US20120295843A1 - Combination therapy for the treatment of hcv infection - Google Patents
Combination therapy for the treatment of hcv infection Download PDFInfo
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- US20120295843A1 US20120295843A1 US13/564,286 US201213564286A US2012295843A1 US 20120295843 A1 US20120295843 A1 US 20120295843A1 US 201213564286 A US201213564286 A US 201213564286A US 2012295843 A1 US2012295843 A1 US 2012295843A1
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- AFDCDDUWKSMTFV-UHFFFAOYSA-N CCN(CC)C1CCN(C(=O)CN2C3=C(C=CC(C(=O)O)=C3)C(C3CCCCC3)=C2C2=CC=C(Cl)C=C2)CC1 Chemical compound CCN(CC)C1CCN(C(=O)CN2C3=C(C=CC(C(=O)O)=C3)C(C3CCCCC3)=C2C2=CC=C(Cl)C=C2)CC1 AFDCDDUWKSMTFV-UHFFFAOYSA-N 0.000 description 3
- PPUDLEUZKVJXSZ-VPCXQMTMSA-N C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=CC(N)=NC1=O Chemical compound C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=CC(N)=NC1=O PPUDLEUZKVJXSZ-VPCXQMTMSA-N 0.000 description 2
- XWBQMUCPNPVEKU-UHFFFAOYSA-N O=C1C(C2=NS(=O)(=O)C3=CC=CC=C3N2)=C(O)C2=C(C=CC=C2)N1NC1CCC1 Chemical compound O=C1C(C2=NS(=O)(=O)C3=CC=CC=C3N2)=C(O)C2=C(C=CC=C2)N1NC1CCC1 XWBQMUCPNPVEKU-UHFFFAOYSA-N 0.000 description 2
- PCYMKFZSWDBCSP-PKPRSWTISA-N [H][C@]12CCC[C@@]1([H])CN(C(=O)[C@@H](CC(=O)[C@@H](NC(=O)C1=NC=CN=C1)C1CCCCC1)C(C)(C)C)[C@@H]2C(=O)C[C@@H](CCC)C(=O)C(=O)CC1CC1 Chemical compound [H][C@]12CCC[C@@]1([H])CN(C(=O)[C@@H](CC(=O)[C@@H](NC(=O)C1=NC=CN=C1)C1CCCCC1)C(C)(C)C)[C@@H]2C(=O)C[C@@H](CCC)C(=O)C(=O)CC1CC1 PCYMKFZSWDBCSP-PKPRSWTISA-N 0.000 description 2
- BBAWEDCPNXPBQM-GDEBMMAJSA-N CCC[C@@H](C(C(NC1CC1)=O)=O)NC([C@H]([C@@H](CCC1)[C@@H]1C1)N1C([C@H](C(C)(C)C)NC([C@H](C1CCCCC1)NC(c1cnccn1)=O)=O)=O)=O Chemical compound CCC[C@@H](C(C(NC1CC1)=O)=O)NC([C@H]([C@@H](CCC1)[C@@H]1C1)N1C([C@H](C(C)(C)C)NC([C@H](C1CCCCC1)NC(c1cnccn1)=O)=O)=O)=O BBAWEDCPNXPBQM-GDEBMMAJSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- HCV hepatitis C virus
- the HCV genome encodes a polyprotein of 3010-3033 amino acids [Q. L. Choo, et. al., “Genetic Organization and Diversity of the Hepatitis C Virus,” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato et al., “Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers,” J.
- the HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication.
- the NS proteins are derived by proteolytic cleavage of the polyprotein [R. Bartenschlager et. al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67, pp. 3835-3844 (1993); A. Grakoui et.
- the HCV NS protein 3 contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decrease viral infectivity [Chambers, T. J. et. al., “Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein,” Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)].
- the first 181 amino acids of NS3 have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157 (1994)].
- HCV NS3 serine protease and its associated cofactor, NS4A help process all of the viral enzymes, and are thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing. HIV protease inhibitors, which inhibit viral protein processing, are potent antiviral agents in man indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently HCV NS3 serine protease is also an attractive target for drug discovery.
- Such inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors. Specifically, such compounds may be useful as antiviral agents, particularly as anti-HCV agents.
- This invention relates to therapeutic combinations comprising VX-950 and a polymerase inhibitor.
- the invention also relates to methods of treating HCV infection or alleviating one or more symptoms thereof in a patient, comprising administering to said patient a therapeutic combination of the present invention.
- compounds of the invention may optionally be substituted with one or more substituents, or as exemplified by particular classes, subclasses, and species of the invention.
- patient refers to a mammal, including a human.
- polymerase inhibitor refers to compounds that inhibit the activity of HCV RNA dependent RNA polymerase (RdRp).
- Polymerase inhibitors of the following invention include, but are not limited to, the compounds of formula I, II and III.
- the polymerase inhibitor can be a nucleoside or non-nucleoside inhibitor.
- a nucleoside polymerase inhibitor binds to the substrate of the enzyme; whereas, the polymerase non-nucleoside binds to different site while still inhibiting the enzyme, e.g., an allosteric inhibitor.
- protease inhibitor refers to means an agent (compound or biological) that is effective to inhibit the function of HCV NS3 protease in a mammal.
- Protease inhibitors of the following invention include, but are not limited to, VX-950.
- VX-950 refers to an HCV inhibitor shown below and described in PCT Publication Number WO 02/18369, which is incorporated herein by reference in its entirety.
- therapeutic combination means a combination of one or more active drug substances, i.e., compounds having a therapeutic utility.
- each such compound in the therapeutic combinations of the present invention will be present in a pharmaceutical composition comprising that compound and a pharmaceutically acceptable carrier.
- the compounds in a therapeutic combination of the present invention may be administered simultaneously or separately, as part of a regimen.
- structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
- Such compounds are useful, for example, as analytical tools or probes in biological assays.
- the present invention relates to therapeutic combinations comprising a protease inhibitor and a polymerase inhibitor for the treatment of HCV.
- the protease inhibitor is VX-950.
- VX-950 an HCV inhibitor with its structure shown below is such a compound in need.
- VX-950 is described in PCT Publication Number WO 02/18369, which is incorporated herein by reference in its entirety.
- VX-950 a potent and specific NS3-4A protease inhibitor demonstrated substantial antiviral activity in a phase 1b trial of subjects infected with HCV genotype 1 (Study VX04-950-101).
- the degree to which a subject responds to treatment and the rate at which viral rebound is observed could in part be due to genotypic differences in sensitivity to the protease inhibitor.
- Mutations resistant to the protease inhibitor BILN 2061 have been found at positions R155Q, A156T, and D168V/A/Y in the NS3 gene, but no mutations have yet been observed in the NS4 region or in the protease cleavage sites.
- a VX-950 resistance mutation has also been found in vitro at position A156S.
- Cross-resistant mutations against both VX-950 and BILN 2061 have also been shown to develop in vitro at position 156 (A156V/T) (Lin et al., 2005, supra).
- the protease inhibitor is described in international patent application publication number WO2007/025307, the entire contents of which is incorporated herein.
- the protease inhibitor is described in one or more of the following publications: WO1997/43310, US20020016294, WO2001/81325, WO2002/08198, WO2001/77113, WO2002/08187, WO2002/08256, WO2002/08244, WO2003/006490, WO2001/74768, WO1999/50230, WO1998/17679, WO2002/48157, US20020177725, WO2002/060926, US20030008828, WO2002/48116, WO2001/64678, WO2001/07407, WO1998/46630, WO2000/59929, WO1999/07733, WO2000/09588, US20020016442, WO2000/09543, WO1999/07734, U.S.
- the polymerase inhibitors can be a nucleoside or a non-nucleoside inhibitor.
- the polymerase inhibitor is the compound of formula (I)
- the polymerase inhibitor is the compound of formula (II)
- the polymerase inhibitor is the compound of formula (III)
- the invention provides a therapeutic combination of VX-950 and the polymerase inhibitor of compound (I)
- the invention provides a therapeutic combination of VX-950 and the polymerase inhibitor of compound (II)
- the invention provides a therapeutic combination of VX-950 and the polymerase inhibitor of compound (III)
- the polymerase inhibitor is selected from the inhibitors known in the art.
- the polymerase inhibitor is described in one or more of the following international patent application publications: WO2008/011337; WO2006/093801; WO2005/019191; WO2004/041818; WO2007/150001; WO2006/066079; WO2006/137706; WO2006/011719; WO2004/108719; WO2004/108068; WO2004/033450; WO2003/084953; WO2008/019477; WO2007/019674; WO2006/007693; WO2005/080388; WO2004/065367; WO2004/064925; WO2003/010141; WO2003/010140; WO2003/007945; WO2002/004425; WO2008/021928; WO2008/021927; WO2007/143521; WO2006/020082; WO2004/014852;
- the polymerase inhibitor is described in one or more of the following U.S. patent application publications: US2004167123; US2004162285; US20040097492; US20040087577; US20070275947; US20070275930; US20070270406; US20070270405; US2005075376; US20070032488; US20030050320; US2005154056; US2006040927; US2006094706; US2006258682; US2006223834; US2006217390; US2006019976; US2005107364; US2006183751; US2006063821; and US2005176701.
- the entire content of each of the foregoing publications is incorporated herein in its entirety.
- polymerase inhibitor is described in U.S. Pat. No. 7,112,600 or European Patent No. EP 1321463. The entire content of each of the foregoing publications is incorporated herein.
- the polymerase inhibitor is selected from A-837093, being developed by Abbott Laboratories; GS-9190, being developed by Gilead Sciences; PF-868 and PF-554, being developed by Pfizer; R1479, R1626 (prodrug of R1479), R7128, and R1728, being developed by Roche Pharmaceuticals; PST 7081, being developed by Pharmasset and Roche Pharmaceuticals; IDX102, IDX184, NM107, NM283 (prodrug of NM107) called Valopicitabine, being developed by Idenix; and VCH-916 and VCH-759, being developed by ViroChem; and HCV-796, being developed by Wyeth.
- Other polymerase inhibitors are in development by Genelabs; Boehringer Ingelheim; Anadys; Celera; Schering; and Medavir.
- kits for use in treating HCV infection in a patient comprise any one of the therapeutic combinations of the present invention.
- the kits further comprise instructions for utilizing the therapeutic combinations.
- the kits may be tailored to the needs of classes or types of patients or other clinically relevant factors such as age, body weight, concomitant diseases/conditions, severity and stage of HCV infection, responsiveness or non-responsiveness to prior treatments, propensity for side effects, etc.
- the therapeutic combination in a kit may be tailored for dosages suitable for patients having a body weight of, e.g., 75 kg.
- the therapeutic combination in a kit may be tailored for dosages suitable for patients having a body weight of, e.g., less than or equal to 75 kg.
- the therapeutic combination in a kit may be tailored for pediatric use, wherein the dosage for children is varied depending on factors such as age, body weight, severity of disease, etc.
- the present invention provides a kit comprising: (i) a plurality of VX-950 compositions; (ii) a plurality of polymerase inhibitor compositions; and (iii) instructions for utilizing the above compositions.
- the invention provides methods of using the therapeutic combinations of the present invention for treating HCV infection or alleviating one or more symptoms thereof in a patient.
- the HCV infection is genotype.
- the patient is a treatment na ⁇ ve patient.
- the patient is non-responsive to interferon monotherapy.
- the patient is non-responsive to combination therapy using ribaviron and an interferon.
- the invention provides a method of reducing HCV-RNA levels in a patient in need thereof, comprising the step of administering to said patient a therapeutic combination of the present invention.
- the HCV-RNA levels in the patient are reduced to a less than detectable level.
- the invention provides a pharmaceutical regimen comprising administering to a patient in need thereof a therapeutic combination of the present invention until the HCV-RNA level in the patient is below a detectable level.
- salts of the compounds of this invention are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, oxalate, pamoate
- Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N methyl D glucamine, and salts with amino acids such as arginine, lysine, and so forth.
- the basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil soluble or dispersible products are thereby obtained.
- lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
- dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
- long chain halides such
- compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties.
- modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat.
- ion exchangers alumina, aluminum stearate, lecithin
- serum proteins such as human serum albumin
- buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride
- the therapeutic combinations of this invention are formulated for pharmaceutical administration to a mammal.
- said mammal is a human being.
- compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra articular, intra synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the compositions are administered orally or intravenously.
- Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- dosage levels of between about 0.01 and about 100 mg/kg body weight per day of VX-950 are useful in a combination therapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
- dosage levels of between about 0.5 and about 75 mg/kg body weight per day of VX-950 are useful in a combination therapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w). In one embodiment, such preparations contain from about 20% to about 80% active compound.
- dosage levels of between about 0.01 and about 100 mg/kg body weight per day of the polymerase inhibitor compounds described herein are useful in a combination for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
- dosage levels of between about 0.5 and about 75 mg/kg body weight per day of the polymerase inhibitor compounds described herein are useful in a combination therapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5% to about 95% active compound (w/w). In one embodiment, such preparations contain from about 20% to about 80% active compound.
- compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers that are commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- compositions of this invention may be administered in the form of suppositories for rectal administration.
- suppositories may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
- compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.
- the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
- the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
- the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
- compositions of this invention may also be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- the therapeutic combination of this invention may additionally comprise another anti-viral agent, preferably an anti-HCV agent.
- anti-viral agents include, but are not limited to, immunomodulatory agents, such as alpha, beta, and gamma-interferons, pegylated derivatized interferon-alpha compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase and other polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., compounds of U.S.
- the present invention provides a method of treating HCV infection or alleviating one or more symptoms thereof, in a patient, comprising administering a composition comprising a polymerase inhibitor of Formula I, II or III.
- a composition comprising a polymerase inhibitor of Formula I, II or III.
- the patient is infected by an HCV variant.
- the composition further comprises VX-950.
- the present invention provides a method of treating HCV infection or alleviating one or more symptoms thereof, in a patient, comprising administering a composition comprising a polymerase inhibitor of Formula I, II, or III, and VX-950.
- a composition comprising a polymerase inhibitor of Formula I, II, or III, and VX-950.
- the patient is infected by an HCV variant.
- the present invention provides a method of eliminating or reducing HCV infection in a cell, comprising administering a composition comprising a polymerase inhibitor of Formula I, II or III.
- a composition comprising a polymerase inhibitor of Formula I, II or III.
- the cell contains an HCV variant.
- the composition further comprises VX-950.
- the present invention provides a method of eliminating or reducing HCV infection in a cell, comprising administering a composition comprising a polymerase inhibitor of Formula I, II or III and VX-950.
- the cell contains an HCV variant.
- PEG-Intron means PEG-INTRON®, peginteferon alfa-2b, available from Schering Corporation, Kenilworth, N.J.;
- Intron means INTRON-A®, interferon alfa-2b available from Schering Corporation, Kenilworth, N.J.;
- ribavirin means ribavirin 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; described in the Merck Index, entry 8365, Twelfth Edition; also available as REBETROL® from Schering Corporation, Kenilworth, N.J., or as COPEGASUS® from Hoffmann-La Roche, Nutley, N.J.;
- Pegasys means PEGASYS®, peginterferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.;
- ROFERON® recombinant interferon alfa-2a available from Hoffmann-La Roche, Nutley, N.J.;
- Berefor means BEREFOR®, interferon alfa 2 available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.;
- SUMIFERON® a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan;
- WELLFERON® interferon alpha n1 available from Glaxo Wellcome LTd., Great Britain;
- ALFERON® a mixture of natural alpha interferons made by Interferon Sciences, and available from Purdue Frederick Co., CT.
- interferon means a member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, and modulate immune response, such as interferon alpha, interferon beta, or interferon gamma.
- the therapeutic combination of the present invention may utilize natural alpha interferon 2a.
- the therapeutic combination of the present invention may utilize natural alpha interferon 2b.
- the therapeutic combination of the present invention may utilize recombinant alpha interferon 2a or 2b.
- the invention may utilize pegylated alpha interferon 2a or 2b.
- Interferons suitable for the present invention include:
- protease and polymerase inhibitors would be preferably administered orally. Interferon is not typically administered orally. Nevertheless, nothing herein limits the methods or combinations of this invention to any specific dosage forms or regime. Thus, each component of a combination according to this invention may be administered separately, together, or in any combination thereof.
- the protease inhibitor and polymerase inhibitor are administered in separate dosage forms.
- any additional agent is administered as part of a single dosage form with the protease inhibitor or as a separate dosage form.
- the specific amounts of each compound may be dependent on the specific amounts of each other compound in the combination.
- dosages of interferon are typically measured in IU (e.g., about 4 million IU to about 12 million IU).
- non-immunomodulatory or immunomodulatory compounds may be used in combination with a compound of this invention including, but not limited to, those specified in WO 02/18369, which is incorporated herein by reference (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11).
- This invention may also involve administering a cytochrome P450 monooxygenase inhibitor.
- CYP inhibitors may be useful in increasing liver concentrations and/or increasing blood levels of compounds that are inhibited by CYP.
- any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in a method of this invention.
- CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
- Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole.
- ritonavir see U.S. Pat. No. 6,037, 157, and the documents cited therein: U.S. Pat. No. 5,484,801, U.S. patent Application Ser. No. 08/402,690, and International Applications WO 95/07696 and WO 95/09614).
- a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
- the amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti-viral agent in the composition.
- the invention provides a method for treating a patient infected with a virus characterized by a virally encoded serine protease that is necessary for the life cycle of the virus by administering to said patient a pharmaceutically acceptable composition of this invention.
- the methods of this invention are used to treat a patient suffering from an HCV infection. Such treatment may completely eradicate the viral infection or reduce the severity thereof.
- the patient is a human being.
- the methods of this invention may additionally comprise the step of administering to said patient an anti-viral agent, preferably an anti-HCV agent.
- anti-viral agents include, but are not limited to, immunomodulatory agents, such as alpha-, beta-, and gamma-interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including but not limited to helicase and other polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in U.S. Pat. Nos. 5,807,876 and 6,498,178, mycophenolic
- Such additional agent may be administered to said patient as part of a single dosage form comprising both a compound of this invention and an additional anti-viral agent.
- the additional agent may be administered separately from the compound of this invention, as part of a multiple dosage form, wherein said additional agent is administered prior to, together with or following a composition comprising a compound of this invention.
- the present invention may also be utilized as a method of pre-treating a biological substance intended for administration to a patient comprising the step of contacting said biological substance with a pharmaceutically acceptable composition comprising a compound of this invention.
- biological substances include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, etc; sperm and ova; bone marrow and components thereof, and other fluids to be infused into a patient such as saline, dextrose, etc.
- the invention may also be utilized as a method of treating materials that may potentially come into contact with a virus characterized by a virally encoded serine protease necessary for its life cycle.
- This method comprises the step of contacting said material with a compound according to the invention.
- materials include, but are not limited to, surgical instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratory instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); blood collection apparatuses and materials; and invasive devices, such as, for example, shunts and stents.
- Huh-7 cells were propagated in Dulbecco's modified Eagle's medium (DMEM, JRH Biosciences, Lenexa, Kans.) supplemented with 10% heat-inactivated FBS (fetal bovine serum), 2 mM L-glutamine, and nonessential amino acids (JRH).
- DMEM Dulbecco's modified Eagle's medium
- FBS fetal bovine serum
- JRH nonessential amino acids
- HCV NS3 protease variant replicons were constructed in the background of the mADE wild-type replicon as described previously [Chao Lin et al., “In Vitro Resistance Studies of Hepatitis C Virus Serine Protease Inhibitors, VX-950 and BILN 2061: Structural Analysis Indicates Different Resistance Mechanisms,” Journal of Biological Chemistry, 279(17); pp. 17508-17514 (2004)].
- the replicon cells were propagated in DMEM supplemented with 10% FBS, 2 mM L-glutamine, nonessential amino acids, and 250 ⁇ g/mL G418. The cells were split twice per week in fresh media upon reaching confluence. There are approximately 200-300 copies of HCV RNA per 24-2 replicon cell.
- HCV replicon RNA from cells was measured using the Quantigene Discover XL kit (Panomics Inc., Fremont Calif.) as per the manufacturer's instructions. Briefly, compound-treated replicon cells were lysed and immobilized on to capture plates using HCV specific oligonucleotides (designed based on the 5′ UTR region of HCV 1b genome sequence AJ238799 in the GenBank database) over night and the relative amounts of captured RNA was measured using oligonucleotide probe sets as per the manufacturer's instructions.
- the replicon cells were incubated with the antiviral agents for 48 h.
- HCV replicon RNA from cells was measured using the Quantigene Discover XL kit (Panomics Inc., Fremont Calif.) as per the manufacturer's instructions. Briefly, compound-treated replicon cells were lysed and immobilized onto capture plates using HCV specific oligonucleotides overnight and the relative amounts of captured RNA was measured using oligonucleotide probe sets as per the manufacturer's instructions. Unless indicated otherwise, each data point represents the average of three replicates.
- the IC 50 is the concentration of the compound at which the HCV replicon RNA level in cells is reduced by 50% as compared to the untreated replicon cell controls.
- replicon cells were treated with serially diluted compounds for 48 h, after which cell viability was determined using a CellTiter Glo assay (Promega, Madison, Wis.).
- Each CC 50 is derived from at least two replicates and is the concentration of the compound at which the number of viable cells is reduced by 50% as compared to untreated cell controls.
- the IC 50 and CC 50 was determined using 4-parameter curve fitting in the SoftMax Pro program (Molecular Devices, Sunnyvale, Calif.).
- the theoretical additive surface is subtracted from the actual experimental surface, resulting in a surface that would appear as a horizontal plane at 0% inhibition if the combination were merely additive. Any peak above this plane would indicate synergy, whereas any depression below it would indicate antagonism.
- the 95% confidence intervals for the experimental dose-response surface are used to evaluate the data statistically.
- the volume of the peak or depression is calculated to quantify the overall synergy or antagonism produced.
- therapeutic combinations of the present invention are determined to be useful HCV replication inhibitors.
- the sensitivity of NS3 protease variants to ribavirin and interferon was assessed in a 2-Day HCV Replicon IC 50 Assay.
- the variants are as follows: at position 36, the wild-type valine was mutated to an alanine (V36A) or a methionine (V36M), the wild-type threonine at position 54 was mutated to an alanine (T54A), the wild-type arginine at position 155 was mutated to lysine (R155K), the wild-type arginine at position 155 was mutated to threonine (R155T) and the wild-type arginine at position 155 was mutated to methionine (R155M).
- the results indicate the sensitivity of the variants to ribavirin and interferon.
- the fold change is the ratio of NS3 protease mutant IC50 to that of the Wild type IC50 for the same inhibitor.
- the sensitivity of replicons with the wild-type alanine at position 156 mutated to threonine (A156T) and the wild-type alanine at position 156 mutated to valine (A156V) is comparable to the wild-type (Lin, et al., 2005, supra).
- the variants are as follows: at position 36, the wild-type valine was mutated to an alanine (V36A) or a methionine (V36M), the wild-type threonine at position 54 was mutated to an alanine (T54A), the wild-type arginine at position 155 was mutated to lysine (R155K), the wild-type alanine at position 156 was mutated to threonine (A156T) and the wild-type alanine at position 156 was mutated to valine (A156V).
- the variant, V36M+R155K, having two mutations was also tested. As shown in Table 8, the results indicate the sensitivity of the variants to VX-950 and to Formula I, II and III.
- the fold change is the ratio of NS3 protease mutant IC50 to that of the Wild type IC50 for the same inhibitor.
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Abstract
The present invention relates to therapeutic combinations comprising a protease inhibitor and a polymerase inhibitor for the treatment of HCV. The present invention also relates to therapeutic combinations comprising VX-950 and a polymerase inhibitor. Also within the scope of the invention are methods using the therapeutic combinations of the present invention for treating HCV infection or alleviating one or more symptoms thereof in a patient. The present invention also provides kits comprising the combinations of the present invention.
Description
- This application claims priority to U.S. provisional applications Ser. Nos. 60/927,581, filed May 4, 2007, and 60/931,425, filed May 23, 2007, the contents of which are incorporated herein by reference in their entireties.
- Infection by hepatitis C virus (“HCV”) is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis, with an estimated human sero-prevalence of 3% globally [A. Alberti et al., “Natural History of Hepatitis C,” J. Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)]. Nearly four million individuals may be infected in the United States alone [M. J. Alter et al., “The Epidemiology of Viral Hepatitis in the United States, Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter “Hepatitis C Virus Infection in the United States,” J. Hepatology, 31, (Suppl. 1), pp. 88-91 (1999)].
- Upon first exposure to HCV only about 20% of infected individuals develop acute clinical hepatitis while others appear to resolve the infection spontaneously. In almost 70% of instances, however, the virus establishes a chronic infection that persists for decades [S. Iwarson, “The Natural Course of Chronic Hepatitis,” FEMS Microbiology Reviews, 14, pp. 201-204 (1994); D. Lavanchy, “Global Surveillance and Control of Hepatitis C,” J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usually results in recurrent and progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma [M. C. Kew, “Hepatitis C and Hepatocellular Carcinoma”, FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saito et. al., “Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma,” Proc. Natl. Acad. Sci. USA, 87, pp. 6547-6549 (1990)]. Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.
- The HCV genome encodes a polyprotein of 3010-3033 amino acids [Q. L. Choo, et. al., “Genetic Organization and Diversity of the Hepatitis C Virus,” Proc. Natl. Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato et al., “Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis,” Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al., “Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers,” J. Virol., 65, pp. 1105-1113 (1991)]. The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The NS proteins are derived by proteolytic cleavage of the polyprotein [R. Bartenschlager et. al., “Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions,” J. Virol., 67, pp. 3835-3844 (1993); A. Grakoui et. al., “Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites,” J. Virol., 67, pp. 2832-2843 (1993); A. Grakoui et. al., “Expression and Identification of Hepatitis C Virus Polyprotein Cleavage Products,” J. Virol., 67, pp. 1385-1395 (1993); L. Tomei et. al., “NS3 is a serine protease required for processing of hepatitis C virus polyprotein”, J. Virol., 67, pp. 4017-4026 (1993)].
- The HCV NS protein 3 (NS3) contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decrease viral infectivity [Chambers, T. J. et. al., “Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein,” Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. The first 181 amino acids of NS3 (residues 1027-1207 of the viral polyprotein) have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al., “Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics”, J. Virol., 68, pp. 8147-8157 (1994)].
- The HCV NS3 serine protease and its associated cofactor, NS4A, help process all of the viral enzymes, and are thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing. HIV protease inhibitors, which inhibit viral protein processing, are potent antiviral agents in man indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently HCV NS3 serine protease is also an attractive target for drug discovery.
- Until recently, the only established therapy for HCV disease was interferon treatment. However, interferons have significant side effects [M. A. Wlaker et al., “Hepatitis C Virus: An Overview of Current Approaches and Progress,” DDT, 4, pp. 518-29 (1999); D. Moradpour et al., “Current and Evolving Therapies for Hepatitis C,” Eur. J. Gastroenterol. Hepatol., 11, pp. 1199-1202 (1999); H. L. A. Janssen et al. “Suicide Associated with Alfa-Interferon Therapy for Chronic Viral Hepatitis,” J. Hepatol., 21, pp. 241-243 (1994); P. F. Renault et al., “Side Effects of Alpha Interferon,” Seminars in Liver Disease, 9, pp. 273-277 (1989)] and induce long term remission in only a fraction (˜25%) of cases [O. Weiland, “Interferon Therapy in Chronic Hepatitis C Virus Infection”, FEMS Microbiol. Rev., 14, pp. 279-288 (1994)]. Recent introductions of the pegylated forms of interferon (PEG-INTRON® and PEGASYS®) and the combination therapy of ribavirin and pegylated interferon (REBETROL®) have resulted in only modest improvements in remission rates and only partial reduction of side effects. Moreover, the prospects for effective anti-HCV vaccines remain uncertain.
- Thus, there is a need for more effective anti-HCV therapies. Such inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors. Specifically, such compounds may be useful as antiviral agents, particularly as anti-HCV agents.
- This invention relates to therapeutic combinations comprising VX-950 and a polymerase inhibitor.
- The invention also relates to methods of treating HCV infection or alleviating one or more symptoms thereof in a patient, comprising administering to said patient a therapeutic combination of the present invention.
- It is yet another object of the present invention to provide a pharmaceutical regimen for treating HCV infection in a patient.
- For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
- As described herein, compounds of the invention may optionally be substituted with one or more substituents, or as exemplified by particular classes, subclasses, and species of the invention.
- As used herein, “patient” refers to a mammal, including a human.
- The term “polymerase inhibitor,” as used herein, refers to compounds that inhibit the activity of HCV RNA dependent RNA polymerase (RdRp). Polymerase inhibitors of the following invention include, but are not limited to, the compounds of formula I, II and III. The polymerase inhibitor can be a nucleoside or non-nucleoside inhibitor. A nucleoside polymerase inhibitor binds to the substrate of the enzyme; whereas, the polymerase non-nucleoside binds to different site while still inhibiting the enzyme, e.g., an allosteric inhibitor.
- The term “protease inhibitor,” as used herein refers to means an agent (compound or biological) that is effective to inhibit the function of HCV NS3 protease in a mammal. Protease inhibitors of the following invention include, but are not limited to, VX-950.
- As used herein, “VX-950” refers to an HCV inhibitor shown below and described in PCT Publication Number WO 02/18369, which is incorporated herein by reference in its entirety.
- The term “therapeutic combination” as used herein means a combination of one or more active drug substances, i.e., compounds having a therapeutic utility. Typically, each such compound in the therapeutic combinations of the present invention will be present in a pharmaceutical composition comprising that compound and a pharmaceutically acceptable carrier. The compounds in a therapeutic combination of the present invention may be administered simultaneously or separately, as part of a regimen.
- Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
- The present invention relates to therapeutic combinations comprising a protease inhibitor and a polymerase inhibitor for the treatment of HCV.
- In one aspect of the invention, the protease inhibitor is VX-950.
- VX-950, an HCV inhibitor with its structure shown below is such a compound in need. VX-950 is described in PCT Publication Number WO 02/18369, which is incorporated herein by reference in its entirety.
- VX-950, a potent and specific NS3-4A protease inhibitor demonstrated substantial antiviral activity in a phase 1b trial of subjects infected with HCV genotype 1 (Study VX04-950-101). The degree to which a subject responds to treatment and the rate at which viral rebound is observed could in part be due to genotypic differences in sensitivity to the protease inhibitor. The rapid replication rate of HCV, along with the poor fidelity of its polymerase, gives rise to an accumulation of mutations throughout its genome [P. Simmonds, “Genetic diversity and evolution of hepatitis C virus—15 years on,” J. Gen. Virol., 85, pp. 3173-88 (2004)]. The degree to which sequence variability in the protease region affects the catalytic efficiency of the enzyme or the binding of an inhibitor is not known. Additionally, the generation of numerous viral genomes with remarkable sequence variation presents potential problems of emerging drug resistant virus in subjects treated with antiviral therapy. Indeed, drug resistance against antiviral drugs, such as HIV protease inhibitors, is well documented [Johnson et al., Top. HIV Med., 12, pp. 119-24 (2004)]. Drug resistant mutations have already been shown to develop in vitro in the presence of HCV protease inhibitors [Lin et al., “In vitro studies of cross-resistance mutations against two hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061,” J. Biol. Chem., 280, pp. 36784-36791 (2005), which is incorporated herein by reference in its entirety; Lin et al., “In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: Structural analysis indicates different resistance mechanisms,” J. Biol. Chem., 279, pp. 17508-17514 (2004), which is incorporated herein by reference in its entirety; Lu et al., Antimicrob. Agents Chemother., 48, pp. 2260-6 (2004); Trozzi et al., “In vitro selection and characterization of hepatitis C virus serine protease variants resistant to an active-site peptide inhibitor,” J. Virol. 77, pp. 3669-79 (2003)]. Mutations resistant to the protease inhibitor BILN 2061 have been found at positions R155Q, A156T, and D168V/A/Y in the NS3 gene, but no mutations have yet been observed in the NS4 region or in the protease cleavage sites. A VX-950 resistance mutation has also been found in vitro at position A156S. Cross-resistant mutations against both VX-950 and BILN 2061 have also been shown to develop in vitro at position 156 (A156V/T) (Lin et al., 2005, supra).
- In other embodiments, the protease inhibitor is described in international patent application publication number WO2007/025307, the entire contents of which is incorporated herein.
- In still other embodiments, the protease inhibitor is described in one or more of the following publications: WO1997/43310, US20020016294, WO2001/81325, WO2002/08198, WO2001/77113, WO2002/08187, WO2002/08256, WO2002/08244, WO2003/006490, WO2001/74768, WO1999/50230, WO1998/17679, WO2002/48157, US20020177725, WO2002/060926, US20030008828, WO2002/48116, WO2001/64678, WO2001/07407, WO1998/46630, WO2000/59929, WO1999/07733, WO2000/09588, US20020016442, WO2000/09543, WO1999/07734, U.S. Pat. No. 6,018,020, U.S. Pat. No. 6,265,380, U.S. Pat. No. 6,608,027, US20020032175, US20050080017, WO1998/22496, U.S. Pat. No. 5,866,684, WO2002/079234, WO2000/31129, WO1999/38888, WO1999/64442, WO2004/072243, and WO2002/18369, the contents of all of which are incorporated herein by reference in their entireties.
- The polymerase inhibitors can be a nucleoside or a non-nucleoside inhibitor.
- In an embodiment of the first aspect, the polymerase inhibitor is the compound of formula (I)
- or a pharmaceutically acceptable salt thereof.
- In another embodiment of the first aspect, the polymerase inhibitor is the compound of formula (II)
- or a pharmaceutically acceptable salt thereof.
- In another embodiment of the first aspect, the polymerase inhibitor is the compound of formula (III)
- or a pharmaceutically acceptable salt thereof.
- In another aspect, the invention provides a therapeutic combination of VX-950 and the polymerase inhibitor of compound (I)
- or a pharmaceutically acceptable salt thereof.
- In another aspect, the invention provides a therapeutic combination of VX-950 and the polymerase inhibitor of compound (II)
- or a pharmaceutically acceptable salt thereof.
- In another aspect, the invention provides a therapeutic combination of VX-950 and the polymerase inhibitor of compound (III)
- or a pharmaceutically acceptable salt thereof.
- In other embodiments, the polymerase inhibitor is selected from the inhibitors known in the art. For instance, the polymerase inhibitor is described in one or more of the following international patent application publications: WO2008/011337; WO2006/093801; WO2005/019191; WO2004/041818; WO2007/150001; WO2006/066079; WO2006/137706; WO2006/011719; WO2004/108719; WO2004/108068; WO2004/033450; WO2003/084953; WO2008/019477; WO2007/019674; WO2006/007693; WO2005/080388; WO2004/065367; WO2004/064925; WO2003/010141; WO2003/010140; WO2003/007945; WO2002/004425; WO2008/021928; WO2008/021927; WO2007/143521; WO2006/020082; WO2004/014852; WO2004/014313; WO2003/026587; WO2003/002518; WO2002/079187; WO2008/011521; WO2008/008912; WO2006/138744; WO2007/039144; WO2006/045613; WO2006/045615; WO2005/103045; WO2005/092863; WO2005/079799; WO2004/076415; WO2004/037818; WO2004/009543; WO2003/037894; WO2003/037893; WO2007/082554; WO2007/028789; WO2006/119975; WO2006/046030; WO2006/046039; WO2006/029912; WO2006/027628; WO2006/008556; WO2005/034941; WO2004/087714; WO2003/062211; WO2002/006246; WO2006/052013; WO2005/080399; WO2005/049622; WO2005/014543; WO2003/000254; WO2007/023381; WO2006/018725; WO2004/074270; WO2004/073599; WO2003/082848; WO2004/002977; WO2004/002944; WO2004/002940; WO2006/117306; WO2006/050035; WO2002/100851; WO2007/147794; WO2007/088148; WO2007/071434; WO2006/100106; WO2006/119646; WO2005/112640; WO2004/052885; WO2004/052879; WO2004/041201; WO2007/092558; WO2005/016932; WO2004/091724; WO2003/099824; WO2003/099275; WO2008/009078; WO2007/034127; WO2007/041632; WO2007/005779; WO2007/002639; WO2006/065590; WO2006/019831; WO2004/080453; WO2003/101993; WO2003/082265; WO2001/077091; and WO1994/12192. The entire content of each of the foregoing publications is incorporated herein in its entirety.
- In other examples, the polymerase inhibitor is described in one or more of the following U.S. patent application publications: US2004167123; US2004162285; US20040097492; US20040087577; US20070275947; US20070275930; US20070270406; US20070270405; US2005075376; US20070032488; US20030050320; US2005154056; US2006040927; US2006094706; US2006258682; US2006223834; US2006217390; US2006019976; US2005107364; US2006183751; US2006063821; and US2005176701. The entire content of each of the foregoing publications is incorporated herein in its entirety.
- In still further examples, the polymerase inhibitor is described in U.S. Pat. No. 7,112,600 or European Patent No. EP 1321463. The entire content of each of the foregoing publications is incorporated herein.
- In still further embodiments, the polymerase inhibitor is selected from A-837093, being developed by Abbott Laboratories; GS-9190, being developed by Gilead Sciences; PF-868 and PF-554, being developed by Pfizer; R1479, R1626 (prodrug of R1479), R7128, and R1728, being developed by Roche Pharmaceuticals; PST 7081, being developed by Pharmasset and Roche Pharmaceuticals; IDX102, IDX184, NM107, NM283 (prodrug of NM107) called Valopicitabine, being developed by Idenix; and VCH-916 and VCH-759, being developed by ViroChem; and HCV-796, being developed by Wyeth. Other polymerase inhibitors are in development by Genelabs; Boehringer Ingelheim; Anadys; Celera; Schering; and Medavir.
- According to another aspect, the present invention provides kits for use in treating HCV infection in a patient. The kits of the present invention comprise any one of the therapeutic combinations of the present invention. The kits further comprise instructions for utilizing the therapeutic combinations. The kits may be tailored to the needs of classes or types of patients or other clinically relevant factors such as age, body weight, concomitant diseases/conditions, severity and stage of HCV infection, responsiveness or non-responsiveness to prior treatments, propensity for side effects, etc. For example, the therapeutic combination in a kit may be tailored for dosages suitable for patients having a body weight of, e.g., 75 kg. Or, the therapeutic combination in a kit may be tailored for dosages suitable for patients having a body weight of, e.g., less than or equal to 75 kg. Or, the therapeutic combination in a kit may be tailored for pediatric use, wherein the dosage for children is varied depending on factors such as age, body weight, severity of disease, etc.
- According to another aspect, the present invention provides a kit comprising: (i) a plurality of VX-950 compositions; (ii) a plurality of polymerase inhibitor compositions; and (iii) instructions for utilizing the above compositions.
- In another aspect, the invention provides methods of using the therapeutic combinations of the present invention for treating HCV infection or alleviating one or more symptoms thereof in a patient.
- In one embodiment, the HCV infection is genotype.
- In another embodiment, the patient is a treatment naïve patient.
- In another embodiment, the patient is non-responsive to interferon monotherapy.
- In another embodiment, the patient is non-responsive to combination therapy using ribaviron and an interferon.
- In another aspect, the invention provides a method of reducing HCV-RNA levels in a patient in need thereof, comprising the step of administering to said patient a therapeutic combination of the present invention.
- In an embodiment of the invention, the HCV-RNA levels in the patient are reduced to a less than detectable level.
- In another aspect, the invention provides a pharmaceutical regimen comprising administering to a patient in need thereof a therapeutic combination of the present invention until the HCV-RNA level in the patient is below a detectable level.
- If pharmaceutically acceptable salts of the compounds of this invention are utilized in the therapeutic combinations, those salts are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 phenyl propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N methyl D glucamine, and salts with amino acids such as arginine, lysine, and so forth.
- Also, the basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil soluble or dispersible products are thereby obtained.
- The compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool fat.
- The therapeutic combinations of this invention are formulated for pharmaceutical administration to a mammal. In one embodiment said mammal is a human being.
- Such pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra articular, intra synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally or intravenously.
- Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- In one embodiment, dosage levels of between about 0.01 and about 100 mg/kg body weight per day of VX-950 are useful in a combination therapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease. In another embodiment, dosage levels of between about 0.5 and about 75 mg/kg body weight per day of VX-950 are useful in a combination therapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). In one embodiment, such preparations contain from about 20% to about 80% active compound.
- In one embodiment, dosage levels of between about 0.01 and about 100 mg/kg body weight per day of the polymerase inhibitor compounds described herein are useful in a combination for the prevention and treatment of antiviral, particularly anti-HCV mediated disease. In another embodiment, dosage levels of between about 0.5 and about 75 mg/kg body weight per day of the polymerase inhibitor compounds described herein are useful in a combination therapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). In one embodiment, such preparations contain from about 20% to about 80% active compound.
- The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
- The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.
- For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
- For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
- The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- The therapeutic combination of this invention may additionally comprise another anti-viral agent, preferably an anti-HCV agent. Such anti-viral agents include, but are not limited to, immunomodulatory agents, such as alpha, beta, and gamma-interferons, pegylated derivatized interferon-alpha compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including helicase and other polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., compounds of U.S. Pat. Nos. 5,807,876, 6,498,178, 6,344,465, 6,054,472, WO 97/40028, WO 98/40381, WO 00/56331, and mycophenolic acid and derivatives thereof, and including, but not limited to VX-497, VX-148, and/or VX-944); or combinations of any of the above. See also W. Markland et al., Antimicrobial & Antiviral Chemotherapy, 44, p. 859 (2000) and U.S. Pat. No. 6,541,496.
- According to another aspect, the present invention provides a method of treating HCV infection or alleviating one or more symptoms thereof, in a patient, comprising administering a composition comprising a polymerase inhibitor of Formula I, II or III. In one embodiment, the patient is infected by an HCV variant. In another embodiment, the composition further comprises VX-950.
- According to another aspect, the present invention provides a method of treating HCV infection or alleviating one or more symptoms thereof, in a patient, comprising administering a composition comprising a polymerase inhibitor of Formula I, II, or III, and VX-950. In one embodiment, the patient is infected by an HCV variant.
- According to another aspect, the present invention provides a method of eliminating or reducing HCV infection in a cell, comprising administering a composition comprising a polymerase inhibitor of Formula I, II or III. In one embodiment, the cell contains an HCV variant. In another embodiment, the composition further comprises VX-950.
- According to another aspect, the present invention provides a method of eliminating or reducing HCV infection in a cell, comprising administering a composition comprising a polymerase inhibitor of Formula I, II or III and VX-950. In one embodiment, the cell contains an HCV variant.
- The following definitions are used herein (with trademarks referring to products available as of this application's filing date):
- “Peg-Intron” means PEG-INTRON®, peginteferon alfa-2b, available from Schering Corporation, Kenilworth, N.J.;
- “Intron” means INTRON-A®, interferon alfa-2b available from Schering Corporation, Kenilworth, N.J.;
- “ribavirin” means ribavirin 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; described in the Merck Index, entry 8365, Twelfth Edition; also available as REBETROL® from Schering Corporation, Kenilworth, N.J., or as COPEGASUS® from Hoffmann-La Roche, Nutley, N.J.;
- “Pegasys” means PEGASYS®, peginterferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.;
- “Roferon” mean ROFERON®, recombinant interferon alfa-2a available from Hoffmann-La Roche, Nutley, N.J.;
- “Berefor” means BEREFOR®, interferon alfa 2 available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.;
- SUMIFERON®, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan;
- WELLFERON®, interferon alpha n1 available from Glaxo Wellcome LTd., Great Britain; and
- ALFERON®, a mixture of natural alpha interferons made by Interferon Sciences, and available from Purdue Frederick Co., CT.
- The term “interferon” as used herein means a member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, and modulate immune response, such as interferon alpha, interferon beta, or interferon gamma. The Merck Index, entry 5015, Twelfth Edition.
- The therapeutic combination of the present invention may utilize natural alpha interferon 2a. Or, the therapeutic combination of the present invention may utilize natural alpha interferon 2b. The therapeutic combination of the present invention may utilize recombinant alpha interferon 2a or 2b. Additionally, the invention may utilize pegylated alpha interferon 2a or 2b. Interferons suitable for the present invention include:
- (a) INTRON-A® (interferon-alpha 2B, Schering Plough),
- (b) PEG-INTRON®,
- (c) PEGASYS®,
- (d) ROFERON®,
- (e) BEREFOR®,
- (f) SUMIFERON®,
- (g) WELLFERON®,
- (h) consensus alpha interferon available from Amgen, Inc., Newbury Park, Calif.,
- (i) ALFERON®;
- (j) VIRAFERON®;
- (k) INFERGEN®; and
- (l) ALBUFERON™.
- As is recognized by skilled practitioners, protease and polymerase inhibitors would be preferably administered orally. Interferon is not typically administered orally. Nevertheless, nothing herein limits the methods or combinations of this invention to any specific dosage forms or regime. Thus, each component of a combination according to this invention may be administered separately, together, or in any combination thereof.
- In one embodiment, the protease inhibitor and polymerase inhibitor are administered in separate dosage forms. In one embodiment, any additional agent is administered as part of a single dosage form with the protease inhibitor or as a separate dosage form. As this invention involves a combination of compounds, the specific amounts of each compound may be dependent on the specific amounts of each other compound in the combination. As recognized by skilled practitioners, dosages of interferon are typically measured in IU (e.g., about 4 million IU to about 12 million IU).
- Accordingly, agents (whether acting as an immunomodulatory agent or otherwise) that may be used in combination with a compound of this invention include, but are not limited to, Albuferon™ (albumin-Interferon alpha) available from Human Genome Sciences; PEG-INTRON® (peginterferon alfa-2b, available from Schering Corporation, Kenilworth, N.J.); INTRON-A®, (interferon alfa-2b available from Schering Corporation, Kenilworth, N.J.); ribavirin 1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; described in the Merck Index, entry 8365, Twelfth Edition); REBETROL® (Schering Corporation, Kenilworth, N.J.), COPEGUS® (Hoffmann-La Roche, Nutley, N.J.); PEGASYS® (peginterferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.); ROFERON® (recombinant interferon alfa-2a available from Hoffmann-La Roche, Nutley, N.J.); BEREFOR® (interferon alfa 2 available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.); SUMIFERON® (a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan); WELLFERON® (interferon alpha n1 available from Glaxo Wellcome Ltd., Great Britain); ALFERON® (a mixture of natural alpha interferons made by Interferon Sciences, and available from Purdue Frederick Co., CT); alpha-interferon; natural alpha interferon 2a; natural alpha interferon 2b; pegylated alpha interferon 2a or 2b; consensus alpha interferon (Amgen, Inc., Newbury Park, Calif.); VIRAFERON®; INFERGEN®; REBETRON® (Schering Plough, Interferon-alpha 2B+Ribavirin); pegylated interferon alpha (Reddy, K. R. et al. “Efficacy and Safety of Pegylated (40-kd) Interferon alpha-2a Compared with Interferon alpha-2a in Noncirrhotic Patients with Chronic Hepatitis C (Hepatology, 33, pp. 433-438 (2001); consensus interferon (Kao J. H., et al., “Efficacy of Consensus Interferon in the Treatment of Chronic Hepatitis,” J. Gastroenterol. Hepatol., 15, pp. 1418-1423 (2000); lymphoblastoid or “natural” interferon; interferon tau (Clayette, P. et al., “IFN-tau, A New Interferon Type I with Antiretroviral activity,” Pathol. Biol., (Paris) 47, pp. 553-559 (1999); interleukin-2 (Davis, G. L. et al., “Future Options for the Management of Hepatitis C,” Seminars in Liver Disease, 19, pp. 103-112 (1999); Interleukin-6 (Davis et al. “Future Options for the Management of Hepatitis C,” Seminars in Liver Disease, 19, pp. 103-112 (1999); interleukin-12 (Davis, G. L. et al., “Future Options for the Management of Hepatitis C,” Seminars in Liver Disease, 19, pp. 103-112 (1999); and compounds that enhance the development of type 1 helper T cell response (Davis et al., “Future Options for the Management of Hepatitis C,” Seminars in Liver Disease, 19, pp. 103-112 (1999)). Also included are compounds that stimulate the synthesis of interferon in cells (Tazulakhova, E. B. et al., “Russian Experience in Screening, analysis, and Clinical Application of Novel Interferon Inducers,” J. Interferon Cytokine Res., 21 pp. 65-73) including, but are not limited to, double stranded RNA, alone or in combination with tobramycin, and Imiquimod (3M Pharmaceuticals; Sauder, D. N. “Immunomodulatory and Pharmacologic Properties of Imiquimod,” J. Am. Acad. Dermatol., 43 pp. S6-11 (2000)).
- Compounds that stimulate the synthesis of interferon in cells (Tazulakhova, E. B. et al., “Russian Experience in Screening, analysis, and Clinical Application of Novel Interferon Inducers,” J. Interferon Cytokine Res., 21, pp. 65-73) include, but are not limited to, double stranded RNA, alone or in combination with tobramycin, and Imiquimod (3M Pharmaceuticals; Sauder, D. N. “Immunomodulatory and Pharmacologic Properties of Imiquimod,” J. Am. Acad. Dermatol., 43 pp. S6-11 (2000)).
- Other non-immunomodulatory or immunomodulatory compounds may be used in combination with a compound of this invention including, but not limited to, those specified in WO 02/18369, which is incorporated herein by reference (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11).
- This invention may also involve administering a cytochrome P450 monooxygenase inhibitor. CYP inhibitors may be useful in increasing liver concentrations and/or increasing blood levels of compounds that are inhibited by CYP.
- If an embodiment of this invention involves a CYP inhibitor, any CYP inhibitor that improves the pharmacokinetics of the relevant NS3/4A protease may be used in a method of this invention. These CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436), ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497. Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, and clomethiazole. For preferred dosage forms of ritonavir, see U.S. Pat. No. 6,037, 157, and the documents cited therein: U.S. Pat. No. 5,484,801, U.S. patent Application Ser. No. 08/402,690, and International Applications WO 95/07696 and WO 95/09614).
- Methods for measuring the ability of a compound to inhibit cytochrome P450 monooxygenase activity are known (see U.S. Pat. No. 6,037,157, and Yun et al., Drug Metabolism & Disposition, 21, pp. 403-407 (1993).
- Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
- It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti-viral agent in the composition.
- The invention provides a method for treating a patient infected with a virus characterized by a virally encoded serine protease that is necessary for the life cycle of the virus by administering to said patient a pharmaceutically acceptable composition of this invention. In one embodiment, the methods of this invention are used to treat a patient suffering from an HCV infection. Such treatment may completely eradicate the viral infection or reduce the severity thereof. In another embodiment, the patient is a human being.
- The methods of this invention may additionally comprise the step of administering to said patient an anti-viral agent, preferably an anti-HCV agent. Such anti-viral agents include, but are not limited to, immunomodulatory agents, such as alpha-, beta-, and gamma-interferons, pegylated derivatized interferon-α compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including but not limited to helicase and other polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in U.S. Pat. Nos. 5,807,876 and 6,498,178, mycophenolic acid and derivatives thereof); inhibitors of cytochrome P-450, such as ritonavir, or combinations of any of the above.
- Such additional agent may be administered to said patient as part of a single dosage form comprising both a compound of this invention and an additional anti-viral agent. Alternatively, the additional agent may be administered separately from the compound of this invention, as part of a multiple dosage form, wherein said additional agent is administered prior to, together with or following a composition comprising a compound of this invention.
- The present invention may also be utilized as a method of pre-treating a biological substance intended for administration to a patient comprising the step of contacting said biological substance with a pharmaceutically acceptable composition comprising a compound of this invention. Such biological substances include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, etc; sperm and ova; bone marrow and components thereof, and other fluids to be infused into a patient such as saline, dextrose, etc.
- The invention may also be utilized as a method of treating materials that may potentially come into contact with a virus characterized by a virally encoded serine protease necessary for its life cycle. This method comprises the step of contacting said material with a compound according to the invention. Such materials include, but are not limited to, surgical instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); laboratory instruments and garments (e.g. clothes, gloves, aprons, gowns, masks, eyeglasses, footwear, etc.); blood collection apparatuses and materials; and invasive devices, such as, for example, shunts and stents.
- All references cited within this document are incorporated herein by reference.
- In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
- A. HCV Replicon Cells
- Huh-7 cells were propagated in Dulbecco's modified Eagle's medium (DMEM, JRH Biosciences, Lenexa, Kans.) supplemented with 10% heat-inactivated FBS (fetal bovine serum), 2 mM L-glutamine, and nonessential amino acids (JRH). The cells were transfected with an in vitro transcribed HCV replicon RNA identical to replicon I377neo/NS3-3′/wt as described by Lohmann et al. (1999). Stable cell clones were selected and maintained in the presence of 250 μg/mL G418 (Invitrogen, Carlsbad, Calif.). One of the clones, 24-2, was used as the wild-type in the subsequent HCV replicon assays for combination studies. The HCV NS3 protease variant replicons were constructed in the background of the mADE wild-type replicon as described previously [Chao Lin et al., “In Vitro Resistance Studies of Hepatitis C Virus Serine Protease Inhibitors, VX-950 and BILN 2061: Structural Analysis Indicates Different Resistance Mechanisms,” Journal of Biological Chemistry, 279(17); pp. 17508-17514 (2004)]. The replicon cells were propagated in DMEM supplemented with 10% FBS, 2 mM L-glutamine, nonessential amino acids, and 250 μg/mL G418. The cells were split twice per week in fresh media upon reaching confluence. There are approximately 200-300 copies of HCV RNA per 24-2 replicon cell.
- HCV replicon RNA from cells was measured using the Quantigene Discover XL kit (Panomics Inc., Fremont Calif.) as per the manufacturer's instructions. Briefly, compound-treated replicon cells were lysed and immobilized on to capture plates using HCV specific oligonucleotides (designed based on the 5′ UTR region of HCV 1b genome sequence AJ238799 in the GenBank database) over night and the relative amounts of captured RNA was measured using oligonucleotide probe sets as per the manufacturer's instructions.
- B. 2-Day HCV Replicon IC50 Assay
- On the day prior to the assay, 10,000 replicon cells were plated per well of a 96-well plate and allowed to attach and grow overnight in DMEM (Invitrogen, Carlsbad, Calif.) supplemented with 10% heat-inactivated FBS (JRH Biosciences, Lenexa, Kans.), 2 mM L-glutamine (Invitrogen), nonessential amino acids (Invitrogen) and 250 μg/ml G418 (Invitrogen). Next day, the medium was removed and antiviral agents that were serially diluted in DMEM containing 2% FBS and 0.5% DMSO (Sigma Chemical Co., St. Louis, Mo.) without G418, was added. The replicon cells were incubated with the antiviral agents for 48 h. HCV replicon RNA from cells was measured using the Quantigene Discover XL kit (Panomics Inc., Fremont Calif.) as per the manufacturer's instructions. Briefly, compound-treated replicon cells were lysed and immobilized onto capture plates using HCV specific oligonucleotides overnight and the relative amounts of captured RNA was measured using oligonucleotide probe sets as per the manufacturer's instructions. Unless indicated otherwise, each data point represents the average of three replicates. The IC50 is the concentration of the compound at which the HCV replicon RNA level in cells is reduced by 50% as compared to the untreated replicon cell controls. To monitor the effect of compounds on cell proliferation or cell viability, replicon cells were treated with serially diluted compounds for 48 h, after which cell viability was determined using a CellTiter Glo assay (Promega, Madison, Wis.). Each CC50 is derived from at least two replicates and is the concentration of the compound at which the number of viable cells is reduced by 50% as compared to untreated cell controls. The IC50 and CC50 was determined using 4-parameter curve fitting in the SoftMax Pro program (Molecular Devices, Sunnyvale, Calif.).
- C. Synergy and Antagonism Analysis
- The effects of drug-drug combinations were evaluated using the Bliss independence model [W. R. Greco et al., “The search for synergy: a critical review from a response surface perspective,” Pharmacol. Rev., 47, pp. 331-385 (1995)]. The experimental data were analyzed by using MacSynergy, a three-dimensional analytical method developed by Prichard and Shipman [M. N. Prichard and C. Shipman, Jr., “A three-dimensional model to analyze drug-drug interactions,” Antivir. Res., 14, pp. 181-205 (1990)]. In this model, the theoretical additive effect is calculated from the dose-response curves of individual compounds by the equation Z=X+Y(1−X), where X and Y represent the inhibition produced by drug 1 alone and drug 2 alone, respectively, and Z represents the effect produced by the combination of drug 1 and drug 2. The theoretical additive surface is subtracted from the actual experimental surface, resulting in a surface that would appear as a horizontal plane at 0% inhibition if the combination were merely additive. Any peak above this plane would indicate synergy, whereas any depression below it would indicate antagonism. The 95% confidence intervals for the experimental dose-response surface are used to evaluate the data statistically. The volume of the peak or depression is calculated to quantify the overall synergy or antagonism produced.
- Using the assays above, therapeutic combinations of the present invention are determined to be useful HCV replication inhibitors.
- Combinations of VX-950 and polymerase inhibitors were tested in a checkerboard format in a 2-day Replicon assay with bDNA quantitation. The results are shown in Table 6. The combination of VX-950 and the polymerase inhibitor of formula I resulted in an additive to modestly synergistic effect. The combination of VX-950 and the polymerase inhibitor of formula II resulted in an additive to modestly synergistic effect. The combination of VX-950 and the polymerase inhibitor of formula III resulted in an additive effect.
-
TABLE 6 2-day Replicon Assay with bDNA quantitation Polymerase Protease Polymerase Checkerboard VX-950 Inhibitor Log Inhibitor Inhibitor Combo Result IC50 IC50 Synergy Volume VX-950 Formula I Additive/Modest 0.42 μM 7.21 μM 21.95 3.15 Synergy VX-950 Formula II Additive/Modest 0.34 μM 1.04 μM 45.13 6.48 Synergy VX-950 Formula III Additive 0.31 μM 0.70 μM 0.37 0.05 - The sensitivity of NS3 protease variants to ribavirin and interferon was assessed in a 2-Day HCV Replicon IC50 Assay. The variants are as follows: at position 36, the wild-type valine was mutated to an alanine (V36A) or a methionine (V36M), the wild-type threonine at position 54 was mutated to an alanine (T54A), the wild-type arginine at position 155 was mutated to lysine (R155K), the wild-type arginine at position 155 was mutated to threonine (R155T) and the wild-type arginine at position 155 was mutated to methionine (R155M). As shown in Table 7, the results indicate the sensitivity of the variants to ribavirin and interferon. The fold change is the ratio of NS3 protease mutant IC50 to that of the Wild type IC50 for the same inhibitor. The sensitivity of replicons with the wild-type alanine at position 156 mutated to threonine (A156T) and the wild-type alanine at position 156 mutated to valine (A156V) is comparable to the wild-type (Lin, et al., 2005, supra).
-
TABLE 7 2-Day HCV Replicon IC50 Assay of NS3 variants and ribavirin or interferon. Replicons Other Inhibitors Protease domain IFN-α (units/ml) Ribavirin (μM) Con1 Avg. IC50 Fold Avg. IC50 Fold Seq. Changes (uM) Change (uM) Change Wild Type — 11.6 ± 1.1 1.0 57.8 ± 17.6 1.0 (mADE) Val 36 V36M 11.3 ± 5.9 1.0 32.9 ± 17.8 0.6 V36A 10.3 ± 6.0 0.9 43.1 ± 21.3 0.7 Arg 155 R155K 15.2 ± 12.3 1.3 37.2 ± 17 0.6 R155T 4.8 ± 3.3 0.4 32.4 ± 17.7 0.6 R155M 4.9 ± 1.0 0.4 38.9 ± 4.7 0.7 Val 36/Arg V36M- 10.1 ± 5.9 0.9 40.6 ± 6.1 0.7 155 R155K V36M- 3.1 ± 0.2 0.3 36.4 ± 1.3 0.6 R155T V36A- 6.8 ± 0.5 0.6 35.8 ± 2.2 0.6 R155K V36A- 3.9 ± 2.1 0.3 41.7 ± 21.6 0.7 R155T Thr 54 T54A 3.9 ± 0.5 0.3 21.7 ± 11.1 0.4 - The sensitivity of NS3 protease variants to VX-950 [Sarrazin, et al., “Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir,” Gastroenterology 132, pp. 1767-1777 (2007), which is incorporated herein by reference in its entirety] and the polymerase inhibitors of Formula I, II and III was assessed in a 2-Day HCV Replicon IC50 Assay. The variants are as follows: at position 36, the wild-type valine was mutated to an alanine (V36A) or a methionine (V36M), the wild-type threonine at position 54 was mutated to an alanine (T54A), the wild-type arginine at position 155 was mutated to lysine (R155K), the wild-type alanine at position 156 was mutated to threonine (A156T) and the wild-type alanine at position 156 was mutated to valine (A156V). The variant, V36M+R155K, having two mutations was also tested. As shown in Table 8, the results indicate the sensitivity of the variants to VX-950 and to Formula I, II and III. The fold change is the ratio of NS3 protease mutant IC50 to that of the Wild type IC50 for the same inhibitor.
-
TABLE 8 2-Day HCV Replicon IC50 Assay of NS3 variants and VX-950, Formula I, II and III Replicon HCV Protease Inhibitor HCV Polymerase Inhibitors Protease VX-950 Formula I Formula II Formula III Domain Avg. IC50 ± Fold Avg. IC50 ± Fold Avg. IC50 ± Fold Avg. IC50 ± Fold Changes STDEV Change STDEV Change STDEV Change STDEV Change Wild Type 0.46 ± 0.101 1 ± 0.2 1.343 ± 0.473 1.0 0.347 ± 0.108 1.0 0.313 ± 0.032 1.0 V36M 3.38 ± 0.775 7.3 ± 1.7 1.589 ± 0.361 1.2 0.36 ± 0.164 1.0 0.227 ± 0.064 0.7 V36A 3.567 ± 1.05 7.7 ± 2.3 2.148 ± 0.874 1.6 0.571 ± 0.093 1.6 0.369 ± 0.066 1.2 R155K 3.587 ± 0.283 7.8 ± 0.6 2.371 ± 0.678 1.8 0.45 ± 0.023 1.3 0.39 ± 0.065 1.2 V36M + R155K 30.61 ± 0.637 ≧65.2 2.716 ± 1.384 2.0 0.578 ± 0.331 1.7 0.419 ± 0.197 1.3 T54A 3.043 ± 0.819 6.6 ± 1.8 1.976 ± 0.388 1.5 0.564 ± 0.111 1.6 0.337 ± 0.045 1.1 A156T >30* >65.2 1.27 ± 0.185 0.9 0.326 ± 0.003 0.9 0.306 ± 0.01 1.0 A156V >30* >65.2 1.313 ± 0.216 1.0 0.264 ± 0.045 0.8 0.297 ± 0.066 0.9 - It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the following claims.
Claims (12)
1. A therapeutic combination comprising VX-950 and a polymerase inhibitor selected from the group consisting of R7128 and IDX184.
2. The therapeutic combination of claim 1 , wherein the polymerase inhibitor is R7128.
3. The therapeutic combination of claim 1 , wherein the polymerase inhibitor is IDX184.
4. A kit comprising: (i) a therapeutic combination of claim 1 ; and (ii) instructions for utilizing said combination.
5. A method of treating HCV infection, or alleviating one or more symptoms thereof in a patient, comprising administering VX-950 in combination with a polymerase inhibitor selected from the group consisting of R7128 and IDX184.
6. The method of claim 5 , wherein the polymerase inhibitor is R7128.
7. The method of claim 5 , wherein the polymerase inhibitor is IDX184.
8. The method of claim 5 , wherein the HCV infection is genotype 1.
9. The method of claim 5 , wherein said patient is a treatment naive patient.
10. The method of claim 5 , wherein said patient is non-responsive to interferon monotherapy.
11. The method of claim 5 , wherein said patient is non-responsive to a combination therapy using ribavirin and an interferon.
12. The method of claim 5 , wherein the patient is infected by an HCV variant.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100174077A1 (en) * | 2005-08-19 | 2010-07-08 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
US8871904B2 (en) | 2005-08-19 | 2014-10-28 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX354958B (en) * | 2011-09-16 | 2018-03-27 | Gilead Pharmasset Llc | Methods for treating hcv. |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
DE202012012954U1 (en) | 2011-10-21 | 2014-08-12 | Abbvie Inc. | A combination of at least two direct-acting antiviral agents (DAAs) for use in the treatment of HCV |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
DK2583677T1 (en) | 2011-10-21 | 2015-01-19 | Abbvie Inc | Methods for treatment of HCV comprising at least two direct-acting antiviral agents ribavirin, interferon but not |
CN106138080A (en) * | 2015-04-03 | 2016-11-23 | 南开大学 | Nucleoside compound catches the application of medicine in preparation treatment hepatitis C virus (HCV) |
EA201892448A1 (en) | 2016-04-28 | 2019-06-28 | Эмори Юниверсити | ALKYN-CONTAINING NUCLEOTIDE AND NUCLEOSIDE THERAPEUTIC COMPOSITIONS AND RELATED APPLICATION METHODS |
Family Cites Families (160)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994012192A1 (en) | 1992-12-01 | 1994-06-09 | Commonwealth Scientific And Industrial Research Organisation | Antiviral agents |
CA2502856C (en) | 1992-12-29 | 2009-01-20 | Abbott Laboratories | Intermediates for retroviral protease inhibiting compounds |
IL110752A (en) | 1993-09-13 | 2000-07-26 | Abbott Lab | Liquid semi-solid or solid pharmaceutical composition for an HIV protease inhibitor |
US5559158A (en) | 1993-10-01 | 1996-09-24 | Abbott Laboratories | Pharmaceutical composition |
IL111991A (en) | 1994-01-28 | 2000-07-26 | Abbott Lab | Liquid pharmaceutical composition of HIV protease inhibitors in organic solvent |
US6037157A (en) | 1995-06-29 | 2000-03-14 | Abbott Laboratories | Method for improving pharmacokinetics |
US6054472A (en) | 1996-04-23 | 2000-04-25 | Vertex Pharmaceuticals, Incorporated | Inhibitors of IMPDH enzyme |
US5807876A (en) | 1996-04-23 | 1998-09-15 | Vertex Pharmaceuticals Incorporated | Inhibitors of IMPDH enzyme |
CZ298463B6 (en) | 1996-04-23 | 2007-10-10 | Vertex Pharmaceuticals Incorporated | Urea derivatives intended for use as IMPDH enzyme inhibitors and pharmaceutical compositions in which the derivatives are comprised |
AU2933797A (en) | 1996-05-10 | 1997-12-05 | Schering Corporation | Synthetic inhibitors of hepatitis c virus ns3 protease |
EA001915B1 (en) | 1996-10-18 | 2001-10-22 | Вертекс Фармасьютикалз Инкорпорейтед | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
GB9623908D0 (en) | 1996-11-18 | 1997-01-08 | Hoffmann La Roche | Amino acid derivatives |
ATE244717T1 (en) | 1997-03-14 | 2003-07-15 | Vertex Pharma | IMPDH ENZYME INHIBITORS |
GB9707659D0 (en) | 1997-04-16 | 1997-06-04 | Peptide Therapeutics Ltd | Hepatitis C NS3 Protease inhibitors |
JP4452401B2 (en) | 1997-08-11 | 2010-04-21 | ベーリンガー インゲルハイム (カナダ) リミテッド | Hepatitis C virus inhibitory peptide analog |
EP1003775B1 (en) | 1997-08-11 | 2005-03-16 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis c inhibitor peptides |
IT1299134B1 (en) | 1998-02-02 | 2000-02-29 | Angeletti P Ist Richerche Bio | PROCEDURE FOR THE PRODUCTION OF PEPTIDES WITH PROTEAS INHIBITING THE NS3 PROTEASIS OF THE HCV VIRUS, PEPTIDES SO OBTAINABLE AND PEPTIDES |
ES2281170T3 (en) | 1998-03-31 | 2007-09-16 | Vertex Pharmaceuticals Incorporated | SERINA PROTEASES INHIBITORS, PARTICULARLY PROTEASE NS3 OF THE HEPATITIS VIRUS C. |
GB9812523D0 (en) | 1998-06-10 | 1998-08-05 | Angeletti P Ist Richerche Bio | Peptide inhibitors of hepatitis c virus ns3 protease |
US6323180B1 (en) | 1998-08-10 | 2001-11-27 | Boehringer Ingelheim (Canada) Ltd | Hepatitis C inhibitor tri-peptides |
DE19836514A1 (en) | 1998-08-12 | 2000-02-17 | Univ Stuttgart | Modification of engineering polymers with N-basic groups and ion exchange groups in the side chain gives membranes of good thermal and mechanical stability useful for fuel cells, diffusion dialysis, electrodialysis, and reverse osmosis |
GB9825946D0 (en) | 1998-11-26 | 1999-01-20 | Angeletti P Ist Richerche Bio | Pharmaceutical compounds for the inhibition of hepatitis C virus NS3 protease |
AR029341A1 (en) | 1999-03-19 | 2003-06-25 | Vertex Pharma | IMPDH ENZYME INHIBITORS (INOSINA-5'-HYDROGENASE MONOPHOSPHATE) |
UA74546C2 (en) | 1999-04-06 | 2006-01-16 | Boehringer Ingelheim Ca Ltd | Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition |
US6608027B1 (en) | 1999-04-06 | 2003-08-19 | Boehringer Ingelheim (Canada) Ltd | Macrocyclic peptides active against the hepatitis C virus |
AU6371900A (en) | 1999-07-26 | 2001-02-13 | Du Pont Pharmaceuticals Company | Lactam inhibitors of hepatitis c virus ns3 protease |
US7122627B2 (en) | 1999-07-26 | 2006-10-17 | Bristol-Myers Squibb Company | Lactam inhibitors of Hepatitis C virus NS3 protease |
SK13752001A3 (en) | 1999-12-27 | 2002-07-02 | Japan Tobacco, Inc. | Fused-ring compounds and use thereof as drugs |
US6770666B2 (en) | 1999-12-27 | 2004-08-03 | Japan Tobacco Inc. | Fused-ring compounds and use thereof as drugs |
WO2001064678A2 (en) | 2000-02-29 | 2001-09-07 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
AU2001251165A1 (en) | 2000-04-03 | 2001-10-15 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
EP1268525B1 (en) | 2000-04-05 | 2008-12-31 | Schering Corporation | Macrocyclic ns3-serine protease inhibitors of hepatitis c virus comprising n-cyclic p2 moieties |
WO2001077091A2 (en) | 2000-04-05 | 2001-10-18 | Tularik Inc. | Ns5b hcv polymerase inhibitors |
AR030558A1 (en) | 2000-04-19 | 2003-08-27 | Schering Corp | MACROCICLIC COMPOUNDS, WHICH INCLUDE ENANTIOMERS, STEROISOMERS, ROTAMERS AND TAUTOMEROS, SALTS AND PHARMACEUTICALLY ACCEPTABLE SOLVATOS, PHARMACEUTICAL COMPOSITION, A METHOD FOR THE PREPARATION AND THE USE OF SUCH COMPUTERS FOR THE INHIBITION, THE SERIES |
US6448281B1 (en) | 2000-07-06 | 2002-09-10 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
GB0017676D0 (en) | 2000-07-19 | 2000-09-06 | Angeletti P Ist Richerche Bio | Inhibitors of viral polymerase |
AR034127A1 (en) | 2000-07-21 | 2004-02-04 | Schering Corp | IMIDAZOLIDINONES AS INHIBITORS OF NS3-SERINA PROTEASA OF THE HEPATITIS C VIRUS, PHARMACEUTICAL COMPOSITION, A METHOD FOR THEIR PREPARATION, AND THE USE OF THE SAME FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
AR029851A1 (en) | 2000-07-21 | 2003-07-16 | Dendreon Corp | NEW PEPTIDES AS INHIBITORS OF NS3-SERINA PROTEASA DEL VIRUS DE HEPATITIS C |
JP4452441B2 (en) | 2000-07-21 | 2010-04-21 | シェーリング コーポレイション | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
RU2355700C9 (en) | 2000-07-21 | 2010-03-20 | Шеринг Корпорейшн | Novel peptides as inhibitors of hepatitis c virus ns3 serine protease |
SV2003000617A (en) | 2000-08-31 | 2003-01-13 | Lilly Co Eli | INHIBITORS OF PROTEASA PEPTIDOMIMETICA REF. X-14912M |
US6846806B2 (en) | 2000-10-23 | 2005-01-25 | Bristol-Myers Squibb Company | Peptide inhibitors of Hepatitis C virus NS3 protein |
EP1337550B1 (en) | 2000-11-20 | 2006-05-24 | Bristol-Myers Squibb Company | Hepatitis c tripeptide inhibitors |
US6727366B2 (en) | 2000-12-13 | 2004-04-27 | Bristol-Myers Squibb Pharma Company | Imidazolidinones and their related derivatives as hepatitis C virus NS3 protease inhibitors |
WO2002048116A2 (en) | 2000-12-13 | 2002-06-20 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
GB0107924D0 (en) | 2001-03-29 | 2001-05-23 | Angeletti P Ist Richerche Bio | Inhibitor of hepatitis C virus NS3 protease |
KR100798579B1 (en) | 2001-03-31 | 2008-01-28 | 동화약품공업주식회사 | Novel methoxy-1,3,5-triazine derivatives and the pharmaceutical compositions containing said derivatives |
CN101624391A (en) | 2001-06-11 | 2010-01-13 | 病毒化学医药公司 | Thiophene derivatives as antiviral agents for flavivirus infection |
AR035543A1 (en) | 2001-06-26 | 2004-06-16 | Japan Tobacco Inc | THERAPEUTIC AGENT FOR HEPATITIS C THAT INCLUDES A CONDENSED RING COMPOUND, CONDENSED RING COMPOUND, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS, BENZIMIDAZOL, THIAZOL AND BIFENYL COMPOUNDS USED AS INTERMEDIARY COMPARTMENTS OF COMPARTMENTS |
KR100713137B1 (en) | 2001-06-28 | 2007-05-02 | 동화약품공업주식회사 | Novel 2,4-difluorobenzamide derivatives |
IL159087A0 (en) | 2001-07-11 | 2004-05-12 | Vertex Pharma | Bridged bicyclic compounds and pharmaceutical compositions containing the same |
JP4558314B2 (en) | 2001-07-20 | 2010-10-06 | ベーリンガー インゲルハイム (カナダ) リミテッド | Viral polymerase inhibitor |
EP2335700A1 (en) | 2001-07-25 | 2011-06-22 | Boehringer Ingelheim (Canada) Ltd. | Hepatitis C virus polymerase inhibitors with a heterobicylic structure |
US20030134853A1 (en) | 2001-09-26 | 2003-07-17 | Priestley Eldon Scott | Compounds useful for treating hepatitis C virus |
EP1440068A1 (en) | 2001-11-02 | 2004-07-28 | Glaxo Group Limited | Acyl dihydro pyrrole derivatives as hcv inhibitors |
US20050043545A1 (en) | 2001-11-02 | 2005-02-24 | Gianpalol Bravi | 4-(5-Membered)-heteroaryl acyl pyrrolidine derivatives as hcv inhibitors |
US6936629B2 (en) | 2001-12-21 | 2005-08-30 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
GB0201179D0 (en) | 2002-01-18 | 2002-03-06 | Angeletti P Ist Richerche Bio | Therapeutic agents |
MXPA04009672A (en) | 2002-04-01 | 2004-11-12 | Pfizer | Pyranon and pyrandion inhibitors of hepatitis c virus rna-dependent rna polymerase. |
KR100516434B1 (en) | 2002-04-04 | 2005-09-22 | (주) 비엔씨바이오팜 | 6-(4-substituted-anilino)pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
TW200400963A (en) | 2002-05-21 | 2004-01-16 | Wyeth Corp | R-enantiomers of pyranoindole derivatives and the use thereof for the treatment of hepatitis C virus infection or disease |
TW200400818A (en) | 2002-05-21 | 2004-01-16 | Wyeth Corp | Method for the use of pyranoindole derivatives to treat infection with hepatitis C virus |
US7449488B2 (en) | 2002-06-04 | 2008-11-11 | Schering Corporation | Pyrazolopyrimidines as protein kinase inhibitors |
DE60319820T2 (en) | 2002-06-04 | 2009-03-26 | Schering Corp. | PYRAZOLOE1,5-ATPYRIMIDIN COMPOUNDS AS ANTIVIRAL AGENTS |
WO2004002940A1 (en) | 2002-07-01 | 2004-01-08 | Pharmacia & Upjohn Company | Inhibitors of hcv ns5b polymerase |
EP1532128A1 (en) | 2002-07-01 | 2005-05-25 | Pharmacia & Upjohn Company LLC | Inhibitors of hcv ns5b polymerase |
GB0216985D0 (en) | 2002-07-22 | 2002-08-28 | Glaxo Group Ltd | Compounds |
US7183302B2 (en) | 2002-08-12 | 2007-02-27 | Bristol-Myers Squibb Company | Iminothiazolidinones as inhibitors of HCV replication |
AU2003304040A1 (en) | 2002-10-08 | 2004-11-04 | Viropharma Incorporated | Anthranilic acid derivatives useful in treating infection with hepatitis c virus |
KR100453946B1 (en) | 2002-10-11 | 2004-10-20 | (주) 비엔씨바이오팜 | 6-methylpyridine derivative, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
JP2006506455A (en) | 2002-10-24 | 2006-02-23 | グラクソ グループ リミテッド | 1-acyl-pyrrolidine derivatives for the treatment of viral infections |
US20040162285A1 (en) | 2002-11-01 | 2004-08-19 | Pratt John K. | Anti-infective agents |
NZ539727A (en) | 2002-11-01 | 2008-01-31 | Viropharma Inc | Benzofuran compounds, compositions and methods for treatment and prophylaxis of hepatitis C viral infections and associated diseases |
US7902203B2 (en) | 2002-11-01 | 2011-03-08 | Abbott Laboratories, Inc. | Anti-infective agents |
CA2504385C (en) | 2002-11-01 | 2012-12-18 | Abbott Laboratories | Thiadiazine compounds and uses thereof |
US20040097492A1 (en) | 2002-11-01 | 2004-05-20 | Pratt John K | Anti-infective agents |
AU2003291886A1 (en) | 2002-12-10 | 2004-06-30 | Virochem Pharma Inc. | Thiophenederivatives for the treatment of flavivirus infections |
MXPA05006196A (en) | 2002-12-10 | 2006-01-27 | Virochem Pharma Inc | Compounds and methods for the treatment or prevention of flavivirus. |
US7098231B2 (en) | 2003-01-22 | 2006-08-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
US7223785B2 (en) | 2003-01-22 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
WO2004072243A2 (en) | 2003-02-07 | 2004-08-26 | Enanta Pharmaceuticals, Inc. | Macrocyclic hepatitis c serine protease inhibitors |
CA2516328A1 (en) | 2003-02-18 | 2004-09-02 | Pfizer Inc. | Inhibitors of hepatitis c virus, compositions and treatments using the same |
US7148226B2 (en) | 2003-02-21 | 2006-12-12 | Agouron Pharmaceuticals, Inc. | Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same |
GB0304494D0 (en) | 2003-02-27 | 2003-04-02 | Glaxo Group Ltd | Compounds |
ATE431737T1 (en) | 2003-03-10 | 2009-06-15 | Mitsubishi Corp | ANTHEPATITIS C VIRUS AGENTS AND ANTHIV AGENTS |
GB0307891D0 (en) | 2003-04-04 | 2003-05-14 | Angeletti P Ist Richerche Bio | Chemical compounds,compositions and uses |
WO2004092161A1 (en) | 2003-04-11 | 2004-10-28 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
KR100502394B1 (en) | 2003-06-04 | 2005-07-19 | (주) 비엔씨바이오팜 | 2-[2-(4-Morpholino)ethylamino]pyridine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
KR100502395B1 (en) | 2003-06-04 | 2005-07-19 | (주) 비엔씨바이오팜 | 4-[4-(4-Morpholino)anilino]pyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
WO2005014543A1 (en) | 2003-08-06 | 2005-02-17 | Japan Tobacco Inc. | Condensed ring compound and use thereof as hcv polymerase inhibitor |
WO2005016932A1 (en) | 2003-08-14 | 2005-02-24 | Wyeth | Pyranobenzothiophene derivatives to treat infection with hepatitis c virus |
WO2005019191A2 (en) | 2003-08-25 | 2005-03-03 | Abbott Laboratories | 1, 1-dioxido-4h-1,2,4-benzothiadiazine derivate und verwandte verbindungen als inhibitoren der hcv polymerase zur behandlung von hepatitis c |
US7378414B2 (en) | 2003-08-25 | 2008-05-27 | Abbott Laboratories | Anti-infective agents |
US7112601B2 (en) | 2003-09-11 | 2006-09-26 | Bristol-Myers Squibb Company | Cycloalkyl heterocycles for treating hepatitis C virus |
GB0323845D0 (en) | 2003-10-10 | 2003-11-12 | Angeletti P Ist Richerche Bio | Chemical compounds,compositions and uses |
US7026339B2 (en) | 2003-11-07 | 2006-04-11 | Fan Yang | Inhibitors of HCV NS5B polymerase |
EP1688420A4 (en) | 2003-11-19 | 2008-10-22 | Japan Tobacco Inc | 5-5-membered fused heterocyclic compound and use thereof as hcv polymerase inhibitor |
WO2005079799A1 (en) | 2004-02-13 | 2005-09-01 | Glaxo Group Limited | 4-acyl-piperazines as anti-viral agents |
CN103319464A (en) | 2004-02-20 | 2013-09-25 | 贝林格尔.英格海姆国际有限公司 | Viral polymerase inhibitors |
DE602005013922D1 (en) | 2004-02-24 | 2009-05-28 | Japan Tobacco Inc | CONDENSED HETEROTETRACYCLIC COMPOUNDS AND THEIR USE AS HCV POLYMERASE INHIBITOR |
DE602005002357T2 (en) | 2004-03-26 | 2008-05-29 | Smithkline Beecham Corp. | 4-CARBOXYPYRAZOL DERIVATIVES SUITABLE AS ANTIVIRAL AGENTS |
GB0408995D0 (en) | 2004-04-22 | 2004-05-26 | Glaxo Group Ltd | Compounds |
WO2005112640A2 (en) | 2004-05-13 | 2005-12-01 | Viropharma Incorporated | Compounds, compositions and methods for treatment and prophylaxis of hepatitis c viral infections and associated diseases |
GB0413087D0 (en) | 2004-06-11 | 2004-07-14 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
WO2006019831A1 (en) | 2004-07-14 | 2006-02-23 | Ptc Therapeutics, Inc. | Methods for treating hepatitis c |
PE20060569A1 (en) | 2004-07-16 | 2006-06-22 | Boehringer Ingelheim Int | INDOL CARBONYLAMINE COMPOUNDS AS INHIBITORS OF HCV POLYMERASE NE5B |
GB0416396D0 (en) | 2004-07-22 | 2004-08-25 | Angeletti P Ist Richerche Bio | Therapeutic agents |
CA2578636A1 (en) | 2004-07-22 | 2006-02-23 | Ptc Therapeutics, Inc. | Thienopyridines for treating hepatitis c |
KR100638709B1 (en) | 2004-07-28 | 2006-10-25 | (주) 비엔씨바이오팜 | N?Substituted?sulfamoylbenzoic acid derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
US7153848B2 (en) | 2004-08-09 | 2006-12-26 | Bristol-Myers Squibb Company | Inhibitors of HCV replication |
CA2577525C (en) | 2004-08-18 | 2010-03-30 | Pfizer Inc. | Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same |
JP4624419B2 (en) | 2004-08-23 | 2011-02-02 | エフ.ホフマン−ラ ロシュ アーゲー | Antiviral heterocyclic compounds |
GB0419850D0 (en) | 2004-09-07 | 2004-10-13 | Angeletti P Ist Richerche Bio | Therapeutic agents |
JP2008514611A (en) | 2004-09-23 | 2008-05-08 | ワイス | Derivatives of carbazole and cyclopentaindole for treating infection with hepatitis C virus |
GB0423673D0 (en) | 2004-10-25 | 2004-11-24 | Glaxo Group Ltd | Compounds |
GB0423672D0 (en) | 2004-10-25 | 2004-11-24 | Glaxo Group Ltd | Compounds |
KR20070068427A (en) | 2004-10-26 | 2007-06-29 | 이스티투토 디 리세르쉐 디 비올로지아 몰레콜라레 피. 안젤레티에스.피.에이. | Tetracyclic indole derivatives as antiviral agents |
JP4663733B2 (en) | 2004-10-29 | 2011-04-06 | シェーリング コーポレイション | Substituted 5-oxopyrazoles and substituted [1,2,4] triazoles as antiviral substances |
US7659263B2 (en) | 2004-11-12 | 2010-02-09 | Japan Tobacco Inc. | Thienopyrrole compound and use thereof as HCV polymerase inhibitor |
WO2006065590A2 (en) | 2004-12-16 | 2006-06-22 | Xtl Biopharmaceuticals Inc. | Pyridine and pyrimidine antiviral compositions |
JP2008526687A (en) | 2004-12-17 | 2008-07-24 | アナディス ファーマシューティカルズ インク | Pyridazinone compounds |
US8329703B2 (en) | 2005-02-15 | 2012-12-11 | Xtl Biopharmaceuticals Ltd. | Pyrazole compounds |
US20060217390A1 (en) | 2005-02-24 | 2006-09-28 | Esmir Gunic | Cycloalkl, aryl and heteroaryl amino isothiazoles for the treatment of Hepatitis C virus |
WO2006093801A1 (en) | 2005-02-25 | 2006-09-08 | Abbott Laboratories | Thiadiazine derivatives useful as anti-infective agents |
GB0505735D0 (en) | 2005-03-21 | 2005-04-27 | Glaxo Group Ltd | Compounds |
US20060223834A1 (en) | 2005-04-04 | 2006-10-05 | Vasu Nair | Diketo acids on nucleobase scaffolds as inhibitors of Flaviviridae |
WO2006117306A1 (en) | 2005-05-04 | 2006-11-09 | F. Hoffmann-La Roche Ag | Heterocyclic antiviral compounds |
GB0509326D0 (en) | 2005-05-09 | 2005-06-15 | Angeletti P Ist Richerche Bio | Therapeutic compounds |
EP2546246A3 (en) | 2005-05-13 | 2013-04-24 | Virochem Pharma Inc. | Compounds and methods for the treatment or prevention of flavivirus infections |
US7994360B2 (en) | 2005-05-16 | 2011-08-09 | Xtl Biopharmaceuticals Ltd. | Benzofuran compounds |
CA2613261A1 (en) | 2005-06-24 | 2006-12-28 | Genelabs Technologies, Inc. | Heteroaryl derivatives for treating viruses |
EP1910279A2 (en) | 2005-06-24 | 2008-04-16 | Migenix Inc. | Non-nucleoside anti-hepacivirus agents and uses thereof |
KR100700676B1 (en) | 2005-06-24 | 2007-03-28 | (주) 비엔씨바이오팜 | 6-4-Substituted-anilinopyrimidine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same |
US20070032522A1 (en) | 2005-07-01 | 2007-02-08 | Kumar Dange V | Antiviral agents |
US20070032488A1 (en) | 2005-08-05 | 2007-02-08 | Genelabs Technologies, Inc. | 6-Membered aryl and heteroaryl derivatives for treating viruses |
EP1915378A4 (en) | 2005-08-12 | 2009-07-22 | Boehringer Ingelheim Int | Viral polymerase inhibitors |
US7807838B2 (en) | 2005-08-24 | 2010-10-05 | Pfizer Inc. | Methods for the preparation of HCV polymerase inhibitors |
AR055395A1 (en) | 2005-08-26 | 2007-08-22 | Vertex Pharma | INHIBITING COMPOUNDS OF THE ACTIVITY OF SERINA PROTEASA NS3-NS4A OF HEPATITIS C VIRUS |
WO2007028789A1 (en) | 2005-09-07 | 2007-03-15 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Quinazoline derivatives as antiviral agents |
EP1928465A1 (en) | 2005-09-19 | 2008-06-11 | Arrow Therapeutics Limited | Benzodiazepine derivatives for treating hepatitis c infection |
GB0519485D0 (en) | 2005-09-23 | 2005-11-02 | Glaxo Group Ltd | Compounds |
EP1933859A2 (en) | 2005-09-30 | 2008-06-25 | Scynexis, Inc. | Methods and pharmaceutical compositions for the treatment and prevention of hepatitis c infection |
PE20070814A1 (en) | 2005-12-22 | 2007-08-16 | Smithkline Beecham Corp | COMPOUNDS DERIVED FROM 2-CARBOXYTHIOPHENE AS INHIBITORS OF HEPATITIS C VIRUS POLYMERASE (HCV) |
WO2007082554A1 (en) | 2006-01-23 | 2007-07-26 | Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa | Modulators of hcv replication |
GB0602046D0 (en) | 2006-02-01 | 2006-03-15 | Smithkline Beecham Corp | Compounds |
CA2640229A1 (en) | 2006-02-08 | 2007-08-16 | Wyeth | Sulfonamide derivatives to treat infection with hepatitis c virus |
US7456166B2 (en) | 2006-05-17 | 2008-11-25 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US7521441B2 (en) | 2006-05-22 | 2009-04-21 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
US7521442B2 (en) | 2006-05-25 | 2009-04-21 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
ES2343914T3 (en) | 2006-05-25 | 2010-08-12 | Bristol-Myers Squibb Company | INDOLOBENZAZEPIN HCV NS5B INHIBITORS CONDENSED WITH CYCLOPROPYL. |
US7452876B2 (en) | 2006-06-08 | 2008-11-18 | Bristol-Myers Squibb Company | Cyclopropyl fused indolobenzazepine HCV NS5B inhibitors |
WO2007147794A1 (en) | 2006-06-19 | 2007-12-27 | Smithkline Beecham Corporation | Furan derivatives and their use as antiviral agents |
US7462611B2 (en) | 2006-06-22 | 2008-12-09 | Anadys Pharmaceuticals, Inc. | Pyrro[1,2-b]pyridazinone compounds |
EP2044083A1 (en) | 2006-07-14 | 2009-04-08 | Genelabs Technologies, Inc. | Antiviral agents |
US7662958B2 (en) | 2006-07-19 | 2010-02-16 | Rolf Wagner | Anti-infective agents |
WO2008009078A2 (en) | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
PE20081113A1 (en) | 2006-07-20 | 2008-10-03 | Genelabs Tech Inc | POLYCYCLIC VIRAL INHIBITORS |
US8329159B2 (en) | 2006-08-11 | 2012-12-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
US7659270B2 (en) | 2006-08-11 | 2010-02-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
EP2054388A4 (en) | 2006-08-17 | 2009-10-28 | Boehringer Ingelheim Int | Viral polymerase inhibitors |
-
2008
- 2008-05-05 WO PCT/US2008/005758 patent/WO2008137126A2/en active Application Filing
- 2008-05-05 AT AT08767561T patent/ATE548044T1/en active
- 2008-05-05 US US12/598,802 patent/US8258116B2/en not_active Expired - Fee Related
- 2008-05-05 CN CN2012103709383A patent/CN102872461A/en active Pending
- 2008-05-05 AU AU2008248116A patent/AU2008248116A1/en not_active Abandoned
- 2008-05-05 ES ES08767561T patent/ES2381410T3/en active Active
- 2008-05-05 CN CN200880022055A patent/CN101815533A/en active Pending
- 2008-05-05 EP EP08767561A patent/EP2142215B1/en not_active Not-in-force
- 2008-05-05 CA CA002686051A patent/CA2686051A1/en not_active Abandoned
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- 2008-05-05 JP JP2010507423A patent/JP2010526143A/en active Pending
- 2008-05-05 EP EP12158199A patent/EP2494991A1/en not_active Withdrawn
- 2008-05-05 NZ NZ580917A patent/NZ580917A/en not_active IP Right Cessation
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100174077A1 (en) * | 2005-08-19 | 2010-07-08 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
US8637457B2 (en) | 2005-08-19 | 2014-01-28 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
US8871904B2 (en) | 2005-08-19 | 2014-10-28 | Vertex Pharmaceuticals Incorporated | Processes and intermediates |
Also Published As
Publication number | Publication date |
---|---|
CA2686051A1 (en) | 2008-11-13 |
US20100172866A1 (en) | 2010-07-08 |
US8258116B2 (en) | 2012-09-04 |
NZ580917A (en) | 2012-06-29 |
CN102872461A (en) | 2013-01-16 |
CN101815533A (en) | 2010-08-25 |
AU2008248116A1 (en) | 2008-11-13 |
ES2381410T3 (en) | 2012-05-28 |
MX2009011930A (en) | 2009-11-18 |
EP2142215B1 (en) | 2012-03-07 |
EP2142215A2 (en) | 2010-01-13 |
JP2010526143A (en) | 2010-07-29 |
WO2008137126A3 (en) | 2009-04-09 |
ATE548044T1 (en) | 2012-03-15 |
EP2494991A1 (en) | 2012-09-05 |
WO2008137126A2 (en) | 2008-11-13 |
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