WO2010081149A1 - Composés antiviraux, compositions et méthodes d'application - Google Patents

Composés antiviraux, compositions et méthodes d'application Download PDF

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Publication number
WO2010081149A1
WO2010081149A1 PCT/US2010/020767 US2010020767W WO2010081149A1 WO 2010081149 A1 WO2010081149 A1 WO 2010081149A1 US 2010020767 W US2010020767 W US 2010020767W WO 2010081149 A1 WO2010081149 A1 WO 2010081149A1
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phenyl
imidazo
isoxazol
trifluoromethyl
pyridazine
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PCT/US2010/020767
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English (en)
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Stephanie Chan
Ryan Lauchli
Martin Leivers
Sebastian Liehr
Son Pham
Tony Ton
Adam Villa
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Glaxosmithkline Llc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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

Definitions

  • This invention relates to the field of pharmaceutical industry.
  • compounds and compositions, methods for their preparation, and methods for their use in treating viral infections in patients mediated, at least in part, by a virus in the Flaviviridae family of viruses are disclosed.
  • Chronic infection with HCV is a major health problem associated with liver cirrhosis, hepatocellular carcinoma, and liver failure.
  • An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. 1 ' 2
  • In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
  • Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years.
  • Liver cirrhosis can ultimately lead to liver failure.
  • Liver failure resulting from chronic HCV infection is now recognized as a leading cause of liver transplantation.
  • HCV is a member of the Flaviviridae family of RNA viruses that affect animals and humans.
  • the genome is a single ⁇ 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
  • the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
  • the organization of structural and non- structural proteins in the HCV polyprotein is as follows: C-El-E2-p7-NS2-NS3- NS4a-NS4b-NS5a-NS5b.
  • HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes. 3 ' 4
  • IFN-alpha interferon alpha
  • ribavirin the standard treatment for chronic HCV.
  • IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections.
  • IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control.
  • a number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
  • the viral targets the NS3/4a protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. 6"8
  • antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication.
  • Watashi et al 9 show how antiviral activity can be achieved by inhibiting host cell cyclophilins.
  • a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans. 10 [0008] In view of the worldwide epidemic level of HCV and other members of the Flaviviridae family of viruses, and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses.
  • R 1 is H or F
  • R 2 is selected from the group consisting of H, Ci-C 6 alkyl, and Ci-C 6 alkyl substituted with
  • R 7 or one to three halo
  • Y is selected from the group consisting Of C 2 -C 6 alkoxy, Ci-C 6 alkoxy substituted with 1 to 3 R 5 , aryl, heteroaryl, and heteroaryl substituted with 1 to 2 R 6 ;
  • R 4 is CF 3 or CN;
  • R 5 is independently selected from the group consisting of halo, cyano, and cyclopropyl
  • R 6 is independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 5 alkoxy, and R 1 R 13 N- wherein R a and R b are independently H or Ci-C 5 alkyl; and
  • R 7 is selected from the group consisting of alkoxy, hydroxyl, carboxyl, cyano, and R c R d N- wherein R c and R d are independently H or C 1 -C 3 alkyl.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • a method for treating a viral infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to said patient a composition comprising a compound Formula (I), or a pharmaceutically acceptable salt thereof.
  • the viral infection is mediated by hepatitis C virus.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • C x _ y alkyl refers to alkyl groups having from x to y carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.
  • Aryl or “Ar” refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • Aryl or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • Cyano or “carbonitrile” refers to the group -CN.
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to an unsubstituted aromatic group of from 1 to 14 carbon atoms and 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6- yl). As used herein, the term heteroaryl does not refer to aromatic groups having two adjacent ring heteroatoms.
  • heteroaryl For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, the term "heteroaryl” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g. l,2,3,4-tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl).
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfmyl, or sulfonyl moieties.
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, imidazolyl, pyrrolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazolyl, or benzothienyl.
  • Compound and “compounds” as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgeneric formulae, including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.
  • Patient refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to 1) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups.
  • impermissible substitution patterns are well known to the skilled artisan.
  • R 2 is selected from the group consisting of H, Ci-C 6 alkyl, and Ci-C 6 alkyl substituted with R 7 or one to three halo;
  • Y is selected from the group consisting Of C 2 -C 6 alkoxy, Ci-C 6 alkoxy substituted with 1 to 3 R 5 , aryl, heteroaryl, and heteroaryl substituted with 1 to 2 R 6 ;
  • R 4 is CF 3 or CN
  • R 5 is independently selected from the group consisting of halo, cyano, and cyclopropyl
  • R 6 is independently selected from the group consisting of halo, C1-C3 alkyl, C1-C5 alkoxy, and R ⁇ 13 N- wherein R a and R b are independently H or C1-C5 alkyl; and R 7 is selected from the group consisting of alkoxy, hydroxyl, carboxyl, cyano, and R c R d N- wherein R c and R d are independently H or Ci-C 3 alkyl.
  • R 2 is H.
  • Y is Ci-C 6 alkoxy substituted with 1 to 3 R 5 ; and R 1 , R 5 , and L are as defined in Formula (I).
  • Y is C 1 - C 6 alkoxy substituted with three F.
  • Y is Ci-C 6 alkoxy substituted with cyano.
  • Y is Ci-C 6 alkoxy substituted with cyclopropyl.
  • Y is selected from the group consisting of aryl, heteroaryl and heteroaryl substituted with 1 to 2 R 6 ; and R 1 , R 6 , and L are as defined in Formula (I).
  • Y is selected from the group consisting of phenyl, pyrrolyl, thiophenyl, and pyridinyl.
  • Y is selected from the group consisting of unbranched alkoxys such as ethoxy, n-propoxy, n-butoxy, n-pentoxy, and n-hexoxy.
  • R 1 is H. In some embodiments, R 1 is F. [0038] In some embodiments, L is
  • L is N
  • compositions comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of one of the compounds, or pharmaceutically acceptable salts, described herein or mixtures of one or more of such compounds, or pharmaceutically acceptable salts.
  • kits for treating in patients a viral infection mediated at least in part by a virus in the Flaviviridae family of viruses, such as HCV which methods comprise administering to a patient that has been diagnosed with said viral infection or is at risk of developing said viral infection a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of one of the compounds, or pharmaceutically acceptable salts, described herein or mixtures of one or more of such compounds, or pharmaceutically acceptable salts.
  • present provided are use of the compounds of Formula (I), or pharmaceutically acceptable salts, for the preparation of a medicament for treating or preventing said infections.
  • the patient is a human.
  • RNA molecules are provided in some embodiments, provided are methods of treating or preventing viral infections in patients in combination with the administration of a therapeutically effective amount of one or more agents active against HCV.
  • Active agents against HCV include ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, pegylated interferon-alpha, alone or in combination with ribavirin or viramidine.
  • the additional agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or viramidine.
  • the active agent is interferon.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • stereoisomers i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the biphasic mixture was allowed to stir at 0 0 C for 20 minutes and then heated to 50 0 C. After 1 hour, the reaction mixture was cooled, quenched with saturated, aqueous NaHCO 3 and partitioned. The aqueous phase was extracted with CH 2 Cl 2 (2x) and the combined organic phases were washed with brine (Ix), dried over Na 2 SO 4 , filtered and concentrated to afford the chloromethyl aryl isoxazole.
  • the reaction initially became a clear solution upon DMF addition, subsequently developed a white precipitate upon removal of the cold bath, and then became a clear solution again upon further warming to RT.
  • the reaction was quenched with H 2 SO 4 (ca. 100 mL, IN), and was stirred vigorously for 15 min. The layers were separated, and the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated.
  • the product was purified via SiO 2 flash chromatography using 0-10% EtOAc in hexanes to give the product as a colorless liquid. Yield: 15.6 g, 95%.
  • the 4-trifluoromethoxy-2-trifluoromethyl-phenylamine (607 mg, 2.5 mmol) was suspended in water (2.6 mL), and cone, sulfuric acid (1 mL) was added. The mixture was heated to boiling and rapidly stirred, and then allowed to cool to RT with continued stirring. The resulting suspension was stirred in an ice bath as sodium nitrite solution (190 mg in 1.2 mL of water) was added drop-wise. After stirring for 20 min in the ice bath, a solution of potassium iodide (0.83 g in 1.0 mL of water) was added in a steady stream. A trace of copper bronze was added and the reaction was briefly heated to boiling.
  • the reaction was stirred at 80 0 C for 3 h more.
  • the reaction mixture was diluted with 1.5 L of hexanes and filtered through celite. The solvents were removed to give tan crystals. These crystals were dissolved in methanol (250 mL) and potassium carbonate (Ig) was added.
  • the mixture was stirred at RT for 2 h.
  • the reaction mixture was then partitioned between ether (500 mL) and water (150 mL). The organic layer was washed with water until it was no longer basic by pH paper (about 10 times).
  • the organic layer was washed with brine, dried over sodium sulfate, and concentrated then purified via silica gel chromatography using EtOAc in hexanes (2-10%).
  • the product was then treated with acetic acid (250 mL), THF (120 mL), and water (60 mL) and heated to 93 0 C for 1 h.
  • the cooled reaction mixture was partitioned between EtOAc and water.
  • the organic layer was washed with water, saturated sodium bicarbonate several times until the aqueous layer was neutral, water, and brine.
  • the organic layer was dried over sodium sulfate, concentrated onto celite, and purified on silica eluting with EtOAc in hexanes (10- 90%).
  • the product was collected as a yellow solid, which was shown by NMR to be impure.
  • the product was triturated with 3:1 hexanes : EtOAc.
  • the solid material was collected by filtration.
  • the mixture was filtered, triturated with ethanol and re-filtered.
  • the ethanol solution was purified on silica yielding the desired product (1.4 g).
  • the insoluble material from the trituration was purified on silica eluting with methanol in dichloromethane (0-10%) to give more of the product as an off-white solid (4.7 g).
  • the organic layer was washed with water, 1 N HCl, water, and brine, and was dried over sodium sulfate.
  • the organic layer was concentrated onto celite and the product was purified on silica eluting with EtOAc in hexanes (10-50%). The yield was 0.83 g.
  • the alcohol 301 mg was dissolved in DCM (7 niL) under Ar and Dess-Martin periodinane (450 mg) was added. The reaction was stirred at room temperature for 1 h.
  • the reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate/sodium thiosulfate, water, and brine, and dried over sodium sulfate.
  • Flaviviridae family viruses such as hepatitis C virus.
  • the compounds, or pharmaceutically acceptable salts, described herein inhibit viral replication by inhibiting the enzymes involved in replication, including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of Flaviviridae viruses.
  • the compounds, or pharmaceutically acceptable salts, described herein will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound, or pharmaceutically acceptable salt, described herein, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • the drug can be administered more than once a day, such as once or twice a day.
  • Therapeutically effective amounts of compounds, or pharmaceutically acceptable salts, described herein may range from approximately 0.01 to 50 mg per kilogram body weight of the recipient per day; such as about 0.01-25 mg/kg/day, for example, from about 0.1 to 10 mg/kg/day. Thus, in some embodiments, for administration to a 70 kg person, the dosage range would be about 7-70 mg per day.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous or subcutaneous
  • the manner of administration is oral using a convenient daily dosage regimen that can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Another manner for administering compounds of described herein is inhalation.
  • the choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance.
  • the compound can be formulated as liquid solution, suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDI metered dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract.
  • MDFs typically are formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose.
  • a measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
  • compositions are comprised of in general, a compound, or pharmaceutically acceptable salt, described herein in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds.
  • excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound, or pharmaceutically acceptable salt, described herein in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of a compound, or pharmaceutically acceptable salt, described herein based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In some embodiments, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations are described in the Formulation Examples section below.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound, or pharmaceutically acceptable salt, described herein in combination with a therapeutically effective amount of another active agent against RNA-dependent RNA virus and, in particular, against HCV.
  • Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of HCV NS3 serine protease, or an inhibitor of inosine monophosphate dehydrognease, interferon- ⁇ , pegylated interferon- ⁇ (peginterferon- ⁇ ), a combination of interferon- ⁇ and ribavirin, a combination of peginterferon- ⁇ and ribavirin, a combination of interferon- ⁇ and levovirin, and a combination of peginterferon- ⁇ and levovirin.
  • Interferon- ⁇ includes, but is not limited to, recombinant interferon- ⁇ 2a (such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ), interferon- ⁇ 2b (such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA), a consensus interferon, and a purified interferon- ⁇ product.
  • interferon- ⁇ 2a such as ROFERON interferon available from Hoffman-LaRoche, Nutley, NJ
  • interferon- ⁇ 2b such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA
  • a consensus interferon such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA
  • the agents active against hepatitis C virus also include agents that inhibit HCV proteases, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and inosine 5 '-monophosphate dehydrogenase.
  • Other agents include nucleoside analogs for the treatment of an HCV infection.
  • Still other compounds include those disclosed in WO 2004/014313 and WO 2004/014852 and in the references cited therein.
  • the patent applications WO 2004/014313 and WO 2004/014852 are hereby incorporated by references in their entirety.
  • Specific antiviral agents include Omega IFN (BioMedicines Inc.), BILN-2061 (Boehringer Ingelheim), Summetrel (Endo Pharmaceuticals Holdings Inc.), Roferon A (F. Hoffman-La Roche), Pegasys (F. Hoffman-La Roche), Pegasys/Ribaravin (F. Hoffman-La Roche), CellCept (F.
  • compositions and methods described herein contain a compound, or pharmaceutically acceptable salt, described herein and interferon.
  • the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.
  • compositions and methods described herein contain a compound, or pharmaceutically acceptable salt, described herein and a compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti- sense RNA, Imiquimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • a compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti- sense RNA, Imiquimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.
  • the compound having anti-HCV activity is Ribavirin, levovirin, viramidine, thymosin alpha- 1, an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, or pegylated interferon-alpha alone or in combination with Ribavirin or viramidine.
  • the compound having anti-HCV activity is said agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with Ribavirin or viramidine.
  • Compounds can exhibit anti-hepatitis C activity by inhibiting viral and host cell targets required in the replication cycle.
  • a number of assays have been published to assess these activities.
  • a general method that assesses the gross increase of HCV virus in culture is disclosed in U.S. Patent No. 5,738,985 to Miles et al.
  • In vitro assays have been reported in Ferrari et al J. of Vir., 73:1649- 1654, 1999; Ishii et al, Hepatology, 29:1227-1235, 1999; Lohmann et al, J. of Bio. Chem., 274:10807-10815, 1999; and Yamashita et al, J. of Bio. Chem., 273:15479-15486, 1998.
  • a cell line, ET Human-lucubineo-ET was used for screening of compounds, or pharmaceutically acceptable salts, described herein for inhibition of HCV RNA dependent RNA polymerase.
  • the ET cell line was stably transfected with RNA transcripts harboring a I389luc-ubi- neo/NS3-37ET; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I; K1846T) (Krieger at al, 2001 and unpublished).
  • the ET cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM Glutamine, Penicillin (100 IU/mL)/Streptomycin (100 ⁇ g/mL), Ix nonessential amino acids, and 250 ⁇ g/mL G418 ("Geneticin"). They were all available through Life Technologies (Bethesda, MD). The cells were plated at 0.5-1.0 xlO 4 cells/well in the 96 well plates and incubated for 24 hrs before adding the test compounds. The compounds were then added to the cells to achieve a final concentration of 5 or 50 ⁇ M.
  • Luciferase activity was measured 48-72 hours later by adding a lysis buffer and the substrate (Catalog number Glo-lysis buffer E2661 and Bright-Glo luciferase system E2620 Promega, Madison, WI). Cells should not be too confluent during the assay. Percent inhibition of replication was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell proliferation reagent, WST-I (Roche, Germany). The compounds showing antiviral activities, but no significant cytotoxicities were chosen to determine the EC 50 and TC 50 , the effective concentration and toxic concentration at which 50% of the maximum inhibition is observed . For these determinations, 6 dilutions of each compound were used. Compounds were typically diluted 3 fold to span a concentration range of 250 fold. EC50 and similarly TC50 values were calculated by fitting %inhibition at each concentration to the following equation:
  • compounds of Formula (I) are active in treating viral infections in patients mediated, at least in part, by a virus in the Flaviviridae family of viruses, as shown by the data below. It is further discovered that compounds of Formula (I) such as those in Tables 2a, 3a, 4a, 5a, 6a, 7a, 8a, and 9a are unexpectedly more active than compounds of similar structures such as those in Tables 2b, 3b, 4b, 5b, 6b, 7b, and 8b, which were previously disclosed in U.S. Patent Application No.: 12/216,920. Table 2a
  • Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mg distilled water q.s. (quantity sufficient) to 100 mL Formulation Example 4
  • a suppository of total weight 2.5 g is prepared by mixing the compound with Witepsol® H- 15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:

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  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de Formule (I), leurs sels de qualité pharmaceutique, leurs compositions et leurs méthodes de synthèse et d'application au traitement d'infections virales faisant intervenir au moins un virus de la famille virale Flaviviridae.
PCT/US2010/020767 2009-01-12 2010-01-12 Composés antiviraux, compositions et méthodes d'application WO2010081149A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004099241A1 (fr) * 2003-05-09 2004-11-18 Boehringer Ingelheim International Gmbh Poche de liaison de l'inhibiteur de la polymerase ns5b du virus de l'hepatite c
WO2006033703A1 (fr) * 2004-07-27 2006-03-30 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, procedes d'utilisation et de preparation correspondants

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004099241A1 (fr) * 2003-05-09 2004-11-18 Boehringer Ingelheim International Gmbh Poche de liaison de l'inhibiteur de la polymerase ns5b du virus de l'hepatite c
WO2006033703A1 (fr) * 2004-07-27 2006-03-30 Gilead Sciences, Inc. Imidazo[4,5-d]pyrimidines, procedes d'utilisation et de preparation correspondants

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