WO2010034105A1 - Composés inhibiteurs de l'hépatite c - Google Patents

Composés inhibiteurs de l'hépatite c Download PDF

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Publication number
WO2010034105A1
WO2010034105A1 PCT/CA2009/001237 CA2009001237W WO2010034105A1 WO 2010034105 A1 WO2010034105 A1 WO 2010034105A1 CA 2009001237 W CA2009001237 W CA 2009001237W WO 2010034105 A1 WO2010034105 A1 WO 2010034105A1
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Prior art keywords
alkyl
compound
substituted
cycloalkyl
halogen
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PCT/CA2009/001237
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English (en)
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WO2010034105A8 (fr
Inventor
Jeffrey O'meara
Josée BORDELEAU
Vida Gorys
Mélissa LEBLANC
Kirsten Lenhardt
Montse Llinas-Brunet
Mathieu Parisien
Marc-André Poupart
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Boehringer Ingelheim International Gmbh
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Priority to CA2737958A priority Critical patent/CA2737958A1/fr
Priority to EP09815517A priority patent/EP2344487A4/fr
Priority to JP2011527161A priority patent/JP2012502925A/ja
Publication of WO2010034105A1 publication Critical patent/WO2010034105A1/fr
Publication of WO2010034105A8 publication Critical patent/WO2010034105A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • 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
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
  • HCV hepatitis C virus
  • HCV is an enveloped positive strand RNA virus in the genus Hepacivirus in the Fiavivm ⁇ ae family
  • the single stran ⁇ HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF), f ⁇ an ⁇ ed by 5' ana 3' non-translated regions
  • the HCV 5' non-translated region is 341 nucleotides in iength and functions as an internal ⁇ bosome entry site for cap-independent translation initiation
  • the open reading frame encodes a single large polyprotein of about 3000 ammo acids which is cleaved at multiple sites by cellular and viral proteases to produce the mature structural and non-structural (NS2 NS3 NS4A, NS4B NS5A, and NS5B) proteins
  • the viral NS2/3 protease cleaves at the NS2- NS3 junction while the viral NS3 protease mediates the cleavages downstream of !
  • HCV NS3 protease inhibitors The first evidence of the clinical antiviral activity of HCV NS3 protease inhibitors is provided by the results of a two day dinical trial, which indicate that the HCV NS3 protease inhibitor BiLN 2081 is effective m rapidly reducing viral loads m patients infected with the hepatitis C virus (Gastioenterology (2004) 127(5) 1347-1355) More recently, in 14- and 28-day dinical trials with the HCV NS3 protease inhibitor VX-95Q, alone (Gastroenterology (2006) 131 (4) 997-1002) or in combination with pegylated interferon with or witnout ribavirin, viral load for most HCV patients rapidly decreased to undetectable levels dunng treatment (Hepatology i 2006) 44(4 s1 ) 532A and 614A)
  • R 2 may be O-R 2 Q and R 2 Q nay be a Het, either unsubstituted or mono-, d ⁇ - or tri-substituted, are described as hepatitis C viral NS3 protease inhibitors, an enzyme essential for the replication of the hepatitis C virus
  • Oral administration is one of the most commonly used drug dosing route.
  • In vitro approaches evaluating absorption distribution, metabolism and excretion have been developed to speed up characterization of the increased number of compounds synthesized in drug discovery programs These experiments are designed to identify candidates that are most likely to have adequate PK profile (Prediction of pharmacokinetic properties using experimental approaches during early drug discovery, Pravin R Chalurvedi * , Caroline J Decker and Aieksandrs Odinecs Current Opinion in Chemical Biology, 2001 , 5 452-463.) but do not yet replace in vivo methods (Pharmacokinetics and metabolism in early drug discovery, Dennis A Smith and Han van de Wate ⁇ eemd. Current Opinion in Chemical Biology, 1999. 3, 373-378) herein incorporated by reference.
  • the rat is among the most commonly used animal in preclinical PK studies and the fraction of oral dose absorbed in rats can be correlated to that observed in humans for many drugs (Lmear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Win L. Chiou and Abhyit Barve Pharmaceutical Research,Mo ⁇ . 15 No. 1 1 , 1792-1795,1998), herein incorporated by reference.
  • the present invention provides a novel series of compounds having at least one of the following surprising advantages:
  • One aspect of the invention provides a racemate, diastereoisomer, or optical isomer of a compound of Formula (I):
  • R 3 is (C 2 - 8 )alkyl, (C ⁇ cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl, wherein each of said alkyl, cycloalkyl, and alkyl-cycloalkyl groups may be mono-, di- or tri- substituted with (C 1-4 )alkyl;
  • L 0 is halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(C 1-4 )alkyl or -N((C 1-4 )alkyl) 2 ;
  • L 1 is halogen, (C 1-4 )alkyl, -O-(Ci ⁇ )alkyl, -S-(C 1-4 )alkyl, -SO-(d ⁇ )alkyl, or -SO 2 - (Ci- 4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms;
  • R 2 is -NR 22 COR 20 , -NR 22 COOR 20 , -NR 22 R 21 or -NR 22 CONR 21 R 23 , wherein
  • R 20 is (C 1- ⁇ )alkyl, (C ⁇ cycloalkyl or (C 1 . 4 )alkyl-(C 3-7 )cycloalkyl, wherein said alkyl, cycloalkyl or alkyl-cycloalkyl may be mono-, di- or tri-substituted with
  • R 21 is H or R 20 as defined above, R 22 and R 23 are independently H or methyl, R 1 is (C 1-4 )alkyl, (Cjwjalkenyl or (C ⁇ Jcycloalkyl;
  • R c is hydroxy or NHSO 2 R 8 wherein R s is (C 1- ⁇ )alkyl, (C ⁇ Jcycloalkyl, (C 1-6 )alkyl- (C 3-7 )CyClOaI kyl, aryl or Het; each of which optionally being mono-, di- or tri- substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 )alkyl, O-(C 1-6 )alkyl, -CO-NH 2 , -CO-NHfd ⁇ alkyl, -CO-Ntfd- ⁇ alkylk, -NH 2 , -NH(C 1-4 )alkyl and -N((C 1-4 )alkyl) 2 , wherein (C 1-4 )alkyl and O-(C 1-6 )alkyl are optionally substituted with one to three halogen atoms;
  • alkyl and O-alkyl groups may be optionally substituted with 1 to 3 halogen atoms; and wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O 1 N and S 1 or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 ;
  • compounds according to this invention exhibit one or more of the following surprising advantages: « unexpectedly good cell-based potency; and/or * unexpectedly good DMPK profile.
  • Another aspect of this invention provides compounds of Formula (!) showing at least one of the following surprising advantages:
  • Another aspect of this invention provides a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as a medicament.
  • composition comprising an anti-hepatitis C viraliy effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or ester 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 mammal 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 m a mammal by administering to the mammal an anti-hepatitis C viraily effective amount of a compound of Formula (! ⁇ , a pharmaceutically acceptable salt or ester thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
  • An additional aspecl oi this invention refers to an article o1 man ⁇ _1aclure comprising a composition effective to treat a hepatitis C virai infection, and packaging material comprising a labei 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 or ester thereof
  • Still another aspect of this invention reiates 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 or ester thereof, under conditions where replication of hepatitis C virus is inhibited
  • the invention is the use of a compound of formula (I), or a salt or ester 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 mammal by administering a compound of Formula (I), including a pharmaceutically acceptable salt or ester thereof
  • Another aspect of this invention provides a method of decreasing the NS3 protease activity of the hepatitis C virus infecting a mammal by administering a compound of Formula (!), including a pharmaceutically acceptable salt or ester thereof
  • 'vinyl-AGCA refers to a compound of formula
  • ethyl-ACCA refers to a compound of formula
  • haio or “haiogen” as used herein means a halogen substituent selected from fluoro, chioro bromo or iodo
  • esters advantageously contains 1 to 16 carbon atoms, particularly 1 to 8 carbon atoms
  • Any aryl moiety present in such esters advantageously comprises a phenyl group
  • the esters may be a C ⁇ ⁇ 6 a'kyi ester an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C 1 6 alkyi, C, R aikoxy, nitro or tnfluoromethyl
  • B is aryi or Het, optionally mono- or di-substituted with halogen, (Chalky!, O-(Ci_6)alkyl, O-phenyi, O-tetrahydropyranyl, S-(Ci_6)a!kyl, wherein said aikyl and O-alkyl groups may be optionally substituted with 1 to
  • L 0 is -OCH 3 .
  • L 1 -B In another embodiment, L 1 is halogen, (C 1-4 )alkyl or -O-(C 1-4 )alkyl.
  • L 1 -C In another embodiment, L 1 is -CH 3 , -C 2 H 5 , -C 3 H 7 , -F, -Cl, -Br 1 -OCH 3 , -OC 2 H 5 or -OC 3 H 7 .
  • L 1 -D In another embodiment, L 1 is -CH 3 , -C 2 H 5 , -Cl or -Br.
  • L 1 -E In another embodiment, L 1 is CH 3 , -Cl or -Br.
  • L 1 any and each individual definition of L 1 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R c , R 3 , B and L 0 as set out herein.
  • R 2 -A In one embodiment, R 2 is -NR 22 COR 20 , -NR 22 COOR 20 , -NR 22 R 21 or -
  • R 22 and R 23 are independently H or methyl.
  • R 2 -B In another embodiment, R 2 is -NR 22 COR 20 , -NR 22 COOR 20 or -NR 22 R 21 , wherein R 20 is (C 1 6 )aikyi, (C 3 . 7 )cycloalky! or (C,.,:)aikyl ⁇ (C 3 7 )cydoa!kyl, wherein said alkyi, cycloalkyl or alkyl-cycioaikyl may be mono-, di- or tri-subslituled With (C 1 3 )alkyl or -O(C 1 3 )alkyl; R 21 is H or R 20 as defined above, R 22 is H or methyl.
  • R 2 -C in another embodiment, R 2 is -N(H)COR 28 , -N(H)COOR 20 or -N(H)R 21 , wherein
  • R 2 -D in another embodiment, R 2 is -N(H)COR 20 , -N(H)COOR 20 or -N(H)R 21 , wherein
  • R ? -E In another embodiment, R 2 is -N(H)CQR ?0 , -N(H)COOR 20 or -N(H)R 21 , wherein
  • R 2 -F in st ⁇ l another embodiment, R 2 is
  • R c -B In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R s is (C 1- ⁇ )alkyl,
  • R c -D In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is (Ci- ⁇ )alkyl,
  • R c -E In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is (C 1-6 )alkyl,
  • R c -F In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is
  • R c -G In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is cyclopropyl optionally being mono-substituted with (C M )alkyl.
  • R c -H In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is
  • R c -I In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 cyclopropyl.
  • R c -J In another embodiment, R c is hydroxy. Any and each individual ⁇ eiinition of R c as sel out herein may be combined witn any ana each individual definition o1 R 1 , R 2 , R 3 L 0 L 1 and B as sel out herein
  • R 1 is (C- i)alkyl, (C 24 )ai ⁇ enyi or (C 3 7 )cycloalkyi.
  • R 1 -B In another embodiment, R 1 is (C 2 i )alkyl, (C 2 4 )al ⁇ eny! or (C 3 5 )cycloal ⁇ yi. R 1 -C in another embodiment, R 1 is ethyl, vinyi or cyciopropyl
  • R 1 any and each individual definition of R 1 as set out herein may be combined with any and each individual definition of R 2 , R 3 R c L 0 L 1 and B as set out herein
  • R 1 is cyciopropyl
  • the asymmetric carbon atoms in the cyciopropy! group take the R, S configuration according to the subformula'
  • the pharmaceutical composition o! this invention nay additionally comp ⁇ se at least one other anti-HCV agent.
  • anti-HCV agents include, ⁇ - (alpha), ⁇ - (beta), ⁇ - (delta), y- (gamma), ⁇ - (omega) or ⁇ (tau) interferon, pegylated ⁇ 'nterferon, ribavirin and amantadine
  • the pharmaceutical composition of this invention may additionally comprise at least one otner inhibitor of HCV NS3 protease
  • the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of HCV polymerase
  • the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of other targets in the HCV life cycle, including but not limited to, hehcase NS2/3 protease or internal ⁇ bosome entry site (IRES).
  • at least one inhibitor of other targets in the HCV life cycle including but not limited to, hehcase NS2/3 protease or internal ⁇ bosome entry site (IRES).
  • the pharmaceutical composition of this invention may be administered orally parenteraliy or via an implanted reservoir Orai administration or administration by iniection is preferred
  • the pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceiilicaliy-acceptable carriers, adjuvants or venicles
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance tne stability of the formulated compound c its delivery form.
  • parenteral as used herein ⁇ eludes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articuiar, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques
  • the pharmaceutical composition of this invention may be orally administered in any oraily acceptable dosage form including, but not limited to, aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets
  • aqueous suspensions and solutions including, but not limited to, aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets
  • earners which are commonly used include iactose and corn starch Lubricating agents such as magnesium stearate are aiso typically added For orai administration !
  • useful diluents include lactose and d ⁇ ed corn stanch
  • the active ingredient is combined with emulsifying and suspending agents
  • certain sweetening and/or flavoring and/or coloring agents may be ad ⁇ ed
  • systemic administration including but not limited to administration Dy subcutaneous intracutaneous, intravenous, intramuscular, intra-articiiiar, intrasynovial, intrasternal intrathecal and intralesional injection or miusion techniques, it is preferred to use a solution of the compound, or a pharmaceutically acceptable salt or ester thereof , in a pharmaceutically acceptable ste ⁇ le aqueous venicle
  • Dosage levels of between about 0 01 and about 100 mg/kg body weight per day preferably between about 0 1 and about 50 mg/kg body weight per day of the protease inhibitor compound described herein are useful in a monotherapy or in combination therapy 1or the prevention and treatment oi HCV mediated disease
  • the pharmaceutical composition of this invention will be administered 1rom about 1 to about 5 times per day or alternatively, as a continuous infusion
  • Such administration can be used as a chronic or acute therapy
  • the amount of active ingredient that may be combined with the earner materials to produce a single dosage form will vary depending upon the host treated and the particular node of administration
  • a typical preparation will contain from about 5% to aoout 95% active compound (w/w)
  • such preparations contain from about 20% to about 80% active compound
  • composition of this invention comprises a combination of a compound of Formula (!) 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
  • this metnod is useful in decreasing the NS3 protease activity of the nepatitis C virus infecting a mammal
  • combination therapy is contemplated wherein a compound of formula (I), or a pharmaceutically acceptable sait or ester thereof, is co-administered with at ieast one additional antiviral agent
  • Preferred antiviral agents are described nereinbefore ana examples of such agents are provided in the Definitions section
  • These 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 formula (i), or a pharmaceutically acceptable salt or ester thereof
  • a compound of formula (J), including a pharmaceutically acceptable sait or ester thereof set forth herein may also be used as a research reagent
  • a compound of formula (Ij, including a pharmaceutically acceptable salt or ester thereof, may aiso be used as positive control to validate surrogate cell-based assays or in vitro or in vivo viral replication assays
  • dipeptide 1 The synthesis of dipeptide 1 is carried out by coupling the P1 residue to the properly protected frans-hydroxy proline under standard conditions. The stereochemistry of the hydroxyl group is inverted by the well known Mitsunobu reaction using para- nitrobenzoic acid. Coupling of the dipeptide with the P3 moiety (2a-h) (obtained from commercial sources) yields t ⁇ peplide 3 Introduction of tne quinohne moiety to the hydroxyl group of the tripeptide 3 with inversion of stereochemistry can be earned out using either a Mitsonobu reaction or by converting tne free hydroxy!
  • the qui ⁇ oiine used contains a 2-carbomethoxy group as shown in 5 Conversion of the carboxyiate group to the aminothiazoie derivative !
  • ester is hydrolyzed under basic aqueous conditions to provide compounds oi formula (! in which R1 is vinyl Tne vinyl group can De reduces using hydrazine monohydrale as a source of di ⁇ i ⁇ »de to provide compounds of formula (I) in which R1 is ethyl
  • Scheme 2 describes another reaction sequence for making compounds o1 Formula ⁇ I ⁇
  • the quinohne moiety is introduced to the dipeptide in a similar way as desc ⁇ bed in Scheme 1
  • the PZ moiety (2a-h) is coupled under standard conditions with the dipeptide 17 to provide the corresponding t ⁇ peptide analogs 9
  • Conversion of the resulting t ⁇ peotides (9) to the desired inhibitors (11 and 12) of formula (i) is earned out as described in Scheme 1
  • Scheme A describes an alternative synthetic route for the synthesis of compounds of formula (Ij in which R1 is ethyl
  • the vinyl cyiopropane derivative 23 is reduced using Rh/C under 45 ps* of hydrogen gas to provide the ethyl-cyclopropane derivative 24
  • This compound is then sequentially coupled with protected amino acids 25 and 2a-fo to provide the t ⁇ peptide analog 28
  • the t ⁇ peptide 28 is converted to the quinohne aminothiazoie derivative 30 using similar transformations to those described in Scheme 1 for the conversion of 3 to 9.
  • 30 can be converted to compounds of formula (i) where R1 is ethyl using similar transformations to those described in Scheme 1 for the conversion of 9 to 10,
  • Scheme 5 described a reaction sequence for making compounds of formula (I) where R 1 is cyclopropyi.
  • the vinyl cyclopropane derivative 17 is cyclopropanated using palladium acetate and diazomethane to give intermediate 33 Peptide coupling between the deprotected dipeptide 33 and one of the P3 fragments 2a-h or 19a-h provides tripeptide derivatives which can be converted to compounds of formula (I) using reaction sequences already described m Schemes 1 to 4
  • Scheme 6 describes a reaction sequence which permits the conversion of carboxylic acids of formula (I) to the corresponding acyl sulfonamides.
  • the acid is activated by a peptide coupling agent or a chloroformate and is thereby converted to the corresponding aza-lactone.
  • the azalactone is opened by the nucleophilic addition of a sulfonamide to obtain the corresponding acyl sulfonamide analogs.
  • ⁇ -Bromoketone 7a 700 mg, 0 85 mmoij and thiourea 8h ( 134 mg, 1 02 mmol) are dissolved in isopropanoi (5 mLj and the yellow solution is heated at 75°C lor about 1 n Tne solution is allowed to cooi Io RT and evaporated to dryness Tms crude material 9a is used as such for next step
  • Compound 1003 is prepared using the protocol desc ⁇ oed in Example 8, sleps 1 to 7
  • 15b is converted to 2001 using protocol described in Example 7, steps 6 and 7, using cyclobutyl acetic acid instead of cyclopropyl acetic acid.
  • 3002 is reduced using the hydrazine monohydrate procedure described in Example 6, step 8 to provide compound 3004 in 20% yield.
  • Hi ⁇ h-7 cells with a stable subgenomic HCV rephcon that encodes a modified iuciferase reporter gene (expressed as a iuc!ferase-FMDV2A-neomyc ⁇ n phosphotransferase fusion gene) are established as previously described (Lohman et a!., 1999. Science 285 1 10-1 13. Vroljik et al . 2003 J Virol Methods 110 201-209.

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Abstract

L'invention porte sur des composés représentés par la formule (I) : dans laquelle B, R3, L0, L1, R2, Rc et R1 sont tels que définis dans la description. Les composés sont utiles comme inhibiteurs de la protéase NS3 du VHC pour le traitement d'une infection virale de type hépatite C. En particulier, la présente invention porte sur de nouveaux analogues peptidiques, sur des compositions pharmaceutiques contenant de tels analogues et sur des utilisations de ces analogues dans le traitement d'une infection à VHC.
PCT/CA2009/001237 2008-09-23 2009-09-14 Composés inhibiteurs de l'hépatite c WO2010034105A1 (fr)

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Application Number Priority Date Filing Date Title
CA2737958A CA2737958A1 (fr) 2008-09-23 2009-09-14 Composes inhibiteurs de l'hepatite c
EP09815517A EP2344487A4 (fr) 2008-09-23 2009-09-14 Composés inhibiteurs de l'hépatite c
JP2011527161A JP2012502925A (ja) 2008-09-23 2009-09-14 Ｃ型肝炎阻害化合物

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US9929208P 2008-09-23 2008-09-23
US61/099,292 2008-09-23
US18663209P 2009-06-12 2009-06-12
US61/186,632 2009-06-12

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100119479A1 (en) * 2008-10-15 2010-05-13 Intermune, Inc. Therapeutic antiviral peptides
US8420596B2 (en) 2008-09-11 2013-04-16 Abbott Laboratories Macrocyclic hepatitis C serine protease inhibitors
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8951964B2 (en) 2010-12-30 2015-02-10 Abbvie Inc. Phenanthridine macrocyclic hepatitis C serine protease inhibitors
US9334279B2 (en) 2012-11-02 2016-05-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
US9409943B2 (en) 2012-11-05 2016-08-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9499550B2 (en) 2012-10-19 2016-11-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9527885B2 (en) 2011-05-05 2016-12-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9580463B2 (en) 2013-03-07 2017-02-28 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
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2370396A1 (fr) * 2002-02-01 2003-08-01 Boehringer Ingelheim (Canada) Ltd. Tri-peptides inhibiteur de l'hepatite c
CA2522577A1 (fr) * 2003-05-21 2004-12-02 Boehringer Ingelheim International Gmbh Composes inhibiteurs de l'hepatite c
CA2568008A1 (fr) * 2004-05-25 2005-12-05 Boehringer Ingelheim International Gmbh Processus de preparation d'inhibiteurs de protease hcv acyclique
CA2556669A1 (fr) * 2004-06-28 2006-01-05 Boehringer Ingelheim International Gmbh Analogues peptidiques d'inhibiteurs de l'hepatite c
WO2009005676A2 (fr) * 2007-06-29 2009-01-08 Gilead Sciences, Inc. Composés antiviraux
WO2009005677A2 (fr) * 2007-06-29 2009-01-08 Gilead Sciences, Inc. Composés antiviraux

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2010006210A (es) * 2007-12-05 2010-08-10 Enanta Pharm Inc Inhibidores de serina proteasa de hcv de tripeptido fluorado.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2370396A1 (fr) * 2002-02-01 2003-08-01 Boehringer Ingelheim (Canada) Ltd. Tri-peptides inhibiteur de l'hepatite c
CA2522577A1 (fr) * 2003-05-21 2004-12-02 Boehringer Ingelheim International Gmbh Composes inhibiteurs de l'hepatite c
CA2568008A1 (fr) * 2004-05-25 2005-12-05 Boehringer Ingelheim International Gmbh Processus de preparation d'inhibiteurs de protease hcv acyclique
CA2556669A1 (fr) * 2004-06-28 2006-01-05 Boehringer Ingelheim International Gmbh Analogues peptidiques d'inhibiteurs de l'hepatite c
WO2009005676A2 (fr) * 2007-06-29 2009-01-08 Gilead Sciences, Inc. Composés antiviraux
WO2009005677A2 (fr) * 2007-06-29 2009-01-08 Gilead Sciences, Inc. Composés antiviraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2344487A4 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8420596B2 (en) 2008-09-11 2013-04-16 Abbott Laboratories Macrocyclic hepatitis C serine protease inhibitors
US8642538B2 (en) 2008-09-11 2014-02-04 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US9309279B2 (en) 2008-09-11 2016-04-12 Abbvie Inc. Macrocyclic hepatitis C serine protease inhibitors
US20100119479A1 (en) * 2008-10-15 2010-05-13 Intermune, Inc. Therapeutic antiviral peptides
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8951964B2 (en) 2010-12-30 2015-02-10 Abbvie Inc. Phenanthridine macrocyclic hepatitis C serine protease inhibitors
US9527885B2 (en) 2011-05-05 2016-12-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201541B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US9499550B2 (en) 2012-10-19 2016-11-22 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
US9334279B2 (en) 2012-11-02 2016-05-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
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
US9744170B2 (en) 2014-01-03 2017-08-29 Abbvie Inc. Solid antiviral dosage forms
US10105365B2 (en) 2014-01-03 2018-10-23 Abbvie Inc. Solid antiviral dosage forms
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms

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EP2344487A4 (fr) 2012-03-21
JP2012502925A (ja) 2012-02-02
TW201016694A (en) 2010-05-01
WO2010034105A8 (fr) 2011-01-06
AR073659A1 (es) 2010-11-24
EP2344487A1 (fr) 2011-07-20
CA2737958A1 (fr) 2010-04-01

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