WO2011091532A1 - Composés inhibiteurs du virus de l'hépatite c - Google Patents

Composés inhibiteurs du virus de l'hépatite c Download PDF

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Publication number
WO2011091532A1
WO2011091532A1 PCT/CA2011/050041 CA2011050041W WO2011091532A1 WO 2011091532 A1 WO2011091532 A1 WO 2011091532A1 CA 2011050041 W CA2011050041 W CA 2011050041W WO 2011091532 A1 WO2011091532 A1 WO 2011091532A1
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Prior art keywords
alkyl
compound
pharmaceutically acceptable
added
mmol
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PCT/CA2011/050041
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English (en)
Inventor
Cyrille Kuhn
Punit K . Bhardwaj
Marc-Andre Poupart
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Boehringer Ingelheim International Gmbh
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Priority to EP11736580.9A priority Critical patent/EP2528926A4/fr
Priority to JP2012550280A priority patent/JP2013518062A/ja
Publication of WO2011091532A1 publication Critical patent/WO2011091532A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds, and their use as inhibitors of the function of N5A protein encoded by HCV, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.
  • HCV hepatitis C virus
  • WO 2009/102633 disclose NS5A inhibitors that are described as being useful to treat HCV infection.
  • the present invention provides a novel series of compounds having inhibitory activity against HCV replication.
  • the compounds of the invention may be used to inhibit the function of the NS5A protein encoded by HCV and may be used to reduce HCV replication.
  • the invention provides a compound of Formula (I) and a racemate, diastereoisomer, optical isome
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 are each independently selected from CH or N;
  • R A and R B are each 1 or 2 substituents independently selected from hydrogen, (C 1-6 )alkyl, (C 1-6 )haloalkyl, halo, -0-(C 1-6 )alkyl, NH 2 , -NH((C-,.
  • R 1 and R 2 are each independently selected from (C 1-6 )alkyl, (C 3 . 7 )cycloalkyl and -(C -6 )alkyl-aryl;
  • the invention provides a compound of Formula (II) and a racemate, diastereoisomer optical isomer or salt thereof:
  • R 1 and R 2 are each independently selected from (C -6 )alkyl, (C 3 . 7 )cycloalkyl and -(C _ 6 )alkyl-aryl;
  • each said alkyl, cycloalkyl and alkyl-aryl is optionally substituted 1 to 3 times with aryl, -0-(C 1-6 )alkyl and -N(R f )R g ;
  • Another aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as a medicament.
  • composition comprising an anti-hepatitis C virally effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable carrier medium or auxiliary agent.
  • the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent.
  • the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a hepatitis C viral infection in a human being having or at risk of having the infection.
  • Another important aspect of the invention involves a method of treating or preventing a hepatitis C viral infection in a human being by administering to the human being an anti-hepatitis C virally effective amount of a compound of Formula (I), a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of hepatitis C viral infection in a human being.
  • An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat a hepatitis C viral infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound of Formula (I) according to this invention or a pharmaceutically acceptable salt thereof.
  • Still another aspect of this invention relates to a method of inhibiting the replication of hepatitis C virus comprising exposing the virus to an effective amount of the compound of Formula (I), or a salt thereof, under conditions where replication of hepatitis C virus is inhibited.
  • the invention provides novel intermediates useful in the production of compounds of Formua (I) or Formula (II).
  • the novel intermediates comprise one or more of the intermediates selected from the group consisting of intermediates designated 15a1 , 15b1 , 15c1 , 15d1 , 16a1 , 16b1 , 17a1 , 17a1 , 18a1 , 26a3, 27a1 , 27a2, 28a1 , 29a1 and 30a1 , as disclosed in the Examples.
  • C-i_ 6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • the first named subgroup is the radical attachment point, for example, the substituent "-C-i. 3 -alkyl-aryl” means an aryl group which is bound to a -C-i_ 3 -alkyl group, wherein the -C-i_ 3 -alkyl-group is bound to the core.
  • n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
  • C-i_ 5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )
  • Carbocyde means a mono- or multi-ring ring structure consisting only of carbon containing between one and four rings wherein such rings may be attached together in a pendent manner or may be fused.
  • the term “carbocyde” refers to fully saturated and aromatic ring systems and partially saturated ring systems.
  • the term “carbocyde” additionally encompasses spiro systems, and bridged systems.
  • C 3 . n -cycloalkyl wherein n is an integer 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
  • C 3 . 7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • aryl denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
  • halo as used herein is intended to mean a halogen substituent selected from fluoro, chloro, bromo or iodo.
  • An asterisk or the designation ' is used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
  • enantiomers of the compounds of the present invention Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or enantiomeric purity, are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • such salts include acetates, ascorbates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca- edetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, edisylates, ethane disulfonates, estolates esylates, fumarates, gluceptates, gluconates, glutamates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, malates, maleates, mandelates, methanesulfonates, mesylates, methylbromides, methylnitrates, methylsulfates, mucate
  • phosphates/diphosphates polygalacturonates, propionates, salicylates, stearates subacetates, succinates, sulfamides, sulfates, tannates, tartrates, teoclates, toluenesulfonates, triethiodides, ammonium, benzathines, chloroprocaines, cholines, diethanolamines, ethylenediamines, meglumines and procaines.
  • Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1 -19; and Handbook of Pharmaceutical Salts, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley- VCH, 2002).
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention e.g. trifluoro acetate salts
  • Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
  • treatment is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the hepatitis C disease and/or to reduce viral load in a patient.
  • treatment also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood.
  • prevention means the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease.
  • terapéuticaally effective amount means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • R 1 -A is selected from (C -6 )alkyl, (C 3 . 7 )cycloalkyl and -(C _ 6 )alkyl-aryl;
  • R 1 -B R 1 is selected from (C 1-5 )alkyl, (C 3 . 5 )cycloalkyl and -(C-i. 3 )alkyl-phenyl;
  • R 1 -C R 1 is selected from (C 1-5 )alkyl, (C 3 )cycloalkyl and -(C-i_ 2 )alkyl-phenyl;
  • each said alkyl, cycloalkyl and alkyl-phenyl is optionally substituted 1 to 2 times with phenyl, -0-(C 1-2 )alkyl and -N(R f )R g ;
  • R 1 -D R 1 is selected from (C _ 5 )alkyl
  • each said alkyl is optionally substituted 1 to 2 times with -0-(d)alkyl and -N(R f )R g ;
  • R 1 is selected from
  • R 1 is selected from
  • R 2 is selected from (C -6 )alkyl, (C 3 . 7 )cycloalkyl and -(C-i_ 6 )alkyl-aryl;
  • R 2 -C R 2 is selected from (C 1-5 )alkyl, (C 3 )cycloalkyl and -(C _ 2 )alkyl-phenyl;
  • each said alkyl, cycloalkyl and alkyl-phenyl is optionally substituted 1 to 2 times with phenyl, -0-(d. 2 )alkyl and -N(R f )R g ;
  • R 2 -D R 2 is selected from (C 1-5 )alkyl
  • each said alkyl is optionally substituted 1 to 2 times with -0-(d)alkyl and -N(R f )R g ;
  • R 2 -E R 2 is selected from
  • R 2 is selected from
  • Suitable preparations for administering the compounds of Formula I will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc.
  • compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.- % of the composition as a whole.
  • Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants .
  • the tablets may also consist of several layers.
  • the pharmaceutical composition of this invention may additionally comprise at least one other anti-HCV agent.
  • other anti-HCV agent means those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms of disease.
  • agents can be selected from: immunomodulatory agents, inhibitors of HCV NS3 protease, inhibitors of the function of NS5A protein encoded by HCV, inhibitors of HCV polymerase or inhibitors of another target in the HCV life cycle.
  • anti-HCV agents examples include, a- (alpha), ⁇ - (beta), ⁇ - (delta), ⁇ - (gamma), ⁇ - (omega) or x- (tau) interferon, pegylated a-interferon, ribavirin, amantadine, taribavirin (Viramidine), Nitazoxannide and BMS-791325.
  • immunomodulatory agent includes those agents
  • Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors, class I interferons, class II interferons, consensus interferons, asialo-interferons, pegylated interferons and conjugated interferons, including but not limited to interferons conjugated with other proteins including but not limited to human albumin.
  • Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class II interferons all bind to receptor type II.
  • class I interferons include, but are not limited to, ⁇ -, ⁇ -, ⁇ -, ⁇ -, and ⁇ -interferons
  • class II interferons include, but are not limited to, ⁇ -interferons.
  • inhibitor of HCV NS5A means an agent (compound or biological) that is effective to inhibit the function of HCV NS5A in a human being.
  • Inhibitors of HCV NS5A include, for example, BMS-790052, AZD7295 and PPI-461.
  • inhibitor of HCV NS3 protease means an agent
  • HCV NS3 protease (compound or biological) that is effective to inhibit the function of HCV NS3 protease in a human being.
  • Inhibitors of HCV NS3 protease include, for example, those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO
  • inhibitor of HCV polymerase means an agent (compound or biological) that is effective to inhibit the function of an HCV polymerase in a human being. This includes, for example, inhibitors of HCV NS5B polymerase. Inhibitors of HCV polymerase include for example, those compounds described in: WO 03/007945, WO 03/010140, WO 03/010141 , US 6,448, 281 , WO 02/04425, WO 2008/019477, WO 2007/087717, WO 2009/018656, WO2009/018657, WO
  • inhibitors of an HCV polymerase include RG-7128, GS9190, IDX184, IDX375, PSI-7977, MK-3281 , filibuvir (PF868554), VCH-222, VCH-759, ANA598, ABT-333, ABT-072 and Bl 207127.
  • inhibitor of another target in the HCV life cycle means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HCV in a human being other than by inhibiting the function of the HCV NS3 protease. This includes agents that interfere with either host or HCV viral targets necessary for the HCV life cycle or agents which specifically inhibit in HCV cell culture assays through an undefined or incompletely defined mechanism.
  • Inhibitors of another target in the HCV life cycle include, for example, agents that inhibit viral targets such as Core, E1 , E2, p7, NS2/3 protease, NS3 helicase, NS4A, NS5B polymerase, NS5A and internal ribosome entry site (IRES), or host targets such as cyclophilin B, phosphatidylinositol 4-kinase Ilia, CD81 , SR-B1 , Claudin 1 , VAP-A, VAP-B.
  • viral targets such as Core, E1 , E2, p7, NS2/3 protease, NS3 helicase, NS4A, NS5B polymerase, NS5A and internal ribosome entry site (IRES)
  • host targets such as cyclophilin B, phosphatidylinositol 4-kinase Ilia, CD81 , SR-B1 , Claudin 1 , VAP-
  • inhibitors of another target in the HCV life cycle include SCY-635, ITX5061 , NOV-205, AZD7295, BIT-225, NA808, MK-1220, PF-4878691 , MX-3253, GS 9450, BMS-790052, ISIS-14803, GS9190, NIM-81 1 , and DEBIO-025.
  • HIV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HIV in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HIV in a human being. HIV inhibitors include, for example, nucleoside inhibitors, non-nucleoside inhibitors, protease inhibitors, fusion inhibitors and integrase inhibitors.
  • HAV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HAV in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HAV in a human being.
  • HAV inhibitors include Hepatitis A vaccines, for example, Havrix ® (GlaxoSmithKline), VAQTA ® (Merck) and Avaxim ® (Aventis Pasteur).
  • HBV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HBV in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HBV in a human being.
  • HBV inhibitors include, for example, agents that inhibit HBV viral DNA polymerase or HBV vaccines.
  • HBV inhibitors include Lamivudine (Epivir-HBV ® ), Adefovir Dipivoxil, Entecavir, FTC (Coviracil ® ), DAPD (DXG), L-FMAU (Clevudine ® ), AM365 (Amrad), Ldt (Telbivudine), monoval-LdC (Valtorcitabine), ACH-126,443 (L- Fd4C) (Achillion), MCC478 (Eli Lilly), Racivir (RCV), Fluoro-L and D nucleosides, Robustaflavone, ICN 2001-3 (ICN), Bam 205 (Novelos), XTL-001 (XTL), Imino- Sugars (Nonyl-DNJ) (Synergy), HepBzyme; and immunomodulator products such as: interferon alpha 2b, HE2000 (Hollis-Eden), Theradigm (Epivudi
  • combination therapy is contemplated wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, is co-administered with at least one additional agent selected from: an antiviral agent, an
  • immunomodulatory agent an inhibitor of HCV NS3 protease, an inhibitor of HCV polymerase, an inhibitor of another target in the HCV life cycle, an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form.
  • these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit.
  • Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • the dose range of the compounds of the invention applicable per day is usually from 0.01 to 100 mg/kg of body weight, preferably from 0.1 to 50 mg/kg of body weight.
  • Each dosage unit may conveniently contain from 5% to 95% active compound (w/w).
  • Preferably such preparations contain from 20% to 80% active compound.
  • the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
  • composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
  • Analytical UPLC is performed under standard conditions using one of the following specific measuring conditions: Analytical UPLC is carried out under standard conditions using a Waters ACQUITY UPLC ® HSS T3 column (1.8 ⁇ , 2.1 x 50 mm) eluting with a segmented linear acetonitrile gradient containing 0.06%TFA (v/v) over 2.6 minutes at 0.9 ml/min.
  • Analytical UPLC is also carried out under standard conditions using a Waters ACQUITY UPLC ® BEH C18 column (1.8 ⁇ , 2.1 x 30 mm) eluting with a linear methanol gradient containing 10 mM Ammonium Bicarbonate (pH 10) over 2.2 min at 0.75 ml/min or a Waters ACQUITY UPLC ® HSS C18 column (1.8 ⁇ , 2.1 x 30 mm) eluting with a linear methanol gradient containing 10 mM Ammonium Formate (pH 3.8) over 2.3 minutes at 0.8 ml/min.
  • Mass spectral analyses are recorded using electrospray mass spectrometry. Abbreviations or symbols used herein include:
  • HPLC high performance liquid chromatography
  • HOBt 1 -hydro xybenzotriazole
  • HSS high strength silica
  • IC 50 50% inhibitory concentration
  • 'Pr or i-Pr 1- methylethyl (/so-propyl)
  • LC-MS liquid chromatography-mass spectrometry
  • m/z mass-to-charge ratio
  • [M+H] + protonated molecular ion
  • Me methyl
  • MeCN MeCN
  • NBS N-bromosuccinimide
  • NMP N-Methyl-2- pyrrolidone
  • NMR nuclear magnetic resonance spectroscopy
  • OBD optimum bed density
  • Pd(dppf)CI 2 1 ,1 '-bis(diphenylphosphino)-ferrocenedichloropalladium(ll);
  • Ph phenyl
  • Pr propyl
  • Prep LCMS preparative liquid chromatography-mass spectrometry
  • RP-HPLC reversed-phase high pressure liquid chromatography
  • RT room temperature (approximately 18°C to 25°C)
  • ferf-butyl or t-butyl 1 ,1- dimethylethyl
  • TBTU 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TLC thin layer chromatography
  • TMSOTf trifluoromethanesulfonic acid trimethylsilylester
  • t R retention time
  • UPLC ultra performance liquid chromatograhy.
  • Step 1
  • Pd(P(Ph) 3 ) 4 (1.9 g, 1.6 mmoles) is added and the solution is degassed for 10 minutes.
  • the reaction mixture is heated at 1 15°C for 5 hours, cooled to RT, diluted with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over Na 2 S0 4 , filtered and concentrated.
  • the product is purified by flash chromatography using 15%-25% EtOAc in petroleum ether to afford 3a1.
  • reaction mixture is cooled to RT and poured into water (400 mL).
  • the precipitate is collected by filtration and dissolved in DCM (500 mL).
  • the organic layer is washed with water, dried over Na 2 S0 4 , filtered and concentrated.
  • the residue is dissolved in 2% MeOH in DCM and filtered over a silica gel column to afford 6a2.
  • Step 1
  • Boc-O-methyl-L-serine dicyclohexylammonium salt 11a1 (Chem-lmpex) (4.5 g, 1 1.2 mmoles) in 1 ,4-dioxane at 0°C is added an 8M HCI solution in 1 ,4-dioxane and the mixture is stirred for 2 hours at RT. The reaction mixture is concentrated and co- distilled with 1 ,4-dioxane until dryness.
  • the salt is dissolved in 1 N NaOH (22.5 ml_, 22.5 mmoles) and Na 2 C0 3 (0.6 g, 5.6 mmoles) is added at 0°C followed by dropwise addition of methyl chloroformate (0.87 ml_, 1 1.2 mmoles).
  • the reaction mixture is stirred at RT for 3 hours.
  • the aqueous layer is extracted with DCM and the organic layer is washed with brine, dried over Na 2 S0 4 and concentrated to afford 11a2.
  • Step 1
  • 12a2 is dissolved in a mixture of THF (1 .7 mL) / MeOH (0.6 mL). 1 N NaOH (0.5 mL, 0.5 mmol) is added and the mixture is stirred at RT for 2 hours. The reaction is concentrated, co-evaporated successively with MeOH, MeCN and Et 2 0 and dried under high vacuum to afford 12a3.
  • Step 1
  • Step 2 14a3 (415 g, 2022 mmol) is dissolved in DMF (1250 mL) at RT. TFA (156 ml_, 2022 mmol) is added, followed after 2 minutes by freshly distilled cyclopentadiene (Aldrich) 14a4 (267 g, 4044 mmol) and water (1.1 ml, 60.7 mmol). The mixture is stirred at RT overnight. The reaction is concentrated and the residue is poured into a 10% aqueous solution of NaHC0 3 . To this mixture is added Et 2 0, water and solid Na 2 C0 3 until the pH is ⁇ 8. The organic layer is separated and the aqueous layer is extracted with Et 2 0. The combined organic layers are washed with water, brine and dried over Na 2 S0 4 . The solvent is evaporated and the product is purified by flash chromatography using 15% EtOAc in heptanes to afford 14a5.
  • Step 3
  • 14a6 (102 g, 329 mmol) is dissolved in EtOH (400 mL).
  • K 2 C0 3 (45.5 g, 329 mmol) is added and the mixture is degassed with nitrogen.
  • Pd/C (7.0 g, 65.8 mmol) is added and H 2 -pressure (8 bar) is applied.
  • the reaction is stirred at RT for 20 hours.
  • the reaction mixture is degassed with nitrogen and filtered.
  • the filtrate is concentrated and the residue is suspended in Et 2 0. 4N HCI in 1 ,4-dioxane (82 mL, 329 mmol) is then added.
  • the resulting solid is filtered, washed with Et 2 0 and dried to afford 14a7.
  • Step 1
  • 10h2 (19.1 mg, 100 ⁇ ) is loaded in an 8 mL vial. Solutions of 16a1 (25 mg, 40 ⁇ ) in DMF (0.5 mL) and HATU (36.1 mg, 95 ⁇ ) in DMF (0.5 mL) are added followed by DIPEA (75 ⁇ , 429 ⁇ ). The mixture is stirred at RT for 1 hour and neutralized with AcOH (100 y L). The product is purified by preparative RP-HPLC. The fractions are concentrated and lyophilized to afford 1016.
  • Example 21 The following compounds are prepared analogously to the procedure described in Example 20 starting from the appropriate amino acid derivative: 1006, 1007, 1015, 1017, 1018, 1019 and 1021 .
  • Example 21 The following compounds are prepared analogously to the procedure described in Example 20 starting from the appropriate amino acid derivative: 1006, 1007, 1015, 1017, 1018, 1019 and 1021 .
  • 10d2 (28.0 mg, 133 ⁇ ), 16a1 (27 mg, 43 ⁇ ) and HATU (50 mg, 132 ⁇ ) are loaded in an 8 mL vial.
  • DMF (1 mL) is added followed by DIPEA (40 ⁇ _, 230 ⁇ ) and the mixture is stirred at RT for 1 hour.
  • the product is purified by preparative RP-HPLC. The fractions are concentrated and lyophilized to afford 1004.
  • 10b2 (20 mg, 1 15 ⁇ ) is loaded in an 8 mL vial. Solutions of 16b1 (25 mg, 38 ⁇ ) in DMF (0.5 mL) and HATU (34.3 mg, 90 ⁇ ) in DMF (0.5 mL) are added followed by DIPEA (90 ⁇ , 515 ⁇ ). The mixture is stirred at RT for 1 hour and neutralized with AcOH (100 y L). The product is purified by preparative RP-HPLC. The fractions are concentrated and lyophilized to afford 2011 .
  • Step 1
  • 26a2 (27.5 g, 59.6 mmol) is dissolved in xylene (300 mL) and NH 4 OAc (92 g, 1 192 mmol) is added. The reaction is heated to 140°C and stirred for 18 hours. After cooling to RT, the mixture is diluted with water and extracted with EtOAc. The combined organic layers are washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated. The residue is purified by flash chromatography using 33% EtOAc in heptanes to afford 26a3 (t R (min) 1.7; (M+H) + 418.2/420.2).
  • Step 1
  • 29a1 (204 mg, 0.43 mmol), a mixture of 27a1 and 27a2 (200 mg, 0.43 mmol) and a 2M aqueous solution of Na 2 C0 3 (0.7 ml_, 1.4 mmol) are loaded in a 20 mL vial.
  • DME 2.2 mL
  • Pd(P(Ph) 3 ) 4 is added, the mixture is degassed with argon for 5 minutes and heated to 90°C for 60 hours.
  • the reaction mixture is partitioned between EtOAc and water and the layers are separated.
  • the aqueous layer is extracted with DCM.
  • the combined organic layers are dried with MgS0 4 , filtered and concentrated.
  • the product is purified by flash chromatography using 0% to 10% MeOH in DCM to afford 30a1 (t R (min) 1.6; (M+H) + 634.2).
  • 30a1 (267 mg, 0.36 mmol) is dissolved in a 4M solution of HCI in 1 ,4-dioxane (1.8 mL, 7.3 mmol) and stirred at RT overnight. The mixture is concentrated and dried under high vacuum to afford 30a2.
  • 11 a2 (8.8 mg, 60 ⁇ ) is loaded in an 8 mL vial. Solutions of 30a2 (30 mg, 40 ⁇ ) in DMF (0.5 mL) and HATU (20 mg, 53 ⁇ ) in DMF (0.5 mL) are added followed by DIPEA (75 ⁇ , 429 ⁇ ). The mixture is stirred at RT for 1 hour and neutralized with AcOH (100 y L). The product is purified by preparative RP-HPLC The fractions are concentrated and lyophilized to afford 1013.
  • HCVPVI a and HCVPVI b Two subgenomic replicons designated HCVPVI a and HCVPVI b are generated based on the wildtype sequence for genotype 1 a, strain H77 (GenBank accession no. AF009606) and the wildtype sequence CON-1 genotype b (GenBank accession number AJ238799), see Science 1999, 285: 1 10-1 13.
  • HCV genotype 1 a subgenomic fragment NS2-NS3-NS4A-NS4B-NS5A-NS5B is drawn from the reference nucleic acid encoding residues 81 1 to 301 1 of AF009606, HCV genotype 1 b subgenomic fragment NS2-NS3-NS4A-NS4B-NS5A-NS5B is drawn from the reference nucleic acid encoding residues 81 1 to 3010 of CON-1 (GenBank accession number AJ238799).
  • Both subgenomic replicons contain a hybrid HCV- poliovirus (PV) 5'UTR, a modified luciferase reporter gene expressed as a luciferase-FMDV2A-neomycin phosphotransferase gene fusion and a NS2-NS5B subgenomic fragment with its 3'UTR.
  • PV HCV- poliovirus
  • the replication of both HCV NS2-NS5B subgenomic replicons is enhanced by cell-culture adaptive mutations in the NS3 and the NS4B coding regions for the genotype 1 a replicon and in the NS3, NS4A and NS5A coding regions for the genotype 1 b.
  • Stable replicon cell lines are established as described, for example, in Science 1999, 285: 1 10-1 13.
  • the amount of luciferase expressed by selected cells directly correlates with the level of HCV RNA replication, as measured by real-time PCR.
  • HCV replicon RNA replication assay To generate cell lines harboring the replicon containing the NS3 substitutions, Huh-7 cells are electroporated with 1-10 ⁇ g of purified in vitro transcripts and stable cell lines are selected in the presence of G418 (0.25 mg /ml). The stable HCV replicon cells are maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS and 0.25 mg/ml G418 (standard medium). During the assay, DMEM supplemented with 10% FBS, containing 0.5% DMSO and lacking neomycin are used as assay medium.
  • DMEM Dulbecco's Modified Eagle Medium
  • the cell stocks are trypsinized and diluted in assay medium to distribute 70 ⁇ (8,000 ells) in black 96-well plates. The plates are then incubated at 37° until compound addition.
  • the test compound in 100% DMSO is first diluted in assay medium to a final DMSO concentration of 0.5%. Serial dilutions are prepared in assay medium to generate nine-concentration dose response curves. A fixed volume from each well of the compound dilution plate is transferred to a
  • the cell culture plate is incubated at 37°C with 5% C0 2 for 72 hours. Following the 72h incubation period, the medium is aspirated from the 96-well assay plate and a volume of 50 ⁇ of 1X Glo Lysis Buffer (Promega) is added to each well.
  • the luciferase activity is determined using Bright- Glo luciferase substrate (Promega) according to the manufacturer's instructions and the luminescence is detected on a Packard Topcount instrument.
  • the luminescence (CPS) in each well of the culture plate is a measure of the amount of HCV RNA replication in the presence of various concentrations of inhibitor. The % inhibition is calculated for each inhibitor concentration and used to determine the concentration that results in 50% inhibition of HCV replication (EC 50 ).
  • Retention times (t R ) for each compound are measured using the standard analytical HPLC or UPLC conditions described in the Examples.
  • retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different HPLC or UPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC or UPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual measurements taken on different occasions.
  • a person skilled in the art will recognize that obvious modifications to the synthetic methods, including the amount of time indicated to perform the various steps, may be required to generate each of the specific compounds listed in Tables 1 and 2.

Abstract

La présente invention concerne des composés de formule (I), dans laquelle R1, R2, RA, RB, Z1, Z2, Z3, Z4, Z5 et Z6 sont tels que définis ici. Lesdits composés peuvent être utilisés en tant qu'inhibiteurs de l'action de la protéine NS5A encodée par le VHC, en vue du traitement d'une infection par le virus de l'hépatite C.
PCT/CA2011/050041 2010-01-28 2011-01-24 Composés inhibiteurs du virus de l'hépatite c WO2011091532A1 (fr)

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US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
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