WO2012019299A1 - Composés inhibiteurs de l'hépatite c - Google Patents

Composés inhibiteurs de l'hépatite c Download PDF

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Publication number
WO2012019299A1
WO2012019299A1 PCT/CA2011/050484 CA2011050484W WO2012019299A1 WO 2012019299 A1 WO2012019299 A1 WO 2012019299A1 CA 2011050484 W CA2011050484 W CA 2011050484W WO 2012019299 A1 WO2012019299 A1 WO 2012019299A1
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Prior art keywords
alkyl
compound
cycloalkyl
mmol
het
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PCT/CA2011/050484
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WO2012019299A9 (fr
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Paul J. Edwards
Mélissa LEBLANC
Benoît MOREAU
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Boehringer Ingelheim International Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/503—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses
    • C12N9/506—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses derived from RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to macrocycle peptide analogs and their use as inhibitors of hepatitis C virus (HCV) NS3 protease activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment of HCV infection.
  • HCV hepatitis C virus
  • HCV hepatitis C virus
  • WO 2007/056120 describes macrocydic peptides that are useful for inhibiting HCV.
  • This invention provides novel compounds which show potent activity against hepatitis C virus protease, more particularly the NS3 protease encoded by HCV. Furthermore, the compounds of the invention have activity as inhibitors in a cell- based HCV replication assay.
  • R 1 is (C -6 )alkyl, (C 3 . 7 )cycloalkyl or -(C-i_ 6 )alkyl-(C 3 _ 7 )cycloalkyl;
  • each said alkyl and cycloalkyl is optionally substituted with (C-,.
  • n 0, 1 , 2 or 3;
  • R 20 and R 21 are each independently (C -6 )alkyl, (C 3 . 7 )cycloalkyl or -(C 1- )alkyl- (C 3-7 )cycloalkyl;
  • R 3 is (C 3-7 )cycloalkyl, aryl, Het, -0-(C 1-6 )alkyl, -0-(C 3-7 )cycloalkyl, -O-aryl, -O-Het, - NH((C 1-6 )alkyl) or -N((C 1-6 )alkyl)2, wherein each said alkyl, cycloalkyl, aryl and
  • Het is optionally substituted with (C -6 )alkyl or halo;
  • 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 human being.
  • composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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 the invention, 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.
  • 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 the invention, or a salt thereof, under conditions where replication of hepatitis C virus is inhibited.
  • a compound of the invention or a salt thereof, to inhibit the replication of hepatitis C virus.
  • Yet another aspect of this invention provides a method of inhibiting HCV NS3 protease activity in a human being by administering a compound of the invention, including a pharmaceutically acceptable salt thereof.
  • Another aspect of this invention provides a method of decreasing the NS3 protease activity of the hepatitis C virus infecting a human being by administering a compound of the invention, including a pharmaceutically acceptable salt thereof.
  • 3 -alkyl-aryl means an aryl group which is bound to a C-i_ 3 -alkyl- group, with the C-i_ 3 -alky group bound to the core. Unless specifically stated otherwise, for groups comprising two or more subgroups, the substituent may be attached to either subgroup.
  • An asterisk may be 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.
  • 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
  • compositions can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).
  • 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.
  • halo generally denotes fluorine, chlorine, bromine and iodine.
  • 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-CH2-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 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH
  • C 4 . n -alkylene wherein n is an integer 4 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 4 to n carbon atoms.
  • C 4 _ -,0-alkylene includes, but is not limited to, -(CH 2 -CH 2 -CH 2 -CH 2 )-, -(CH 2 -CH 2 -CH 2 - CH 2 -CH 2 )-, -(CH 2 -CH 2 -CH 2 -CH 2 -CH 2 )-, -(CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 )-, - (CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 )-, -(CH 2 -CH 2 _ CH(CH3))-, - (CH(CH 3 )-CH2-CH2-CH 2 )-, -( CH2-CH 2 -CH(CH3)-CH 2 )-, -(CH 2 -C(CH 3 ) 2 )-, -(CH 2 -C(CH 3 ) 2
  • Carbocyclyl as used either alone or in combination with another radical, means a mono- bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms.
  • the term “carbocycle” refers to fully saturated and aromatic ring systems and partially saturated ring systems.
  • the term “carbocycle” encompasses fused, bridged and spirocyclic 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 as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to at least one other 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.
  • Het as used herein, either alone or in combination with another radical, denotes a heterocyclyl or heteroaryl ring system.
  • heterocyclyl is intended to include all the possible isomeric forms.
  • heterocydyl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • heteroaryl is intended to include all the possible isomeric forms.
  • heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
  • antiviral agent means an agent (compound or biological) that is effective to inhibit the formation and/or replication of a virus in a human being. This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a human being. Such agents can be selected from: another anti-HCV agent, HIV inhibitor, HAV inhibitor and HBV inhibitor.
  • 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 HCV polymerase or inhibitors of another target in the HCV life cycle.
  • anti-HCV agents include, a-
  • 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 NS3 protease means an agent
  • Inhibitors of HCV NS3 protease include, for example, the candidates telaprevir, boceprevir, danoprevir, vaniprevir, ABT-450, ACH-1625, BMS-650032, and Bl 201335.
  • the term "inhibitor of HCV polymerase” as used herein 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, nucleoside analogs or non-nucleosides inhibitors of HCV polymerase and inhibitors of HCV NS5B polymerase.
  • Inhibitors of HCV polymerase include for example, the candidates Bl 207127, R-7128, GS9190, IDX184, PSI-7977, MK-3281 , PF868554, VX-222, ANA598, ABT-333 and ABT-072.
  • 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, NS5A, NS5B polymerase, and internal ribosome entry site (IRES), or host targets such as cyclophilin A or 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, NS5A, NS5B polymerase, and internal ribosome entry site (IRES)
  • host targets such as cyclophilin A or B, phosphatidylinositol 4-kinase Ilia, CD81 , SR-B1 , Claudin
  • 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 (Epivir
  • treatment means 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.
  • 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 R 1 is (C 1-6 )alkyl, (C 3 . 7 )cycloalkyl or -(C 1-6 )alkyl-(C 3- 7)cycloalkyl;
  • each said alkyl and cycloalkyi is optionally substituted with
  • R 1 -B R 1 is (C 3 . 5 )cycloalkyl or -(C-i.3)alkyl-(C 3 .5)cycloalkyl; wherein said cycloalkyi is optionally substituted with (C 1-3 )alkyl.
  • R 1 -C R 1 is (C 3 . 5 )cycloalkyl; wherein said cycloalkyi is optionally substituted with (d_ 3 )alkyl.
  • R 1 -D R 1 is ⁇ 7 or ⁇ 7 .
  • n R 1 is ⁇ 7 or ⁇ 7 .
  • n-A n is 0, 1 , 2 or 3.
  • n-B n is 0, 1 or 2.
  • n 0 or 1.
  • R 3 is (C 3 _ 7 )cycloalkyl, aryl, Het, -0-(C 1-6 )alkyl, -0-(C 3 . 7 )cycloalkyl, -O-aryl, -O- Het, -NH((C-i_ 6 )alkyl) or -N((C _ s )alkyl) 2 , wherein each said alkyl, cycloalkyl, aryl and Het is optionally substituted with (C _ 6 )alkyl or halo.
  • R 3 is (C 3-5 )cycloalkyl, Het, -0-(C 1-4 )alkyl, -0-(C 3-5 )cycloalkyl, -O-Het, - NH((C-i_ 3 )alkyl) or -N((C _ 3 )alkyl) 2 , wherein each said alkyl, cycloalkyl and Het is optionally substituted with (C 1-3 )alkyl, F, CI or Br; wherein Het is defined as a 5- or 6-membered saturated, unsaturated or aromatic heterocycle or heteroaryl having 1 to 2 heteroatoms each independently selected from O, N and S.
  • R 4 -A is a 4 to 10-atom saturated or unsaturated alkylene chain optionally
  • R 4 -B R 4 is a 4 to 7-atom unsaturated alkylene chain optionally containing one (C 3 . 5 )cycloalkyl group.
  • Examples of most preferred compounds according to this invention are each single compound listed in Tables 1 to 4.
  • Suitable preparations for administering the compounds of the invention 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.
  • the content of the pharmaceutically active 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 the invention with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • the tablets may also consist of several layers.
  • 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, another 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. Alternatively 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.
  • 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.
  • intermediates can be purified on a Teledyne ISCO Combiflash R f System at 254 nm using commercial normal phase silica 4-120 g Redisep R f or Silicycle columns eluting in 0-100% EtOAc / Hexane or 0-10% MeOH / DCM at a flow rate of 18-85 mL /min depending on column size.
  • Mass spectral analyses are recorded using flow injection analysis mass spectrometry or Waters Acquity Ultraperformance LC System consisting of a sample organizer, PDA detector, column manager, sample manager, binary solvent manager and SQ detector.
  • HBTU [0-(1 H-benzotriazol-1 -yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate]
  • HPLC high performance liquid chromatography
  • i-Pr isopropyl
  • LiHMDS lithium bis(trimethylsilyl) amide
  • Me Me:
  • TFA triethylamine
  • TFA trifluoroacetic acid
  • THF tetrahydrofuran
  • TMSCN trimethylsilyl cyanide
  • Example 1 Synthesis of Advanced Intermediate F
  • the synthesis of a close related analog (cyclopentyl carbamate instead of f-butyl carbamate) has been previously described in several patent applications and literature: (see for example: WO 2007030656; Tsantrizos et al. , J. Organometallic Chem. 2006, 691, 5163-5171 ; Yee et al. , J. Org. Chem. 2006, 71, 7133-7145).
  • the synthesis of intermediates A and of C has been extensively described in the literature (see above references and references cited within).
  • Step 1
  • the dioxane is evaporated at 40°C.
  • the volume of the reaction mixture is adjusted to 1 L with water and then 1 M NaOH (aqueous) is added to adjust the pH to approximately 12.
  • the reaction mixture is filtered and the aqueous solution is washed with a 50/50 mixture of t-BME/hexane (2 x 200 mL). The organic portions are discarded and the aqueous portion is transferred to a 2 L Erlenmeyer flask.
  • t-BME 600 mL
  • the pH is adjusted to approximately 3 using 4 M HCI.
  • the reaction mixture is filtered and the filtrate is collected.
  • the aqueous portion is extracted with t-BME (200 ml_).
  • the organic portions are combined and washed with 0.2 M KHS0 4 (2 x 200 mL) and brine (200 ml_), dried over Na 2 S0 4 , filtered and evaporated to give D.
  • the tripeptide E (25 g, 34.4 mmol, 1 eq) is dissolved in toluene (2.1 L) and then heated to 80°C. While the reaction mixture is heated, argon is bubbled through the solution for 1 h.
  • the catalyst Hoveyda-Grubbs 2 nd generation catalyst from Aldrich, 0.3 g x 4) is added in 4 equal portions, 30 min apart.
  • the reaction mixture is cooled to 50°C, a solution of trihydroxymethyl phosphine (see below) is added and the resulting mixture is stirred at this temperature for 1 h.
  • the reaction mixture is cooled to RT, silica gel (21 g) is added and then the reaction mixture is stirred for 30 min.
  • a gummy solid forms which is stirred for about 48 h.
  • a suspension forms which is further diluted with f-BME (40 mL) and the volume is adjusted to 800 mL with hexanes. The suspension is stirred for 30 min. The solids are collected and washed with hexanes and air-dried to obtain macrocycle F.
  • Step 1 Intermediate F (3.0 g, 4.3 mmol) is dissolved in THF/MeOH (3/1 , 28 mL) and 1 .0 N NaOH (12.9 mL, 12.9 mmol) is added. The reaction mixture is stirred overnight at RT, concentrated in vacuo, acidified with 10% citric acid to pH ⁇ 6 and extracted with EtOAc (3x). The combined organic extracts are washed with H 2 0 (3x), brine (1 x), dried over MgS0 4 , filtered and concentrated in vacuo to yield carboxylic acid G.
  • Carboxylic acid G (1 1 .5 g, 16.8 mmol) is dissolved in DCM (160 mL) and TEA (7.73 mL, 55.4 mmol) is added. The reaction mixture is cooled to 0 °C in an ice bath. Isobutylchloroformate (3.70 mL, 28.6 mmol) is added dropwise and the mixture is stirred at 0 °C for 1 h and then allowed to warm slowly to RT and stirred overnight. The mixture is concentrated in vacuo and purified by flash chromatography using 35 - 100% EtOAc/hexanes as the eluent. The pure fractions are combined and concentrated in vacuo to give azalactone H.
  • Glacial HOAc (2.0 mL) is added and the reaction mixture is concentrated to dryness. The material is purified by flash chromatography using 30 - 85% EtOAc/hexanes as the eluent. The pure fractions are combined and concentrated in vacuo to provide J.
  • Compound 1008 is prepared from intermediate J using a procedure analogous to that described in Example 3 using e M instead of K.
  • Compound 1014 is prepared from intermediate J using a procedure analogous to that described in Example 3 using N instead of K.
  • Compound 1010 is prepared from intermediate J using a procedure analogous to that described in Example 3 usin O instead of K.
  • P Compound 1019 is prepared from intermediate J using a procedure analogous to that described in Example 3 using hydroxy pyridine S instead of K.
  • Acid T (2.0 mg, 0.02 mmol) is dissolved in DMF (1 mL), then TEA (0.01 mL, 0.08 mmol,) is added followed by HATU (7.1 mg, 0.02 mmol). The solution is stirred for 15 min, after which the amine hydrochloride (9.8 mg, 0.016 mmol) is added in DMF (0.5 mL) and this solution is stirred at RT for 16 h. Water (2 mL) is added to the solution, and then the organic layer is extracted with EtOAc (3 x 5 mL) and dried over MgS0 4 . The solvent is evaporated and the residue is purified on preparative
  • Compound 1017 is prepared from compound 1013 using a procedure analogous to
  • Compound 1015 is prepared from compound 1014 using a procedure analogous to that described in Example 4, using carboxylic acid U instead of T.
  • Compound 1018 is prepared from compound 1014 using a procedure analogous to that described in Example 4, using carboxylic acid T.
  • Compound 1012 is prepared from compound 1010 using a procedure analogous to that described in Example 4 using carboxylic acid U instead of T.
  • Compound 1011 is prepared from compound 1010 using a procedure analogous to that described in Example 4 using carboxylic acid T.
  • Compound 1021 is prepared from compound 1019 using a procedure analogous to that described in Example 4 using carboxylic acid U instead of T.
  • Compound 1020 is prepared from compound 1019 using a procedure analogous to that described in Example 4 using carboxylic acid T.
  • Intermediate W is prepared from intermediate J1 using a procedure analogous to that described in Example 3 using hydroxy pyridine K.
  • Intermediate Z is prepared from intermediate J using a procedure analogous to that described in Example 3 using hydroxy pyridine Q instead of K.
  • Compound 1002 is prepared using a procedure analogous to that described in Example 8 using intermediate Z2 instead of Z1.
  • Compound 1003 is prepared using a procedure analogous to that described in Example 8 using intermediate Z3 instead of Z1.
  • Compound 1004 is prepared using a procedure analogous to that described in Example 8 using intermediate Z4a instead of Z1.
  • Compound 1005 is prepared using a procedure analogous to that described in Example 8 using intermediate Z4b instead of Z1.
  • Compound 1006 is prepared using a procedure analogous to that described in Example 8 using intermediate Z5 instead of Z1.
  • Compound 1007 is prepared using a procedure analogous to that described in Example 8 using intermediate Z6 instead of Z1.
  • the synthesis of intermediates Z1-Z6 is analogous to that described in Tetrahedron Letters, 33(20), 2781-2784 (1992), herein incorporated by reference.
  • Step 1
  • reaction mixture is stirred for 15 min at RT and the aqueous layer is separated and washed with Et 2 0 (2 x 50 mL) to remove organic impurities. Water is then removed in vacuo and the residue is co- evaporated with DCM (2x) to give P-5.
  • P-5 (2.38 g, 9.09 mmol) and Boc 2 0 (2.38 g, 10.91 mmol) are suspended in 30 mL of anhydrous DCM. To this is added TEA (27.27 mmol, 3.8 mL) at RT under argon. The reaction mixture is stirred at this temperature for 2 h. The reaction mixture is concentrated in vacuo and the crude is purified by flash chromatography using 5% to 25% EtOAc in hexanes as the eluent to give P-6.
  • Step 7 P-6 (1 .9 g, 5.84mmol) is dissolved in 1 ,4-dioxane (43 mL) with stirring. To this is added a solution of LiOH (2N; 43 mL) via syringe. The resulting reaction mixture is stirred at RT under argon overnight. The reaction mixture is diluted with H 2 0 (50 mL), then concentrated in vacuo to remove the bulk of organic solvent. The residue is treated with Et 2 0 and H 2 0, the aqueous phase is acidified to pH 3 by addition of 1 N HCI and the aqueous phase is then extracted with EtOAc (2 x 75 mL). The combined organic phase is dried over Na 2 S0 4 , then concentrated in vacuo to give P-7.
  • Flask A A 250 mL 2-necked flask is charged with P-7 (1.77 g, 5.78 mmol) dissolved in anhydrous THF (60 mL) under argon. To this is added HBTU (2.63 g, 6.94 mmol). The reaction mixture is cooled in an ice-water bath. To this cooled solution is added DIPEA (6.82 mmol, 1.2 mL). The resulting solution is stirred at 0°C for 20 min.
  • Flask B P-8 (3.10 g, 6.01 mmol) is dissolved in anhydrous THF (60 mL) and DIPEA (6.82 mmol, 1.2 mL) is added to this solution. The contents of flask B is added to flask A via a cannula at 0°C under argon. The reaction mixture is stirred at 0°C for 1 h then allowed to warm to RT. The resulting mixture is stirred at RT overnight. The mixture is then concentrated in vacuo and the residue is treated with EtOAc and saturated NaHC0 3 . The organic phase is washed with brine, dried over Na 2 S0 4 and concentrated in vacuo to give crude P-9. This crude material is purified by flash column chromatography using 30 - 50% EtOAc in hexanes as the eluent to give P-9.
  • P-10 (2.69 g, 3.15 mmol) is dissolved in dry toluene (34 mL) and the resulting solution is then degassed with argon whilst being heated to 1 10°C over 30 min.
  • a solution of a catalytic amount of the Hoveyda Grubbs II catalyst dissolved in toluene (1.76 mg/mL, 6.31 x 10 3 mmol, 2.4 mL) is added slowly over 30 min. After stirring for 1 h at 1 10°C, the reaction mixture is concentrated in vacuo. The residue is purified by flash column chromatography using 30 - 50% EtOAc in hexanes as the eluent to provide P-11 .
  • Step 1
  • the acid X (126.6 mg, 1 .0 mmol) is dissolved in DMF (5 mL), DIPEA (0.525 mL, 3.01 mmol) and TBTU (322.3 mg, 1 .0 mmol) are added and the reaction mixture is aged 15 min.
  • the amine hydrochloride P-11a (318mg, 0.50 mmol) is dissolved in DMF (3 mL) and added all at once to the above reaction mixture. The reaction is stirred overnight at RT, transferred to a separatory funnel, diluted with EtOAc (60 mL), washed with H 2 0 (3 x 20 mL), 1 N HCI (1 x 10 mL), and brine (1 x 10 mL).
  • Ester P-12 (388 mg, 0.55 mmol) is dissolved in THF (4 mL) and MeOH (1 .5 mL) and 1 N NaOH (0.66 mL, 0.66 mmol) is added. The reaction mixture is stirred for 48 h at RT. The reaction mixture is concentrated in vacuo and the residue taken up in EtOAc/H 2 0. The two phase mixture is acidified to pH ⁇ 6 with 10% citric acid. The aqueous phase is extracted with EtOAc (5x) and the combined organics are washed with H 2 0 (3x), brine (1 x) and dried over MgS0 4 , filtered and concentrated in vacuo to give the acid P-13 which is used without further purification.
  • the acid P-13 (154 mg, 0.223 mmol) is dissolved in DCM (1 .6 mL), TEA (0.103 mL, 0.737 mmol) is added and the solution is cooled to 0°C in an ice bath.
  • Glacial HOAc (0.1 mL) is added and the reaction mixture is concentrated in vacuo.
  • the material is purified by flash column chromatography using 6 - 10% MeOH/DCM as eluent. The pure fractions are combined and concentrated in vacuo to provide P-15 which is used as such in subsequent reactions.
  • Step 1
  • K1 (380 mg, 1 .66 mmol) is charged in a vial, dissolved in MeOH (19 mL), then injected onto an H-Cube reactor® for hydrogenation (reaction parameters: Full H 2 , 30 °C, 1 mL/min). The solvent is removed in vacuo to give K.
  • Step 1
  • reaction mixture is warmed at 70°C for 1 h, then cooled to RT where H 2 0 and DCM are added.
  • the reaction mixture is extracted with DCM (2x), dried by passing through a phase separator cartridge and concentrated in vacuo.
  • This crude mixture is dissolved in THF / MeOH (20: 10 mL) and a 1 N NaOH aqueous solution (2 mL, 2.0 mmol) is added. Upon stirring for 15 min, the solvents are removed under reduced pressure, then H 2 0 and DCM are added resulting in the formation of heterogeneous material. This solid is collected via suction filtration, washed with H 2 0 and DCM to provide S.
  • Step l
  • Intermediate N is prepared analogously to the procedure described for intermediate O in Example 14, using methylamine instead of tert-butylmethylamine in step 4.
  • Intermediate P is prepared analogously to the procedure described for intermediate O in Example 14, using cyclohexylamine instead of tert-butylmethylamine in step 4.
  • Step 1
  • the NS2-NS5B-3'non coding region is cloned by RT-PCR into the pCR3® vector (Invitrogen) using RNA extracted from the serum of an HCV genotype 1 b infected individual (provided by Dr. Bernard Willems, Hopital St-Luc, Montreal, Quebec, Canada).
  • the NS3-NS4A region (NS3-NS4A full length represented by residues 29-714 of the sequence of Figure 1 in priority application SN 61/372,575 now SEQ ID NO.
  • the NS3-NS4A FL is amplified by PCR from the pFastBac vector and then subcloned into the pET1 1 a E. coli expression vector.
  • Bacteria are grown at 37°C in CircleGrow® medium supplemented with 100 ⁇ g/mL ampicillin and 34 ⁇ g/mL chloramphenicol.
  • the culture is cooled to 22°C and the protein expression induced with 0.5 mM isopropyl-p-D- thiogalactoside for 4 h.
  • cells are harvested by centrifugation and the cell paste is frozen at -80°C.
  • the cell paste is resuspended in 5 mL of lysis buffer (50 mM NaP0 4 , pH 7.5, 20% glycerol, 1 mM EDTA, 0.5% Triton X-100, 0.5 M NaCI) per gram of cells.
  • lysis buffer 50 mM NaP0 4 , pH 7.5, 20% glycerol, 1 mM EDTA, 0.5% Triton X-100, 0.5 M NaCI
  • the suspension obtained is processed in a Dounce homogenizer, supplemented with 20 mM MgCI 2 and 10 ⁇ g/mL DNase I and incubated for 30 min on ice. Following a brief sonication, the extract is clarified by a 30-min centrifugation at 150,000xg. The supernatant is diluted 2-fold in 50 mM NaP0 4 , pH 7.5, 0.5 M NaCI and imidazole added to a final concentration of 25 mM. Then, the solution is applied to a Hi-TrapTM Ni +2 -chelating column.
  • the His-NS3-NS4A full length protein (SEQ ID NO: 1 ) is eluted in 50 mM NaP0 4 , pH 7.5, 0.5 M NaCI, 10% glycerol, 0.1 % NP-40, 5 mM imidazole using a 5 to 500 mM imidazole gradient.
  • the enzyme enriched fractions are pooled and diluted 4-fold in 50 mM NaP0 4 , pH 7.5, 10% glycerol, 0.05% n-dodecyl-p-D-maltoside and applied to a poly(U)-Sepharose affinity column previously equilibrated in 50 mM NaP0 4 , pH 7.0, 10% glycerol, 0.2 M NaCI, 0.05% n-dodecyl-p-D-maltoside, 10 mM ⁇ -mercaptoethanol.
  • the enzyme is eluted in the same buffer containing 2 M NaCI.
  • the purified enzyme is stored at -80°C. It is thawed on ice and diluted just prior to use.
  • the protease activity of His-NS3-NS4A full length protein (SEQ ID NO: 1 ) expressed in E. coli is measured in 50 mM Tris-HCI, pH 7.5, 0.25 M sodium citrate, 0.01 % (w/v) n-dodecyl-p-D-maltoside, 1 mM DTT.
  • One (1 ) ⁇ of the internally quenched substrate Cy3-DDIVPAbu[C(0)-0]-ASK(Cy5Q)-NH 2 in presence of various concentrations of inhibitor are incubated with 0.5 nM of His-NS3-NS4A full length protein (SEQ ID NO: 1 ) for 30 min at 23°C. The final DMSO concentration does not exceed 5.25%.
  • the reaction is terminated with the addition of 1 M MES, pH 5.8.
  • Fluorescence of the N-terminal product is measured using a POLARStar GalaxyTM plate reader (BMG) equipped with a 540 nm excitation filter and a 590 nm emission filter.
  • Huh-7 cells that stably maintained a subgenomic HCV replicon containing the luciferase-FMV2A-neomycin phosphotransferase fusion gene are established as previously described (Lohman et al. , 1999. Science 285: 1 10-1 13) and designated as MP-1 cells.
  • MP-1 cells are maintained in Dulbecco's Modified Earle Medium (DMEM) supplemented with 10% FBS and 0.25 mg/ml neomycin (standard medium). The cells are passaged by trypsinization and frozen in 90% FBS/10% DMSO. During the assay, DMEM medium supplemented with 10% FBS, containing 0.5% DMSO and lacking neomycin used (Assay medium).
  • DMEM Dulbecco's Modified Earle Medium
  • MP-1 cells are trypsinized and diluted to 100 000 cells/ml in assay medium. 100 ⁇ is distributed into each well of a black 96-well ViewPlateTM (Packard) . The plate is then incubated at 37°C with 5% C0 2 for 2 h. Reagents and Materials
  • test compound in 100% DMSO is first diluted in assay medium to a final DMSO concentration of 0.5%.
  • the solution is sonicated for 15 min and filtered through a 0.22 ⁇ Millipore Filter unit.
  • the appropriate volume is transferred into assay medium to obtain the starting concentration (2x) to be tested.
  • 4 to 12 add 200 y L of assay medium (containing 0.5% DMSO).
  • Serial dilutions (1 /2) are prepared by transferring 200 ⁇ _ from column 3 to column 4, then from column 4 to column 5, serially through to column 1 1 .
  • Columns 2 and 12 are the no inhibition controls.
  • the medium is aspirated from the 96-well assay plate and a volume of 100 ⁇ _ of 1 X Glo Lysis Buffer (Promega) previously warmed to RT is added to each well.
  • the plate was incubated at RT for 10 min with occasional shaking. A black tape is put at the bottom of the plate.
  • 100 ⁇ _ of Bright- Glo luciferase substrate (Promega) previously warmed to RT is added to each well followed by gentle mixing.
  • the luminescence is determined on a Packard TopCount instrument using the Data Mode Luminescence (CPS) with a count delay of 1 min and a count time of 2 sec.
  • CPS Data Mode Luminescence
  • the luminescence determination (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 with the following equation:
  • phosphotransferase fusion gene phosphotransferase fusion gene
  • replicon cells were selected with 0.25 mg/mL G418.
  • the amount of luciferase expressed by selected cells directly correlates with the level of HCV replication.
  • MP-1 cells are maintained in Dulbecco's Modified Earle Medium (DMEM) supplemented with 10% FBS and 0.25 mg/mL G418 (standard medium). The cells are passaged by trypsinization and frozen in 90% FBS/10% DMSO.
  • DMEM Dulbecco's Modified Earle Medium
  • DMEM medium supplemented with 10% FBS, containing 0.5% DMSO and lacking G418, is used (Assay medium).
  • Assay medium DMEM medium supplemented with 10% FBS, containing 0.5% DMSO and lacking G418, is used (Assay medium).
  • MP-1 cells are trypsinized and diluted to 15 000 cells/70 uL in assay medium.
  • 70 [ L is distributed into each well of a black 96-well ViewPlateTM (Packard). The plate is then incubated at 37°C until the compound is added.
  • test compound in 100% DMSO is first diluted in assay medium to a final DMSO concentration of 0.5%. The solution is sonicated for 15 min. Into column 3 of a Polypropylene Deep- Well Titer Plate, the appropriate volume is transferred into assay medium to obtain the starting concentration (2x) to be tested. In columns 4 to 1 1 , add 400 ⁇ _ of assay medium (containing 0.5% DMSO). Serial dilutions (1/3) are prepared by transferring 200 ⁇ _ from column 3 to column 4, then from column 4 to column 5, serially through to column 1 1. Column 12 is the no inhibition control.
  • a volume of 70 ⁇ _ from each well of the compound dilution plate is transferred to a corresponding well of the Cell Plate (Three columns will be used as the "No inhibition control"; nine columns are used for the dose response).
  • the cell culture plate is incubated at 37°C with 5% C0 2 for 28 h.
  • Luciferase assay :
  • the medium is aspirated from the 96-well assay plate and a volume of 50 ⁇ _ of 1X Glo Lysis Buffer (Promega) previously warmed to RT is added to each well.
  • the plate is incubated at RT for 10 min with occasional shaking. A black tape is put at the bottom of the plate.
  • 50 ⁇ _ of Bright- Glo luciferase substrate (Promega) previously warmed to RT is added to each well followed by gentle mixing.
  • the luminescence is determined on a Packard Topcount instrument using the Data Mode Luminescence (CPS) with a count delay of 1 min and a count time of 2 sec.
  • CPS Data Mode Luminescence
  • the luminescence determination (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.
  • a non-linear curve fit with the Hill model is applied to the inhibition-concentration data, and the 50% effective concentration (EC 5 o) is calculated by the use of SAS software (Statistical Software; SAS Institute, Inc. Cary, N.C.). All compounds listed in Tables 1 to 3 are tested in at least one of the assays described in Example 16, 17 or 18.
  • Compounds tested in the assay of Example 16 showed IC 50 values in the range of 40 nM or less.
  • Compounds tested in the assay of Example 17 showed EC 50 values in the range of 3.5 ⁇ or less.
  • Compounds tested in the assay of Example 18 showed EC 50 values in the range of 75 nM or less.
  • Retention times (t R ) for each compound are measured using the standard analytical HPLC 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 instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC 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.

Abstract

La présente invention concerne des composés de formule (I) (Formule (I)) dans laquelle R1, R2, R3, R4 et n sont tels que définis dans la description, qui sont utiles en tant qu'inhibiteurs de la protéase NS3 du VHC pour le traitement de l'infection par le virus de l'hépatite C.
PCT/CA2011/050484 2010-08-11 2011-08-10 Composés inhibiteurs de l'hépatite c WO2012019299A1 (fr)

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US9527885B2 (en) 2011-05-05 2016-12-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9296782B2 (en) 2012-07-03 2016-03-29 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US10603318B2 (en) 2012-07-03 2020-03-31 Gilead Pharmasset Llc Inhibitors of hepatitis C virus
US10335409B2 (en) 2012-07-03 2019-07-02 Gilead Pharmasset Llc Inhibitors of hepatitis C virus
US9499550B2 (en) 2012-10-19 2016-11-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9334279B2 (en) * 2012-11-02 2016-05-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9598433B2 (en) 2012-11-02 2017-03-21 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2014071007A1 (fr) * 2012-11-02 2014-05-08 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
US9409943B2 (en) 2012-11-05 2016-08-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9580463B2 (en) 2013-03-07 2017-02-28 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9617310B2 (en) 2013-03-15 2017-04-11 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
CN109354600A (zh) * 2018-11-29 2019-02-19 浙江海洋大学 一种牛磺酸修饰的新型阿拉斯加鳕鱼多功能肽的制备方法
WO2021133839A1 (fr) 2019-12-23 2021-07-01 Synthorx, Inc. Procédés de préparation de n6-((2-azidoéthoxy)carbonyl)lysine

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