982, filed May 20, 2004, 60/572,796, filed May 20, 2004, 60/572,814, filed May 20, 2004, 60/572,805, filed May 20, 2004, 60/572,840, filed May 20, 2004, 60/572,817, filed May 20, 2004, 60/572,816, filed May 20, 2004 and 60/573,540, filed May 21, 2004. The entire disclosure of each of the aforementioned provisional patent applications is incorporated by reference herein.
FIELD OF THE INVENTION 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.
BACKGROUND OF THE INVENTION 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. For responders, a sustained clinical improvement is seen in only a small percentage of
patients; the majority of patients relapse upon cessation of treatment. Thus, the effectiveness of therapy for chronic hepatitis C is variable and its cure rate remains low. Moreover, therapy is often associated with considerable side effects. New therapies and preventatives are clearly needed for infections and diseases caused by the hepatitis C virus. The 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.
This approximately 3,000 residue polyprotein is subsequently cleaved into individual proteins by host peptidases, as well as virally encoded proteases. The HCV genome encodes structural proteins (required for virus assembly) and nonstructural proteins (required for replication). Some of the nonstructural proteins include: NS2, NS3, NS4A, NS4B, NS5A, and NS5B (J. General Virology, 2000, 81, 1631-1648). NS5B is a RNA-dependent RNA polymerase that is essential for viral replication. In positive stranded RNA viruses, such as HCV, RNA is the sole genetic material. 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.
SUMMARY OF THE INVENTION In accordance with one aspect, 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:
III
IV
VII
wherein: i Rlls R21, R31, Ru, R51, Rβi, 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, R53, δ35 and R 3 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and -O(CH2)-C(=O)-R!; R14, R24, R34, R44, R5 , δ4, and R 4 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; R15, R25, R35, R15, R55, Res, and R75 represent a radical selected from the group consisting of an alkyl ( -Cβ) group, cycloalkyl, and cycloalkylalkyl; Riβ, R26, R36, 46, R56> Rδβ, and R76 represent a radical selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; R\ represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy;
said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) 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, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof. 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.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the instant invention provides compounds of formulas I- VII:
III
IV
10 ^74 VII
wherein Rn, R12, R13, Ri4, Ris, Rι6, R21, R22, R23, R24, 25, R26, R31, R32, R33, R34, R35,
R36, R 1, R42, R43, 44, R45, 46, R51, R52, R53, R54, R55, R56, Rδl, Rό2, Rδ35 Rό45 Rό5, Rόδ,
R71, R72, R73, R74, R75 and R 6 are as defined above.
In a second aspect, the instant invention provides compounds of formulas Ia-
Vlla:
la
Ilia
IVa
Vila
wherein: Rπ, R21, R31, Ru, R51, Rβi, and R 1 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; Ri2, R22, R32, R42, R52, Rδ25 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; Ri3a, R23a, R33 , R43a, R53a, ό3a, and R73a represent a radical selected from the group consisting of a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and -O(CH2)-C(=O)-R1; R1 , R24, R34, R44, R54,,R64, and R 4 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; Ris, R∑s, R35, R45, R55, Res, and R 5 represent a radical selected from the group consisting of an alkyl (Ci-C6) group, cycloalkyl, and cycloalkylalkyl;
Ri6, R26, R36, R46, 56, Rδβ, and R76 represent a radical selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; R\ represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy; said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) 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, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy,
hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof.
In a third aspect, the instant invention provides compounds of the formulas Ib- Vllb:
lb
Illb
IVb
R74 Vllb wherein: Rπ, R2ι, R31, Rn, R51, Rei, and R71 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; R12, R22, 32, t25 R52, Rβ2, and R72 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, R53, Rδ3, and R 3 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and -O(CH2)-C(=O)-R1; R1 , R2 , R34, R44, R54, Rδ4, and R74 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; Ris, R25, R3s, Ris, R55, Rδs, and R75 represent a radical selected from the group consisting of an alkyl ( -Cβ) group, cycloalkyl, and cycloalkylalkyl;
Ri6b> R26b, R36b, tøb, R56b, δδb, and R76b represent a radical selected from the group consisting of a substituted aryl group and a substituted or unsubstituted heteroaryl group; Ri represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy; said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) 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, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy,
hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof. In a fourth aspect, the instant invention provides compounds of the formulas Ic-VIIc:
Ic
IIIc
IVc
VIIc
wherein: Rπ, R21, R31, R41, R5ι, Rβi, and R71 represent a radical selected from the group consisting of hydrogen, methyl, and chloro; R12, 22, R32, R42, R52, Rβ2, and R72 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- butoxycarbonylmethoxy, ethoxy, 2-methoxy-ethoxy, 2-chloro-ethoxy, 2- carboxyethoxy, 2,2,2-trifluoroethoxy, 1 -(4-fluoro-phenyl)-ethoxy, 2-(4-fluoro- phenyl)-2-oxo-ethoxy, 2-(4-methoxy-phenyl)-2-oxo-ethoxy, propoxy, isopropoxy, 2- oxo-propoxy, 2-hydroxy-propoxy, 3-hydroxy-propoxy, 2-hydroxy-2-methyl-propoxy, 3-bromo-propoxy, 3-ethoxy-propoxy, butoxy, 2-hydroxy-2-methyl-butoxy, cyclopentyloxy, allyloxy, cyano, chloro, fluoro, methanesulfonic acid, benzyloxy, 2- phenylbenzyloxy, 2-difluoromethoxy-benzyloxy, 3-methoxy-benzyloxy, 3- methoxycarbonyl-benzyloxy, 3-carboxy-benzyloxy, 3-cyano-benzyloxy, 4-methoxy- benzyloxy, 4-fluoro-benzyloxy, 4-cyano-benzyloxy, 4-methoxycarbonyl-benzyloxy, 4-carboxy-benzyloxy, 4-carboxy-3 -hydroxy-benzyloxy, 4-methanesulfonyl- benzyloxy, 3,4-difluoro-benzyloxy, 3,5-dimethoxy-benzyloxy, 2,2-dimethyl-4-oxo- 4H-benzo[l,3]dioxin-5-ylmethoxy, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxin-7- ylmethoxy, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxin-6-ylmethoxy, 3-chloromethyl- [1 ,2,4]thiadiazol-5-yloxy, 5-chloro-[l ,2,4]thiadiazol-3 -ylmethoxy, 5-chloro- [l,2,3]thiadiazol-4-ylmethoxy, 5-p-tolyl-[l,3,4]oxadiazol-2-ylmethoxy, 5-(3,5- dimethyl-isoxazol-4-yl)- [1,2,4] oxadiazol-3 -ylmethoxy, 5 -(cyclopropylmethyl-amino)-
[1 ,2,4]thiadiazol-3 -ylmethoxy, 5 -tert-butyl-[l ,2,4] oxadiazol-3 -ylmethoxy, 5-(4- methoxy-phenyl)-[l ,2,4]oxadiazol-3-ylmethoxy, 5-diethylamino-[l ,2,4]thiadiazol-3- ylmethoxy, [l,3,4]thiadiazol-2-ylcarbamoylmethoxy, 3,5-dimethyl-isoxazol-4-yl, isoxazol-3 -ylmethoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy, 5-methyl-isoxazol-3- ylmethoxy, thiazol-2-ylmethoxy, thiazol-4-ylmethoxy, 2-methyl-thiazol-4-ylmethoxy, 1 -thiazol-2-yl-ethoxy, thiazol-2-ylcarbamoylmethoxy, (4,5-dimethyl-thiazol-2- y lcarbamoyl)-methoxy, 4-chloro- 1 -methyl- 1 H-pyrazol-3 -ylmethoxy, 2-pyrazol- 1 -y 1- ethoxy, 2-(3,5-dimethyl-pyrazol-l-yl)-ethoxy, 4-ethoxycarbonyl-thiazol-2-ylmethoxy, 4-carboxy-thiazol-2-ylmethoxy, 5-amino-4H-[l ,2,4]triazol-3 -ylmethoxy, thiophen-2- yl, furan-2-yl, 2-morpholin-4-yl-ethoxy, 3-piperidin-l-yl-propoxy, tetrahydro-furan-2- yl, 1 -methyl- lH-tetrazol- 5 -ylmethoxy, 1 -methyl- lH-imidazol-2-ylmethoxy, 1-benzyl- lH-imidazol-2-ylmethoxy, 3H-imidazol-4-ylmethoxy, pyridine-4-yl-methoxy, 6- bromomethyl-pyridin-2-ylmethoxy, and 2-(4-cyano-piperidin- 1 -yl)-ethoxy; R13, R23, R33, R43, R53, Rδ3, and R 3 represent a radical selected from the group consisting of hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, 1-hydroxy-ethyl, l-hydroxy-2-methyl-propyl, 1 -hydroxy- 1 -methyl-ethyl, formyl, ureido, vinyl, bromo, chloro, cyano, acetyl, 2-hydroxy-acetyl, carboxy, azetidin-1-yl, carboxylic acid amide, amino, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, tert-butylamino, ethyl-methyl-amino, 2-methoxy-ethylamino, cyclopropylmethyl-amino, 2,3-dihydroxy-propylamino, 1-methylamino-ethyl, dimethylaminomethyl, 1 -amino- 1 -methyl-ethyl, 2-amino- 1 -hydroxy- 1 -methyl-ethyl, acetylamino, 1-acetylamino-l -methyl-ethyl, (2-methoxy-ethyl)-methyl-amino, ethyl- (2-methoxy-acetyl)-amino, 3-chloro-propane- 1 -sulfonylamino, methanesulfonylamino, ethyl-methanesulfonyl-amino, isopropyl-methanesulfonyl- amino, isobutyl-methanesulfonyl-amino, cyclobutyl-methanesulfonyl-amino, cyclopentyl-methanesulfonyl-amino, cyclopropylmethyl-methanesulfonyl-amino, (2- hydroxy-ethyl)-methanesulfonyl-amino, (2-hydroxy-propyl)-methanesulfonyl-amino, (2-fluoro-ethyl)-methanesulfonyl-amino, 2-(4-fluoro-phenyl)-2-hydroxy-ethyl]- methanesulfonyl-amino, (l-hydroxymethyl-cyclopropylmethyl)-methanesulfonyl- amino, (4-carboxy-benzyl)-methanesulfonyl-amino, allyl-methanesulfonyl-amino, acetyl-methanesulfonyl-amino, benzyl-methanesulfonyl-amino, carboxymethyl- methanesulfonyl-amino, methanesulfonylamino-methyl, 1 -methanesulfonylamino- 1 - methyl-ethyl, methanesulfonyl-methyl-amino, 1 -(methanesulfonyl-methyl-amino)- ethyl, methanesulfonyl-propyl-amino, methanesulfonyl-(2-methoxy-ethyl)-amino,
methanesulfonyl-(2,2,2-trifluoro-ethyl)-amino, methanesulfonyl-(2-oxo-propyl)- amino, methanesulfonyl-(2-trifluoromethoxy-ethyl)-amino, methanesulfonyl-(4- methoxy-benzyl)-amino, methanesulfonyl-(4-methoxycarbonyl-benzyl)-amino, methanesulfonyl-methoxymethyl-amino, methanesulfonyl-methylcarbamoylmethyl- amino, (methanesulfonyl-methyl-amino)-methyl, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, cyclopropylsulfamoyl, cyclobutylsulfamoyl, 3- methanesulfonyl-phenyl, 4-methanesulfonyl-phenyl, benzyloxy, lH-pyrazol-4-yl, 2Η- pyrazol-3-yl, 1 -methyl- lH-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 5 -methyl- 1H- pyrazol-4-yl, 5-methyl-2H-pyrazol-3-yl, l,5-dimethyl-lH-pyrazol-3-yl, 2,5-dimethyl- 2H-pyrazol-3-yl, 2,5-dimethyl-2H-pyrazol-3-ylamino, 3,5-dimethyl-lH-pyrazol-4-yl, l,3,5-trimethyl-lH-pyrazol-4-yl, isoxazol-3-yl, 5-methyl-isoxazol-3-yl, 3- cyclopropyl-isoxazol-5-yl, 5-cyclopropyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 3 ,5-dimethyl-isoxazol-4-ylamino, 5 -methoxymethyl-isoxazol-3 -yl, 5 -ethoxymethyl- isoxazol-3-yl, 5-isopropoxymethyl-isoxazol-3-yl, 5-hydroxymethyl-isoxazol-3-yl, 4- (2-hydroxy-ethyl)-isoxazol-3-yl, 3-methoxymethyl-5-methyl-isoxazol-4-yl, 5- methoxymethyl-3 -methyl-isoxazol-4-yl, 5 -cyclopropyl-3 -methoxymethyl-isoxazol-4- yl, 3-cyclopropyl-5-methoxymethyl-isoxazol-4-yl, (3,5-dimethyl-isoxazol-4- ylmethyl)-methanesulfonyl-amino, 3-metho-xymethyl-isoxazol-5-yl), 3-methyl- isoxazol-5-yl, methanesulfonyl-(5-methyl-isoxazol-3-ylmethyl)-amino, thiazol-2-yl, thiazol-5-yl, methanesulfonyl-thiazol-2-ylmethyl-amino, methanesulfonyl-thiazol-4- ylmethyl-amino, methanesulfonyl-(2-methyl-thiazol-4-ylmethyl)-amino, (4-carboxy- thiazol-2-ylmethyl)-methanesulfonyl-amino, (4-ethoxycarbonyl-thiazol-2-ylmethyl)- methanesulfonyl-amino, pyridin-3-yl, pyridin-4-yl, pyridin-4-ylamino, 6-fluoro- pyridin-3 -yl, methanesulfonyl-pyridin-4-ylmethyl-amino, (6-bromomethyl-pyridin-2- ylmethyl)-methanesulfonyl-amino, pyrrolidin- 1 -yl, pyrrolidin-2-yl, pyrrolidine- 1 - sulfonyl, 3-hydroxy-pyrrolidin-l-yl, 3-hydroxy-pyrrolidine-l-sulfonyl, 5-oxo- pyrrolidin-3-yl, l-acetyl-pyrrolidin-2-yl, l-acetyl-pyrrolidin-3-yl, 1-carbamoyl- pyrrolidin-2-yl, 1 -methylcarbamoyl-pyrrolidin-2-yl, 4-methylcarbamoyl-5-oxo- pyrrolidin-3-yl, 1 -cyclopropanecarbonyl-pyrrolidin-2-yl, 1 -methanesulfonyl- pyrrolidin-2-yl, l-methanesulfonyl-pyrrolidin-3-yl, 3-amino-pyrrolidin-l-yl,3- methanesulfonyl-pyrrolidin-1-yl, lH-pyrrol-2-yl, lH-pyrrol-3-yl, 3-cyano-4-hydroxy- 2-oxo-2,5-dihydro-pyrrol-l-ylmethyl, furan-2-yl, furan-3-yl, (furan-3-ylmethyl)- amino, tetrahydro-furan-3-yl, (tetrahydro-furan-2-ylmethyl)-amino, [ 1,3,4] oxadiazol- 2-yl, [l,2,4]oxadiazol-3-yl, 5 -methyl- [1,2,4] oxadiazol-3 -yl, 5-methyl-
[l,3,4]oxadiazol-2-yl, 5-trifluoromethyl-[l,2,4]oxadiazol-3-yl, morpholin-4-yl, 2,6- dimethyl-morpholin-4-yl, 2-morpholin-4-yl-ethylamino, morpholine-4-sulfonyl, methanesulfonyl-(2-morpholin-4-yl-ethyl)-amino, thiomorpholin-4-yl, thiomorpholine-4-sulfonyl, 1 -oxo-thiomorpholin-4-yl, 1 , 1 -dioxido-isothiazolidin-2-yl, 2-oxo-oxazolidin-5-yl, 5-methyl-2-oxo-oxazolidin-5-yl, oxazol-5-yl, lH-imidazol-4- yl, lH-imidazol-2-yl, 2,5-dioxo-imidazolidin-4-yl, 4-methyl-2,5-dioxo-imidazolidin- 4-yl, pyrimidin-5-yl, 2,5-dimethyl-2Η-[l,2,4]triazol-3-yl, 2-methyl-2H-[l,2,4]triazol- 3-yl, 4H-[l,2,4]triazol-3-yl, 5-methyl-2H-[l,2,4]triazol-3-yl, lH-tetrazol-5-yl, 1- methyl-lH-tetrazol-5-ylmethoxy, methanesulfonyl-(l -methyl- lH-tetrazol-5- ylmethyl)-amino, piperidin- 1 -yl, 4-fluoro-piperidin- 1 -yl, 4,4-difluoro-piperidin- 1 -yl, 3 -hydroxy-piperidin- 1 -yl, 4-hydroxy-piperidin- 1 -yl, 4-hydroxy-piperidine- 1 -sulfonyl, 4-carbamoyl-piperazin-l-yl, 4-methyl-piperazin-l-yl, and 5-chloro-[l,2,4]thiadiazol- 3-ylmethyl; R14, R24, R34, R44, R54, Rό4, and R 4 represent a radical selected from the group consisting of hydrogen and methyl; R15, R-5, R35, R45, R55, Res, and R75 represent a radical selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl; and Rι6, R26, R3β, R46, R56, Rδδ, and R76 represent a radical selected from the group consisting of phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-methoxy-phenyl, 4-hydroxy- phenyl, 4-bromo-phenyl, 2-chloro-phenyl, 2-fluoro-phenyl, 4-fluoro-phenyl, 2,4- difluoro-phenyl, 3,4-difluoro-phenyl, 4-bromo-3-fluoro-phenyl, 3-chloro-4-fluoro- phenyl, 4-chloro-3-fluoro-phenyl, 2,4,5-trifluoro-phenyl, 3-fluoro-4-methyl-phenyl, 4- fluoro-3-methyl-phenyl, 4-fluoro-3-hydroxy-phenyl, 2-ethoxy-4-fluoro-phenyl, 3- trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-cyano-phenyl, 4-amino-phenyl, 4-(acetylamino-methyl)-phenyl, 4-morpholin-4-yl-phenyl, 4-pyrrolidin-l-yl-phenyl, furan-2-yl, furan-3-yl, 3-methyl-furan-2-yl, thiophen-2-yl, 5-chloro-thiophen-2-yl, pyridin-4-yl, and pyridin-3-yl . Preferred compounds of formulas I- VII include the compounds wherein Rn, R22, R32, R42, R52, Rό2, and R72 are -OCH3 or -O(CH)(CH3)2, -CH2CH3, and
Other preferred compounds of formulas I- VII include the compounds wherein Ri5, R25, R35, R45, R5S, Res, and R75 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 R16, R26, R36, Rw, R56, Re6, 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.
According to another aspect, 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.
In accordance with yet another aspect, 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. 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.
As used herein, 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. The term "alkyl" as used herein 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. Similarly, the term "alkyl" or any variation thereof, used in combination form to name substituents, such as alkoxy (-O-alkyl), cycloalkylalkyl (-alkyl-cycloalkyl), arylalkyl (-alkyl-aryl), hydroxyalkyl (-alkyl-OH), monoalkylamino (-NH-alkyl), aminoalkyl (-alkyl-NH2), alkylthio (-S-alkyl), alkylsulfinyl (-S(=O)-alkyl), alkylsulfonyl (-S(O)2-alkyl), alkylsulfonic acid (-O- S(O)2-alkyl), or the like also refers to straight or branched chain aliphatic hydrocarbon radicals of up to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably of 1 to 4 carbon atoms. Also "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 Cβ)" denotes an alkyl group having one to six carbon atoms. The term "alkenyl" as used herein 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. The term "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.
The term "phenyl" as used herein refers to a
group. A "substituted phenyl" refers to a phenyl group that is substituted with the indicated substituents. As used herein, the term "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.
The term "heteroaryl," as used herein, 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. As used herein, the term "cycloalkyl" refers to non-aromatic carbocylic groups, having 3 to 7 carbon atoms, as for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkyloxy," as used herein, refers to a radical or substituent of the formula -O-cycloalkyl, wherein cycloalkyl is as defined above. The term "polyfluoroalkyl," as used herein, refers to an alkyl radical or substituent having one or more fluoro substituents and includes perfluoroalkyl groups. Examples include trifluoromethyl and trifluoroethyl. The term "polyfluoroalkoxy," as used herein, refers to an alkoxy radical or substituent having one or more fluoro substituents and includes perfluoroalkoxy groups. Examples include trifluoromethoxy and trifluoroethoxy. The term "heterocyclic," as used herein, 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. Examples of 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. The term "amido," as used herein, refers to a radical or substituent of the formula
-NR"C(=O)R'", wherein R" and R'" independently represent hydrogen, alkyl, or cycloalkyl. Similarly, the term "amidoalkyl," as used herein, refers to a radical or
substituent of the formula -alkyl-NR"C(= )R'", wherein R" and R'" are as previously defined. The term "alkoxyamido," as used herein, refers to a radical or substituent of the formula -NR"C(= )-alkyl-alkoxy, wherein R", alkyl, and alkoxy are as previously defined. The term "carboxamide," as used herein, refers to a radical or substituent of the formula -C(=O)-NR"R'", wherein R" and R'" are as previously defined. The term "ureido," as used herein, refers to a radical or substituent of the formula -NR' C(=O)-NR"R'", wherein R' represents hydrogen or alkyl and R" and R'" are as previously defined. The term "sulfonamide," as used herein, refers to a radical or substituent of the formula -SO2NR"R'" or-NR"SO2R'", wherein R" and R'" are as previously defined. A substituted sulfonamide, as used herein, refers to a radical or substituent of the formula -N(alkyl)-SO2(alkyl) in which at least one alkyl group is further substituted with the indicated substituents. The term "acetylsulfonylamino," as used herein, refers to a radical or substituent of the formula -N(SO2- R")-(C(=O)CH3), wherein R" is as previously defined. The term "heterocyclosulfonyl," as used herein, refers to a radical or substituent of the formula -SO2 -HET, wherein HET is a heterocyclic group as defined above. Preferred heterocyclosulfonyl groups include pyrrolidinylsulfonyl, piperidinylsulfonyl, morpholinylsulfonyl, and thiomorpholinylsulfonyl. The term "arylamino," as used herein, refers to a radical or substituent of the formula -N(R")-aryl, wherein R" and aryl are as previously defined. A substituted arylamino, as used herein, refers to an arylamino radical or substituent in which the aryl group is further substituted with the indicated substituents. The term "heteroarylamino," as used herein, refers to a radical or substituent of the formula -N(R")-heteroaryl, wherein R" and heteroaryl are as previously defined. A substituted heteroarylamino, as used herein, refers to a heteroarylamino radical or substituent in which the heteroaryl group is further substituted with the indicated substituents. A substituted monoalkylamino, as used herein, refers to a radical or substituent of the formula -NH-alkyl in which the alkyl group is further substituted
with the indicated substituents. Similarly, the term "cycloalkyl-alkylamino," as used herein, 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. The term "carboxyl," as used herein, refers to a radical or substituent of the formula -C(=O)OH. The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", denotes -C(=O) -. The term "alkylcarbonyl," as used herein, refers to a radical or substituent of the formula -C(=O)-alkyl, and includes, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, and pentylcarbonyl. Similarly, the term "cycloalkylcarbonyl," as used herein, refers to a radical or substituent of the formula - C(=O)-cycloalkyl. The term "hydroxyalkylcarbonyl," as used herein, refers to a compound of the formula -C(=O)-alkyl-OH. The term "alkoxycarbonyl," as used herein, refers to a radical or substituent -C(=O)-O-alkyl, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy carbonyl, and pentoxycarbonyl. The term "formyl," as used herein, refers to a radical or substituent of the formula -C(=O)-H. The term "mercapto," as used herein, refers to a radical or substituent of the formula -SH. The term "benzyloxy," as used herein, refers to a radical or substituent of the formula
-OCH2-phenyl. A substituted benzyloxy is a benzyloxy in which the phenyl group is further substituted with the indicated substituents. The term "hexanes," as used herein, 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. The term "halogen," as used herein, refers to a radical or substituent selected from the group consisting of chloro, bromo, iodo, and fluoro. The term "haloalkyl," as used herein, refers to an alkyl group as defined above that is further substituted with a halogen, as defined above.
The term "psig" refers to pounds per square inch gauge. The term "HPLC," as used herein, refers to high-performance liquid chromatography. The term "TLC," as used herein, refers to thin layer chromatography. The term "tautomeric form" as used herein refers two or more isomeric structures formed by migration of a hydrogen atom. The term "amino" as used herein refers to an -NH2 group. The term "2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl" as used herein refers to
a radical or substituent of the formula:
The term "living host" as used herein 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. 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.
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. It is to be further understood that for any particular subject, specific dosage regimens and schedules may be adjusted over time according to the individual's need and the professional judgment of the person administering or supervising the administration of the combination therapy. In a further embodiment, 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. In yet a further embodiment, 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. It is intended that 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. The term "interferon-alpha" as used herein means the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Typical 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 such as those described in U.S. 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. 4,503,901. The term "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. The phrase "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. For example, 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.
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. For example, 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. Pharmaceutical 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. As used herein, "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 (William and Wilkins, Baltimore, MD, 2000) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional
carrier medium is incompatible with the antiviral compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention. In the pharmaceutical compositions of the invention, 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. Preferably, 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. Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known medicament components may all be suitable as carrier media or excipients. The compounds of the invention may be administered using any amount and any route of administration effective for attenuating infectivity of the virus. Thus, the expression "amount effective to attenuate infectivity of virus," as used herein, 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" as used herein 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. Typically, 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. Depending on the route of administration, 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. However, 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. In view of the inhibitory effect on viral RNA synthesis produced by the compounds of the invention, it is anticipated that 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.
Compounds of formulas I- VII, Ia-VIIa, Ib-VIIb or Ic-VIIc, above, described herein may be prepared by the following reaction schemes:
Scheme 1: Benzofuran
Scheme 2 : Benzofuran
Scheme 1: Benzothiophene
2) cat. aq. H2N e, non-protic solvent, reflux
cheme 2: Benzothiophene
Scheme 1: Naphthalene
Scheme 2: Naphthalene
Scheme 3: Naphthalene
Scheme 4: Naphthalene
Scheme 1: Benzimidazole
In the second step, isomers may be separated chromatographically.
Scheme 2: Benzimidazole
Scheme 1: Indole
Aprotic Base
Scheme 2: Indole
Scheme 1: Isoindole
Scheme 2: Isoindole
Any isomers obtained in the second step may be separated by chromatography. Bases used may be metal amides such as LD A.
Scheme 3: Isoindole
Additional methods of synthesis of analogous benzofuran derivatives are exemplified in PCT/US03/34962 of Viropharma Incorporated, filed October 31, 2003, the entire disclosure of which is incorporated by reference herein. By following the synthetic methods referred to above, it should be possible to prepare the compounds of formulas I- VII, Ia-VIIa, Ib-VIIb or Ic-VIIc, having the substituents listed in Table 1, below.
16
Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims.
Claims
What is claimed is:
10 1. A compound selected from the group of those having the formulas:
15
III
IV
10 VII wherein: Rπ, R21, R31, π, R51, Reu and R71 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; Ri2, R22, R32, 42, 52, 62, and R72 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, R53> Rβ3> and R73 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstitutedheterocyclic radical, and - (CH2)-C(=O)-R1; R1 , R24, R34, R 4, R5 , δ4, and R74 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; R15, R25, R35, R , R55, Res, and R75 represent a radical selected from the group consisting of an alkyl (Ci-Cβ) group, cycloalkyl, and cycloalkylalkyl; Ri6, R_63 R36, R46J R-5δ, Rβδ, and R76 represent a radical selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; R! represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy; said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) 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, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof.
2. A compound selected from the group of those having the formulas:
la
Ilia
IVa
R 7 Vila wherein: Rπ, R2ι, R3i, Rn, R51, Rei, and R71 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; Ri2, R22, R32, R42, 52, Rβ2, and R72 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; Ri3a, R23a, R33a, βa, R53a, Rδ3a, and R73a represent a radical selected from the group consisting of a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfmyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and -O(CH2)-C(=O)-R1; R14, R2 , R34, Rt4, R54, Rδ4, and R represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; R15, R25, R35, is, R55, Re5, and R75 represent a radical selected from the group consisting of an alkyl ( -Cβ) group, cycloalkyl, and cycloalkylalkyl; Riό, 26, Ra6, tβ, R-56, Rβδ, and R76 represent a radical selected from the group consisting of a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group; RΪ represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy; said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) 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, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof.
3. A compound selected from the group of those having the formula:
lb
Illb
IVb
4 Vllb wherein: Rπ, R21, R31, Ru, R51, Rβb and R71 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and cyano; Ri2> R22, R32, R42, 52, Re2, 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; o, R23, R33, R43, R53, Rδ3, and R73 represent a radical selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl radical, a substituted or unsubstituted alkoxy group, alkenyl, halogen, hydroxy, polyfluoroalkyl, polyfluoroalkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, amino, a substituted or unsubstituted monoalkylamino, dialkylamino, cyano, amido, alkoxyamido, a substituted or unsubstituted heteroarylamino, acetylsulfonylamino, ureido, carboxamide, sulfonamide, a substituted sulfonamide, a substituted or unsubstituted heterocyclosulfonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfonic acid, a substituted or unsubstituted heterocyclic radical, and -O(CH2)-C(=O)-Ri; R14, R24, R34, R44, R54, Re4, and R74 represent a radical selected from the group consisting of hydrogen, alkyl, halogen, and alkoxy; ( R15, R25, R35, , R55, Rδ5, and R75 represent a radical selected from the group consisting of an alkyl (Cj-C6) group, cycloalkyl, and cycloalkylalkyl; Ri6t>, R_6b, R36b, Rtøb, R56b, Rββb, and R76b represents a radical selected from the group consisting of a substituted aryl group and a substituted or unsubstituted heteroaryl group; Ri represents a radical selected from the group consisting of dialkylamino, a substituted or unsubstituted arylamino, a substituted or unsubstituted heteroarylamino, and a substituted or unsubstituted aryl group, said monoalkylamino substituents being one or more radical(s) independently selected from the group consisting of cycloalkyl, hydroxy, alkoxy, and a substituted or unsubstituted heterocyclic radical; said arylamino substituents and said heteroarylamino substituents being one or more radical(s) independently selected from an alkyl group and an alkoxycarbonyl; said sulfonamide substituents being one or more radical(s) independently selected from the group consisting of alkenyl, cycloalkyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, carboxyl, alkylcarbonyl, alkoxycarbonyl, carboxamide, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclosulfonyl substituents being one or more radical(s) independently selected from the group consisting of alkoxy and hydroxy; said alkyl radical substituents and said alkoxy group substituents being one or more radical(s) independently selected from the group consisting of alkenyl, amino, monoalkylamino, dialkylamino, alkoxy, cycloalkyl, hydroxy, carboxyl, halogen, cyano, polyfluoroalkyl, polyfluoroalkoxy, sulfonamide, carboxamide, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxinyl, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heterocyclic radical; said heterocyclic radical substituents being one or more radical(s) 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, a substituted or unsubstituted aryl group, arylalkyl, and a substituted or unsubstituted heteroaryl group; said heteroaryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, amino, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, cycloalkyl, carboxyl, carboxamide, halogen, polyfluoroalkyl, polyfluoroalkoxy, alkylsulfonyl, mercapto, and oxo; said benzyloxy group substituents being one or more radical(s) independently selected from the group consisting of alkyl, alkoxy, polyfluoroalkyl, polyfluoroalkoxy, hydroxy, carboxyl, alkoxycarbonyl, halogen, cyano, alkylsulfonyl, and phenyl; said aryl group substituents being one or more radical(s) independently selected from the group consisting of alkyl, acetylenyl, alkoxy, hydroxy, halogen, polyfluoroalkyl, polyfluoroalkoxy, cyano, amino, monoalkylamino, dialkylamino, aminoalkyl, alkoxyalkoxy, amido, amidoalkyl, carboxyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, mercapto, and a heterocyclic radical; and pharmaceutically acceptable salts thereof.
4. The compound according to claim 1, wherein Rι5, R25, R35, R^, R55, R65, and R75 represent is methyl.
5. A compound selected from the group of those having the formula:
Ic
IIIc
IVc
VIIc wherein: Rπ, R21, R31, Ru, R51, Rei, and R71 represent a radical selected from the group consisting of hydrogen, methyl, and chloro; R12, R22, R32, R42, R52> R62, and R72 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- butoxycarbonylmethoxy, ethoxy, 2-methoxy-ethoxy, 2-chloro-ethoxy, 2- carboxyethoxy, 2,2,2-trifluoroethoxy, l-(4-fluoro-phenyl)-ethoxy, 2-(4-fluoro- phenyl)-2-oxo-ethoxy, 2-(4-methoxy-phenyl)-2-oxo-ethoxy, propoxy, isopropoxy, 2- oxo-propoxy, 2-hydroxy-propoxy, 3-hydroxy-propoxy, 2-hydroxy-2-methyl-propoxy, 3-bromo-propoxy, 3-ethoxy-propoxy, butoxy, 2-hydroxy-2-methyl-butoxy, cyclopentyloxy, allyloxy, cyano, chloro, fluoro, methanesulfonic acid, benzyloxy, 2- phenylbenzyloxy, 2-difluoromethoxy-benzyloxy, 3-methoxy-benzyloxy, 3- methoxycarbonyl-benzyloxy, 3-carboxy-benzyloxy, 3-cyano-benzyloxy, 4-methoxy- benzyloxy, 4-fluoro-benzyloxy, 4-cyano-benzyloxy, 4-methoxycarbonyl-b'enzyloxy, 4-carboxy-benzyloxy, 4-carboxy-3 -hydroxy-benzyloxy, 4-methanesulfonyl- benzyloxy, 3,4-difluoro-benzyloxy, 3,5-dimethoxy-benzyloxy, 2,2-dimethyl-4-oxo- 4H-benzo[l ,3]dioxin-5-ylmethoxy, 2,2-dimethyl-4-oxo-4H-benzo[l ,3]dioxin-7- ylmethoxy, 2,2-dimethyl-4-oxo-4H-benzo[l,3]dioxin-6-ylmethoxy, 3-chloromethyl- [1 ,2,4]thiadiazol-5-yloxy, 5-chloro-[l ,2,4]thiadiazol-3-ylmethoxy, 5-chloro- [l,2,3]thiadiazol-4-ylmethoxy, 5-p-tolyl-[l,3,4]oxadiazol-2-ylmethoxy, 5-(3,5- dimethyl-isoxazol-4-yl)-[l,2,4]oxadiazol-3-ylmethoxy, 5-(cyclopropylmethyl-amino)- [1 ,2,4]thiadiazol-3 -ylmethoxy, 5-tert-butyl-[l ,2,4]oxadiazol-3-ylmethoxy, 5-(4- methoxy-phenyl)-[l ,2,4]oxadiazol-3 -ylmethoxy, 5-diethylamino-[l ,2,4]thiadiazol-3- ylmethoxy, [1 ,3,4]thiadiazol-2-ylcarbamoylmethoxy, 3,5-dimethyl-isoxazol-4-yl, isoxazol-3-ylmethoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy, 5-methyl-isoxazol-3- ylmethoxy, thiazol-2-ylmethoxy, thiazol-4-ylmethoxy, 2-methyl-thiazol-4-ylmethoxy, l-thiazol-2-yl-ethoxy, thiazol-2-ylcarbamoylmethoxy, (4,5-dimethyl-thiazol-2- ylcarbamoyl)-methoxy , 4-chloro- 1 -methyl- 1 H-pyrazol-3 -ylmethoxy, 2-pyrazol- 1 -yl- ethoxy, 2-(3,5-dimethyl-pyrazol-l-yl)-ethoxy, 4-ethoxycarbonyl-thiazol-2-ylmethoxy, 4-carboxy-thiazol-2-ylmethoxy, 5-amino-4H-[l ,2 ,4]triazol-3 -ylmethoxy, thiophen-2- yl, furan-2-yl, 2-morpholin-4-yl-ethoxy, 3-piperidin-l-yl-propoxy, tetrahydro-furan-2- yl, 1 -methyl- lH-tetrazol-5-ylmethoxy, 1 -methyl- lH-imidazol-2-ylmethoxy, 1-benzyl- lH-imidazol-2-ylmethoxy, 3H-imidazol-4-ylmethoxy, pyridine-4-yl-methoxy, 6- bromomethyl-pyridin-2-ylmethoxy, and 2-(4-cyano-piperidin-l -yl)-ethoxy; Ri35 R23, R33, R43, R53, Rδ3, and R 3 represent a radical selected from the group consisting of hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, 1-hydroxy-ethyl, 1 -hydroxy-2-methyl-ρropyl, 1 -hydroxy- 1 -methyl-ethyl, foπnyl, ureido, vinyl, bromo, chloro, cyano, acetyl, 2-hydroxy-acetyl, carboxy, azetidin-1-yl, carboxylic acid amide, amino, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, tert-butylamino, ethyl-methyl-amino, 2-methoxy-ethylamino, cyclopropylmethyl -amino, 2,3-dihydroxy-propylamino, 1 -methylamino-ethyl, dimethylaminomethyl, 1 -amino- 1 -methyl-ethyl, 2-amino- 1 -hydroxy- 1 -methyl-ethyl, acetylamino, 1-acetylamino-l -methyl-ethyl, (2-methoxy-ethyl)-methyl-amino, ethyl- (2-methoxy-acetyl)-amino, 3-chloro-propane-l-sulfonylamino, methanesulfonylamino, ethyl-methanesulfonyl-amino, isopropyl-methanesulfonyl- amino, isobutyl-methanesulfonyl-amino, cyclobutyl-methanesulfonyl-amino, cyclopentyl-methanesulfonyl-amino, cyclopropylmethyl-methanesulfonyl-amino, (2- hydroxy-ethyl)-methanesulfonyl-amino, (2-hydroxy-propyl)-methanesulfonyl-amino, (2-fluoro-ethyl)-methanesulfonyl-amino, 2-(4-fluoro-phenyl)-2-hydroxy-ethyl]- methanesulfonyl-amino, ( 1 -hy droxymethyl-cyclopropylmethyl)-methanesulfonyl- amino, (4-carboxy-benzyl)-methanesulfonyl-amino, allyl-methanesulfonyl-amino, acetyl-methanesulfonyl-amino, benzyl-methanesulfonyl-amino, carboxymethyl- methanesulfonyl-amino, methanesulfonylamino-methyl, 1 -methanesulfonylamino- 1 - methyl-ethyl, methanesulfonyl-methyl-amino, 1 -(methanesulfonyl-methyl-amino)- ethyl, methanesulfonyl-propyl-amino, methanesulfonyl-(2-methoxy-ethyl)-amino, methanesulfonyl-(2,2,2-trifluoro-ethyl)-amino, methanesulfonyl-(2-oxo-propyl)- amino, methanesulfonyl-(2-trifluoromethoxy-ethyl)-amino, methanesulfonyl-(4- methoxy-benzyl)-amino, methanesulfonyl-(4-methoxycarbonyl-benzyl)-amino, methanesulfonyl-methoxymethyl-amino, methanesulfonyl-methylcarbamoylmethyl- amino, (methanesulfonyl-methyl-amino)-methyl, sulfamoyl, methylsulfamoyl, dimethylsulfamoyl, ethylsulfamoyl, cyclopropylsulfamoyl, cyclobutylsulfamoyl, 3- methanesulfonyl-phenyl, 4-methanesulfonyl-phenyl, benzyloxy, lH-pyrazol-4-yl, 2Η- pyrazol-3-yl, 1 -methyl- lH-pyrazol-3-yl, 2-methyl-2H-pyrazol-3-yl, 5-methyl-lH- pyrazol-4-yl, 5-methyl-2H-pyrazol-3-yl, l,5-dimethyl-lH-pyrazol-3-yl, 2,5-dimethyl- 2H-pyrazol-3 -yl, 2,5-dimethyl-2H-pyrazol-3 -ylamino, 3 ,5-dimethyl- 1 H-pyrazol-4-yl, l,3,5-trimethyl-lH-pyrazol-4-yl, isoxazol-3-yl, 5-methyl-isoxazol-3-yl, 3- cyclopropyl-isoxazol-5-yl, 5-cyclopropyl-isoxazol-3-yl, 3,5-dimethyl-isoxazol-4-yl, 3 , 5 -dimethyl-isoxazol-4-ylamino, 5 -methoxymethyl-isoxazol-3 -yl, 5 -ethoxymethyl- isoxazol-3-yl, 5-isopropoxymethyl-isoxazol-3-yl, 5-hydroxymethyl-isoxazol-3-yl, 4- (2-hydroxy-ethyl)-isoxazol-3-yl, 3-methoxymethyl-5-methyl-isoxazol-4-yl, 5- methoxymethyl-3-methyl-isoxazol-4-yl, 5-cyclopropyl-3-methoxymethyl-isoxazol-4- yl, 3-cyclopropyl-5-methoxymethyl-isoxazol-4-yl, (3,5-dimethyl-isoxazol-4- ylmethyl)-methanesulfonyl-amino, 3-metho-xymethyl-isoxazol-5-yl), 3-methyl- isoxazol-5-yl, methanesulfonyl-(5-methyl-isoxazol-3-ylmethyl)-amino, thiazol-2-yl, thiazol-5-yl, methanesulfonyl-thiazol-2-ylmethyl-amino, methanesulfonyl-thiazol-4- ylmethyl-amino, methanesulfonyl-(2-methyl-thiazol-4-ylmethyl)-amino, (4-carboxy- thiazol-2-ylmethyl)-methanesulfonyl-amino, (4-ethoxycarbonyl-thiazol-2-ylmethyl)- methanesulfonyl-amino, pyridin-3-yl, pyridin-4-yl, pyridin-4-ylamino, 6-fluoro- pyridin-3 -yl, methanesulfonyl-pyridin-4-ylmethyl-amino, (6-bromomethyl-pyridin-2- ylmethyl)-methanesulfonyl-amino, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidine-1- sulfonyl, 3-hydroxy-pyrrolidin-l-yl, 3-hydroxy-pyrrolidine-l-sulfonyl, 5-oxo- pyrrolidin-3-yl, l-acetyl-pyrrolidin-2-yl, l-acetyl-pyrrolidin-3-yl, 1-carbamoyl- pyrrolidin-2-yl, 1 -methylcarbamoyl-pyrrolidin-2-yl, 4-methylcarbamoyl-5-oxo- pyrrolidin-3-yl, 1 -cyclopropanecarbonyl-pyrrolidin-2-yl, 1 -methanesulfonyl- pyrrolidin-2-yl, 1 -methanesulfonyl-pyrrolidin-3 -yl, 3 -amino-pyrrolidin- 1 -yl,3 - methanesulfonyl-pyrrolidin-1-yl, lH-pyrrol-2-yl, lH-pyrrol-3-yl, 3-cyano-4-hydroxy- 2-oxo-2,5-dihydro-pyrrol-l-ylmethyl, furan-2-yl, furan-3-yl, (furan-3 -ylmethyl- amino, tetrahydro-furan-3-yl, (tetrahydro-furan-2-ylmethyl)-amino, [ 1,3,4] oxadiazol- 2-yl, [l,2,4]oxadiazol-3-yl, 5-methyl-[l,2,4]oxadiazol-3-yl, 5-methyl- [l,3,4]oxadiazol-2-yl, 5 -trifluoromethyl- [1,2,4] oxadiazol-3 -yl, morpholin-4-yl, 2,6- dimethyl-morpholin-4-yl, 2-morpholin-4-yl-ethylamino, morpholine-4-sulfonyl, methanesulfonyl-(2-morpholin-4-yl-ethyl)-amino, thiomorpholin-4-yl, thiomo holine-4-sulfonyl, 1 -oxo-thiomoφholin-4-yl, 1 , 1 -dioxido-isothiazolidin-2-yl, 2-oxo-oxazolidin-5-yl, 5-methyl-2-oxo-oxazolidin-5-yl, oxazol-5-yl, lH-imidazol-4- yl, lH-imidazol-2-yl, 2,5-dioxo-imidazolidin-4-yl, 4-methyl-2,5-dioxo-imidazolidin- 4-yl, pyrimidin-5-yl, 2,5-dimethyl-2Η-[l,2,4]triazol-3-yl, 2-methyl-2H-[l,2,4]triazol- 3-yl, 4H-[l,2,4]triazol-3-yl, 5-methyl-2H-[l,2,4]triazol-3-yl, lH-tetrazol-5-yl, 1- methyl- 1 H-tetrazol-5 -ylmethoxy, methanesulfonyl-( 1 -methyl- 1 H-tetrazol-5 - ylmethyl)-amino, piperidin-1-yl, 4-fluoro-piperidin-l-yl, 4,4-difluoro-piperidin- 1-yl, 3 -hydroxy-piperidin- 1 -yl, 4-hydroxy-piperidin- 1 -yl, 4-hydroxy-piperidine- 1 -sulfonyl, 4-carbamoyl-piperazin-l-yl, 4-methyl-piperazin-l-yl, and 5 -chloro- [l,2,4]thiadiazol- 3-ylmethyl; R14, R24, R34, Rι4, R5 , Rό4, and R74 represent a radical selected from the group consisting of hydrogen and methyl; R15, R25, R35, R45, R55, Res, and R75 represent a radical selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl; Ri6, R.6, R36, R46, R565 Rβδ, and R76 represent a radical selected from the group consisting of phenyl, 4-methyl-phenyl, 4-ethyl-phenyl, 4-methoxy-phenyl, 4-hydroxy- phenyl, 4-bromo-phenyl, 2-chloro-phenyl, 2-fluoro-phenyl, 4-fluoro-phenyl, 2,4- difluoro-phenyl, 3,4-difluoro-phenyl, 4-bromo-3-fluoro-phenyl, 3-chloro-4-fluoro- phenyl, 4-chloro-3-fluoro-phenyl, 2,4,5-trifluoro-phenyl, 3-fluoro-4-methyl-phenyl, 4- fluoro-3-methyl-phenyl, 4-fluoro-3-hydroxy-phenyl, 2-ethoxy-4-fluoro-phenyl, 3- trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-cyano-phenyl, 4-amino-phenyl, 4-(acetylamino-methyl)-phenyl, 4-morpholin-4-yl-phenyl, 4-pyrrolidin-l -yl-phenyl, furan-2-yl, furan-3-yl, 3-methyl-furan-2-yl, thiophen-2-yl, 5-chloro-thiophen-2-yl, pyridin-4-yl, and pyridin-3-yl and pharmaceutically acceptable salts thereof.
6. The compound according to claim 1, wherein the pharmaceutically acceptable salt is selected from hydrocholoric, sulfuric, acetic, lactic, sodium, potassium, piperidine, or ammonium.
7. The compound according to claim 6, wherein in the pharmaceutically acceptable salt is a potassium salt or a sodium salt.
8. A composition for prophylaxis or treatment of viral infections, said composition comprising a compound as claimed in claim 1, in an amount effective to attenuate viral infectivity, and a pharmaceutically acceptable carrier medium.
9. A composition according to claim 8 further comprising at least one supplemental agent selected from the group of interferon, 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.
10. A method for prophylaxis or treatment of hepatitis C infections and diseases associated with such infections in a living host having said infections, said method comprising administering to said living host a therapeutically effective amount of a compound according to claim 1.
11. The method according to claim 10, wherein said living host is a mammal.
12. The method according to claim 11 , wherein said living host is a human.
13. The method according to claim 10, wherein the compound is administered orally.
14. The method according to claim 13, wherein the compound is administered orally at a dose range of about 0.05 to about 100 mg/kg.
15. The method according to claim 14, wherein the compound is administered from 1 to 4 times daily.
16. The method according to claim 10, wherein the compound is administered in combination, either concurrently or sequentially, with at least one other biologically active agent.
17. The method according to claim 16 wherein said other biologically active agent is selected from the group consisting of interferon, 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.
Applications Claiming Priority (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57101904P | 2004-05-13 | 2004-05-13 | |
| US57113004P | 2004-05-13 | 2004-05-13 | |
| US57118804P | 2004-05-13 | 2004-05-13 | |
| US57145404P | 2004-05-13 | 2004-05-13 | |
| US57145304P | 2004-05-13 | 2004-05-13 | |
| US57144804P | 2004-05-13 | 2004-05-13 | |
| US57298204P | 2004-05-20 | 2004-05-20 | |
| US57281404P | 2004-05-20 | 2004-05-20 | |
| US57280504P | 2004-05-20 | 2004-05-20 | |
| US57281604P | 2004-05-20 | 2004-05-20 | |
| US57284004P | 2004-05-20 | 2004-05-20 | |
| US57281704P | 2004-05-20 | 2004-05-20 | |
| US57279604P | 2004-05-20 | 2004-05-20 | |
| US57354004P | 2004-05-21 | 2004-05-21 | |
| PCT/US2005/016867 WO2005112640A2 (en) | 2004-05-13 | 2005-05-13 | Compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases |
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| Publication Number | Publication Date |
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| EP1746888A2 true EP1746888A2 (en) | 2007-01-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| EP05748433A Withdrawn EP1746888A2 (en) | 2004-05-13 | 2005-05-13 | Compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases |
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| Country | Link |
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| WO (1) | WO2005112640A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| MX2009008439A (en) * | 2007-02-12 | 2009-08-13 | Intermune Inc | Novel inhibitors hepatitis c virus replication. |
| GB0707000D0 (en) * | 2007-04-12 | 2007-05-30 | Istituto Di Ricerche D Biolog | Antiviral agents |
| EP2142215B1 (en) | 2007-05-04 | 2012-03-07 | Vertex Pharmceuticals Incorporated | Combination therapy for the treatment of hcv infection |
| US8324212B2 (en) * | 2010-02-25 | 2012-12-04 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| SG189985A1 (en) | 2010-10-26 | 2013-06-28 | Presidio Pharmaceuticals Inc | Inhibitors of hepatitis c virus |
| CA2822357A1 (en) | 2010-12-22 | 2012-06-28 | Abbvie Inc. | Hepatitis c inhibitors and uses thereof |
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| JPS60233642A (en) * | 1984-05-07 | 1985-11-20 | Fuji Photo Film Co Ltd | Photographic image forming method |
| IL109568A0 (en) * | 1993-05-19 | 1994-08-26 | Fujisawa Pharmaceutical Co | Urea derivatives, pharmaceutical compositions containing the same and processes for the preparation thereof |
| ES2382377T3 (en) * | 2003-05-30 | 2012-06-07 | Gemin X Pharmaceuticals Canada Inc. | Triheterocyclic compounds, compositions, and methods of treating cancer |
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2005
- 2005-05-13 EP EP05748433A patent/EP1746888A2/en not_active Withdrawn
- 2005-05-13 WO PCT/US2005/016867 patent/WO2005112640A2/en not_active Ceased
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| See references of WO2005112640A3 * |
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| WO2005112640A2 (en) | 2005-12-01 |
| WO2005112640A3 (en) | 2007-03-29 |
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