WO2013084165A1 - Inhibiteurs de vhc polymérase - Google Patents

Inhibiteurs de vhc polymérase Download PDF

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Publication number
WO2013084165A1
WO2013084165A1 PCT/IB2012/056994 IB2012056994W WO2013084165A1 WO 2013084165 A1 WO2013084165 A1 WO 2013084165A1 IB 2012056994 W IB2012056994 W IB 2012056994W WO 2013084165 A1 WO2013084165 A1 WO 2013084165A1
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alkyl
compound according
crc
compound
formula
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PCT/IB2012/056994
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Björn KLASSON
Anders Eneroth
Magnus Nilsson
Pedro Pinho
Bertil Samuelsson
Christian Sund
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to inhibitors of the polymerase of hepatitis C virus (HCV), prodrugs thereof and their use in the treatment or prophylaxis of HCV infection.
  • HCV hepatitis C virus
  • HCV is a single stranded, positive-sense RNA virus belonging to the Flaviviridae family of viruses in the hepacivirus genus.
  • the NS5B region of the RNA polygene encodes an RNA dependent RNA polymerase (RdRp), which is essential to viral replication.
  • RdRp RNA dependent RNA polymerase
  • a majority of infected individuals develop chronic hepatitis because HCV replicates preferentially in hepatocytes but is not directly cytopathic.
  • the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection.
  • Chronic hepatitis can progress to liver fibrosis, leading to cirrhosis, end-stage liver disease and HCC (hepatocellular carcinoma), making it the leading cause of liver transplantations.
  • HCV genotype 1 is the predominant genotype in Europe and in the US.
  • the extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to current therapy.
  • HCV HCV
  • Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use.
  • the introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence.
  • the existing infections will continue to present a serious medical and economic burden for decades.
  • HCV therapies are based on (pegylated) interferon-alpha (IFN-a) in combination with ribavirin.
  • IFN-a interferon-alpha
  • This combination therapy yields a sustained virologic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3.
  • this combination therapy has significant side effects and is poorly tolerated in many patients.
  • Major side effects include influenza-like symptoms, hematologic abnormalities and neuropsychiatric symptoms.
  • HIV drugs in particular with HIV protease inhibitors, has taught that sub- optimal pharmacokinetics and complex dosing regimes quickly result in inadvertent compliance failures. This in turn means that the 24 hour trough concentration (minimum plasma
  • NS5B RdRp is absolutely essential for replication of the single-stranded, positive sense HCV RNA genome which makes it an attractive target for the development of antiviral compounds.
  • NNIs non-nucleoside inhibitors
  • nucleoside analogues nucleoside analogues
  • the NNIs bind to allosteric regions of the protein whereas the nucleoside inhibitors are anabolized to the corresponding nucleotide and act as alternative substrate for the polymerase.
  • the formed nucleotide is then incorporated in the nascent RNA polymer chain and can terminate the growth of the polymer chain.
  • both nucleoside and non-nucleoside inhibitors of NS5B are known.
  • the inhibition mechanism of nucleoside inhibitors involves phosphorylation of the nucleoside to the corresponding triphosphate.
  • the phosphorylation is commonly mediated by host cell kinases and is an absolute requirement for the nucleoside to be active as an alternative substrate for the NS5B polymerase.
  • the first phosphorylation step i.e. conversion of the nucleoside to the nucleoside 5'-monophosphate is the rate limiting step.
  • a strategy for increasing nucleoside triphosphate production is to use cell permeable nucleoside prodrugs of the monophosphate, i.e. a nucleoside carrying a masked phosphate moiety, a "prodrug moiety", which are susceptible to intracellular enzymatic activation leading to a nucleoside monophosphate.
  • the thus formed monophosphate is subsequently converted to the active triphosphate by cellular kinases.
  • HCV inhibitors that may overcome the disadvantages of current HCV therapy such as side effects e.g. toxicity, limited efficacy, the emerging of resistance, and compliance failures, as well as improve the sustained viral response.
  • the present invention provides new of HCV inhibiting compounds which have useful properties regarding one or more of the following parameters: antiviral efficacy; favourable profile of resistance development; lack of toxicity and genotoxicity; favourable pharmacokinetics and pharmacodynamics; and ease of formulation and administration.
  • an HCV inhibiting compound of the present invention need not demonstrate an improvement in every respect over all known compounds but may instead provide a balance of properties which in combination mean that the HCV inhibiting compound is a valuable alternative pharmaceutical agent.
  • Compounds of the invention may also be attractive due to the fact that they lack activity against other viruses, i.e. are selective, in particular against HIV. HIV infected patients often suffer from co-infections such as HCV. Treatment of such patients with an HCV inhibitor that also inhibits HIV may lead to the emergence of resistant HIV strains.
  • the present invention provides co rmula I:
  • R 3 is H or CH 3 ;
  • R 4 is a mono-, di- or triphosphate ester, or a group of formula (ii):
  • R 6 is H or together with the adjacent R 8 and the atoms to which they are attached forms a pyrrolidinylene ring;
  • R 8 and R 8 are each independently selected from H, CrC 6 alkyl and benzyl; or R 1 and R 8 together with the carbon atom to which they are attached from a C 3 -
  • R 8 is H, and R 8 together with the adjacent R 6 and the atoms to which they are attached form a pyrrolidinylene ring;
  • R 9 is Ci-Ci 0 alkyl, Ci-Ciohaloalkyl, C 3 -C 7 cycloalkyl, benzyl or phenyl, any of which is optionally substituted with 1 , 2 or 3 substituents each independently selected from hydroxy, CrC 6 alkoxy, amino, mono- and di-Ci-C 6 alkylamino;
  • R 3 is CH 3 .
  • R 3 is typically H.
  • R 22 and R 22 are both H.
  • one of R 22 and R 22 is CrC 3 alkyl, and the other is H or Ci-C 3 alkyl.
  • R 7 include phenyl and phenyl substituted with 1 or 2 substituents independently selected from halo, CrC 6 alkyl, C 2 -C 6 alkenyl and CrC 6 alkoxy. Typically R 7 is phenyl or phenyl substituted with methyl, methoxy or 1 or 2 chloro. Further representative values for R 7 include naphthyl which is optionally substituted with halo, such as bromo. Further representative values for R 7 include indolyl, typically 5-indolyl.
  • R 7 examples include pyridyl and substituted pyridyl.
  • the pyridyl group is linked in the 3-position and the optional substituent is located in the 5- or 6- position, thus affording the following structures:
  • X is halo such as fluoro, or haloalkyl such as CF 3 .
  • Typical configurations for R 9 include CrC 6 alkyl. Of particular interest are Ci-C 4 alkyl, especially methyl, ethyl, isopropyl, isobutyl and tert-butyl. Further typical configurations for R 9 include phenyl and benzyl, especially benzyl.
  • R 8 and R 8 is hydrogen, and the other is hydrogen or CrC 6 alkyl, such as isopropyl or isobutyl.
  • R 8 is hydrogen
  • examples are glycine, (Gly) alanine (Ala), valine (Val), isoleucine (lie) and phenylalanine (Phe) residues, i.e., R 8 is H and R 8 is methyl, isopropyl, isobutyl or benzyl respectively.
  • the configuration at the asymmetric carbon atom is typically that of an L-amino acid, in particular L-Ala, L-Val, L-lle, and L-Phe.
  • R 8 and R 8 are H and the other is or methyl, or R 8 and R 8 are both methyl.
  • R 8 and R 8 together with the carbon atom to which they are attached form C 3 -C 7 cycloalkyl, for example cyclopropyl or cyclobutyl.
  • R 6 is H.
  • R 7 is phenyl
  • R 8 is H
  • R 8 is CrC 3 alkyl (such as methyl, ethyl or isopropyl)
  • R 9 is CrC 6 alkyl or C 3 -C 7 cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl).
  • R 8 is H, and R 8 and R 6 together with the atoms to which they are attached form a pyrrolidine ring, thus affording the group (iia):
  • R 7 is phenyl and R 9 is CrC 6 alkyl such as methyl, ethyl or isopropyl, or C 3 -C 7 cycloalkyl such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the compounds of formula I may optionally be provided in the form of a pharmaceutically acceptable salt and/or solvate. In one embodiment the compound of formula I is provided in the form of a pharmaceutically acceptable salt. In a second embodiment the compound of formula I is provided in the form of a pharmaceutically acceptable solvate. In a third embodiment the compound of formula I is provided in its free form.
  • R 3 is H or CH 3 ;
  • R 4 is a triphosphate ester or a group of formula (iib):
  • R 8 and R 8 are each independently selected from H, CrC 6 alkyl and benzyl; or R 8 and R 8 together with the carbon atom to which they are attached from a C 3 -C 7 cycloalkylene group;
  • R 9 is Ci-Ci 0 alkyl, Ci-Ciohaloalkyl, C 3 -C 7 cycloalkyl, benzyl or phenyl, any of which is optionally substituted with 1 , 2 or 3 substituents each independently selected from hydroxy, CrC 6 alkoxy, amino, mono- and di-Ci-C 6 alkylamino;
  • the compounds of formula lb may optionally be provided in the form of a pharmaceutically acceptable salt and/or solvate.
  • the compound of formula lb is provided in the form of a pharmaceutically acceptable salt.
  • the compound of formula lb is provided in the form of a pharmaceutically acceptable solvate.
  • the compound of formula I is provided in its free form.
  • R 3 is CH 3 .
  • R 3 is typically H.
  • R 4 together with the oxygen atom to which is attached, forms a mono-, di- or tri phosphate thus providing compounds having any of the structur
  • R is the group (iib):
  • Typical configurations for R 9 include CrC 6 alkyl. Of particular interest are CrC 4 alkyl, especially methyl, ethyl, isopropyl, isobutyl and tert-butyl. Further typical configurations for R 9 include phenyl and benzyl, especially benzyl.
  • R 8 and R 8 is hydrogen, and the other is hydrogen or CrC 6 alkyl, such as isopropyl or isobutyl.
  • R 8 is hydrogen
  • examples are glycine, (Gly) alanine (Ala), valine (Val), isoleucine (lie) and phenylalanine (Phe) residues, i.e., R 8 is H and R 8 is methyl, isopropyl, isobutyl or benzyl respectively.
  • R 8 is hydrogen and R 8 is other than hydrogen
  • the configuration at the asymmetric carbon atom is typically that of an L-amino acid, in particular L-Ala, L-Val, L-lle, and L-Phe.
  • one of R 8 and R 8 is H and the other is or methyl, or R 8 and R 8 are both methyl.
  • R 8 and R 8 together with the carbon atom to which they are attached form C 3 -C 7 cycloalkyl, for example cyclopropyl or cyclobutyl.
  • R 7 is phenyl
  • R 8 is H
  • R 8 is CrC 3 alkyl (such as methyl, ethyl or isopropyl)
  • R 9 is CrC 6 alkyl or C 3 -C 7 cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl).
  • R 9 is cyclopropyl
  • R 9 is cyclobutyl
  • R 9 is cyclopentyl
  • R 9 is cyclohexyl
  • R 9 is cycloheptyl
  • R 9 is cyclooctyl
  • R 9 is methyl
  • R 9 is isopropyl
  • R 9 is isobutyl
  • R 9 is n-propyl
  • R 9 is n-pentyl
  • R 9 is n-butyl
  • R 9 is 2-ethylbutyl.
  • R 9 is 2-propylpentyl.
  • R 9 is sec. butyl
  • R 9 is 2,2-dimethylpropyl
  • R 9 is 3,3-dimethylbutyl.
  • R 9 is cyclopropylmethyl.
  • R 9 is (S)-pentan-2-yl
  • R 9 is (R)-pentan-2-yl.
  • R 9 is pentan-3-yl.
  • R 9 is cyclobutylmethyl.
  • R 9 is cyclopentylmethyl.
  • a compound of formula I for use as a medicament, in particular for use in the treatment or prophylaxis of HCV infection, especially the treatment of HCV infection. Further provided is the use of a compound of formula I in the manufacture of a medicament, in particular a medicament for the treatment or prophylaxis of HCV infection, especially a medicament for the treatment of HCV infection.
  • a method for the treatment or prophylaxis of HCV infection comprising the administration of a compound of formula I
  • a method for the treatment of HCV infection comprising the administration of a compound of formula I
  • the invention concerns the use of the compounds of the invention for inhibiting HCV.
  • the invention provides the use of compounds of formula I for the treatment of HCV infection, such as the treatment of HCV infection in humans.
  • the invention relates to a method for manufacturing compounds of formula I, to novel intermediates of use in the manufacture of compounds of formula I and to the
  • the invention provides pharmaceutical compositions comprising a compound of formula I in association with a pharmaceutically acceptable adjuvant, diluent, excipient or carrier.
  • the pharmaceutical composition will typically contain an antivirally effective amount (e.g. for humans) of the compound of formula I, although sub-therapeutic amounts of the compound of formula I may nevertheless be of value when intended for use in combination with other agents or in multiple doses.
  • references to compounds of formula I will include any subgroup of the compounds of formula I described herein.
  • HCV genotypes in the context of treatment or prophylaxis in accordance with the invention include genotype 1 b (prevalent in Europe) and 1 a (prevalent in North America).
  • the invention also provides a method for the treatment or prophylaxis of HCV infection, in particular of the genotype 1 a or 1 b.
  • the invention provides a method for the treatment of HCV infection, in particular of the genotype 1 a or 1 b.
  • the compounds of formula I are represented as a defined stereoisomer. The absolute configuration of such compounds can be determined using art-known methods such as, for example, X-ray diffraction or NMR and/or implication from start materials of known
  • compositions in accordance with the invention will preferably comprise substantially stereoisomerically pure preparations of the indicated stereoisomer.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%.
  • 80% i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers
  • a stereoisomeric excess of 100% i.e. 100% of one isomer and none of the other
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound is synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of the compounds of formula I can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the present invention also includes isotope-labelled compounds of formula I or any subgroup of formula I, wherein one or more of the atoms is replaced by an isotope of that atom, i.e. an atom having the same atomic number as, but an atomic mass different from, the one(s) typically found in nature.
  • isotopes examples include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 31 P and 32 P, sulphur, such as 35 S, fluorine, such as 18 F, chlorine, such as 36 CI, bromine such as 75 Br, 76 Br, 77 Br and 82 Br, and iodine, such as 123 l, 124 l, 125 l and 131 l.
  • isotopes of hydrogen such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively)
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18 0, phosphorus, such as 31 P and 32 P
  • isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 0 will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half life of the compound or reduced dosage requirements.
  • Isotope-labelled compounds of formula I or any subgroup of formula I can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotope-labelled reagent or starting material instead of the corresponding non-isotope-labelled reagent or starting material, or by conventional techniques known to those skilled in the art.
  • the pharmaceutically acceptable addition salts comprise the therapeutically active non-toxic acid and base addition salt forms of the compounds of formula I. Of interest are the free, i.e. non-salt forms of the compounds of formula I.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propionic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of formula I containing an acidic proton may also be converted into their nontoxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g.
  • the lithium, sodium, potassium, magnesium, calcium salts and the like salts with organic bases, e.g. the benzathine, /V-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • solvates covers any pharmaceutically acceptable solvates that the compounds of formula I as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates, e.g. ethanolates, propanolates, and the like, especially hydrates.
  • Such forms although not explicitly indicated in the structural formulae represented herein, are intended to be included within the scope of the present invention.
  • C m -C n alkyl on its own or in composite expressions such as C m -C n haloalkyl, C m - C n alkylcarbonyl, C m -C n alkylamine, etc. represents a straight or branched alkyl radical having the number of carbon atoms designated, e.g. CrC 4 alkyl means an alkyl radical having from 1 to 4 carbon atoms. CrC 6 alkyl has a corresponding meaning, including also all straight and branched chain isomers of pentyl and hexyl.
  • Preferred alkyl radicals for use in the present invention are CrC 6 alkyl, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-buty, tert-butyl, n- pentyl and n-hexyl, especially Ci-C 4 alkyl such as methyl, ethyl, n-propyl, isopropyl, t-butyl, n- butyl and isobutyl. Methyl and isopropyl are typically preferred.
  • C m -C n haloalkyl represents C m -C n alkyl wherein at least one C atom is substituted with a halogen (e.g. the C m -C n haloalkyl group may contain one to three halogen atoms), preferably chloro or fluoro.
  • Typical haloalkyl groups are Ci-C 2 haloalkyl, in which halo suitably represents fluoro.
  • Exemplary haloalkyl groups include fluoromethyl, difluromethyl and trifluoromethyl.
  • C m -C n hydroxyalkyl represents C m -C n alkyl wherein at least one C atom is substituted with one hydroxy group.
  • Typical C m -C n hydroxyalkyl groups are C m -C n alkyl wherein one C atom is substituted with one hydroxy group.
  • Exemplary hydroxyalkyl groups include hydroxymethyl and hydroxyethyl.
  • C m -C n aminoalkyl represents C m -C n alkyl wherein at least one C atom is substituted with one amino group.
  • Typical C m -C n aminoalkyl groups are C m -C n alkyl wherein one C atom is substituted with one amino group.
  • Exemplary aminoalkyl groups include aminomethyl and aminoethyl.
  • C m -C n alkylene represents a straight or branched divalent alkyl radical having the number of carbon atoms indicated.
  • Preferred C m -C n alkylene radicals for use in the present invention are CrC 3 alkylene i.e. methylene, ethylene and propylene.
  • C m -C n alkoxy represents a radical C m -C n alkyl-0- wherein C m -C n alkyl is as defined above.
  • CrC 4 alkoxy which includes methoxy, ethoxy, n-propoxy, isopropoxy, t- butoxy, n-butoxy and isobutoxy. Methoxy and isopropoxy are typically preferred.
  • CrC 6 alkoxy has a corresponding meaning, expanded to include all straight and branched chain isomers of pentoxy and hexoxy.
  • amino represents the radical -NH 2 .
  • halo represents a halogen radical such as fluoro, chloro, bromo or iodo. Typically, halo groups are fluoro or chloro.
  • aryl means a phenyl, biphenyl or naphthyl group.
  • heterocycloalkyl represents a stable saturated monocyclic 3-7 membered ring containing 1 -3 heteroatoms independently selected from O, S and N. In one embodiment of the invention the stable saturated monocyclic 3-7 membered ring contains 1 heteroatom selected from O, S and N. In a second embodiment of the invention the stable saturated monocyclic 3-7 membered ring contains 2 heteroatoms independently selected from O, S and N. In a third embodiment the stable saturated monocyclic 3-7 membered ring contains 3 heteroatoms independently selected from O, S and N.
  • the stable saturated monocyclic 3-7 membered ring containing 1 -3 heteroatoms independently selected from O, S and N may typically be a 5-7 membered ring, such as a 5 or 6 membered ring.
  • heteroaryl represents a stable mono or bicyclic aromatic ring system containing 1 -4 heteroatoms independently selected from O, S and N, each ring having 5 or 6 ring atoms.
  • the stable mono or bicyclic aromatic ring system contains one heteroatom selected from O, S and N, each ring having 5 or 6 ring atoms.
  • the stable mono or bicyclic aromatic ring system contains two heteroatoms independently selected from O, S and N, each ring having 5 or 6 ring atoms.
  • the stable mono or bicyclic aromatic ring system contains three heteroatoms independently selected from O, S and N, each ring having 5 or 6 ring atoms.
  • the stable mono or bicyclic aromatic ring system contains four heteroatoms independently selected from O, S and N, each ring having 5 or 6 ring atoms.
  • C 3 -C n Cycloalkyl represents a cyclic monovalent alkyl radical having the number of carbon atoms indicated, e.g. C 3 -C 7 cycloalkyl means a cyclic monovalent alkyl radical having from 3 to 7 carbon atoms.
  • Preferred cycloalkyl radicals for use in the present invention are C 3 - C 4 alkyl i.e. cyclopropyl and cyclobutyl.
  • aminoC m -C n alkyl represents a C m -C n alkyl radical as defined above which is substituted with an amino group, i.e. one hydrogen atom of the alkyl moiety is replaced by an NH 2 -group.
  • aminoC m -C n alkyl is aminoCi-C 6 alkyl.
  • aminoC m -C n alkylcarbonyl represents a C m -C n alkylcarbonyl radical as defined above, wherein one hydrogen atom of the alkyl moiety is replaced by an NH 2 -group.
  • aminoC m -C n alkylcarbonyl is aminoCi-C 6 alkylcarbonyl.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable. When any variable is present occurs more than once in any moiety, each definition is independent.
  • Scheme 1 illustrates a route to the parent nucleoside 1 h, i.e. the compound having a hydroxy group in the 5'-position.
  • Ribofuranose 1 b Ribofuranose 1 b
  • the 2'-hydroxy compound (1 b) can be obtained from ribofuranoside by first preparing the methyl glycoside using standard conditions such as treatment with methanol under acidic conditions, followed by an appropriate protecting group strategy.
  • a cyclic protecting group can be used to protect the 3'- and 6'-hydroxy groups and leave the 2'-hydroxy group unprotected.
  • a suitable protecting group for this purpose is for instance a cyclic disiloxane like 1 ,1 ,3,3- tetraisopropyl-1 ,3-disiloxane or a cyclic acetal like 2,2-dimethyl-1 ,3-dioxolane.
  • the 2'-, 3'- and 5'-hydroxy groups may be all protected at the same time using for instance a benzyl protecting group or the like whereafter the 2'-group is selectively removed, effected by treatment with tin tetrachloride.
  • the 2'-hydroxy compound is then oxidized using any convenient oxidation method, such as oxidation with Dess Martin periodinane or pyridinium dichromate (PDC) or TEMPO optionally in the presence of the co-oxidant [(diacethoxy)iodo]benzene (BAIB), and the thus afforded 2'-oxo derivative (1 c) is reacted with 2-methyl-2-propane sulphonamide in the presence of titanium tetraethoxide to provide the sulphinylamide derivative (1 d).
  • Any convenient oxidation method such as oxidation with Dess Martin periodinane or pyridinium dichromate (PDC) or TEMPO optionally in the presence of the co-oxidant [(diacethoxy)iodo]benzene (BAIB), and the thus afforded 2'-oxo derivative (1 c) is reacted with 2-methyl-2-propane sulphonamide in the presence of titanium t
  • An organometallic reagent such as a Grignard reagent or an organolithium, organocuprate, organozinc reagent or the like may be used. Suitable conditions are for instance using MeMgBr in an ethereal solvent such as THF, or methyllithium in THF or the like.
  • the sulphinyl group Prior to introduction of uracil, the sulphinyl group is preferably replaced with a more acid stable N-protecting group for instance a trifluoroacetyl group, accordingly, the sulphinyl derivative (1 e) is treated with acid, e.g.
  • methyl glycoside (1f) is then condensed with uracil using standard methods for nucleoside formation, such as reaction with silylated uracil in the presence of a Lewis acid such as SnCI 4 or trimethylsilyl trifluoromethanesulphonate (TMS-OTf) in an inert solvent like acetonitrile, to provide the nucleoside (1 g).
  • a Lewis acid such as SnCI 4 or trimethylsilyl trifluoromethanesulphonate (TMS-OTf) in an inert solvent like acetonitrile
  • TMS-OTf trimethylsilyl trifluoromethanesulphonate
  • Removal finally of the protecting groups using the suitable conditions according to the protecting group used provides the unprotected nucleoside (1 h).
  • the trifluoroacetyl group is removed under basic conditions, such as treatment with sodium hydroxide and sodium carbonate in methanol or equivalent.
  • nucleoside (1 h) can then be transformed into a 5'-mono, di- or tri-phosphate or to a prodrug using any of the methods described herein below, or it may be further transformed to provide additional compounds of the invention.
  • U* is optionally protected uracil
  • a protecting group strategy leading to a 5'-unprotected-3'-protected compound is required.
  • the primary 5'-hydroxy group can be selectively protected with for instance a silyl group such as a tert.butyldimethylsilyl group by treatment with the appropriate silylating agent such as the silyl chloride in the presence of imidazole or equivalent.
  • organometallic reagents for the introduction of the 5'-methyl group may be used, such as an organocuprate or organozinc reagent.
  • N-protecting group on the base using the appropriate conditions according to the protecting groups used, for instance, in the case of a benzoate, treatment with base such as ammonia in methanol or the like provides the 5'-hydroxy compound (2e).
  • base such as ammonia in methanol or the like
  • the afforded compound is then suitable for introduction of a mono-, di- or triphosphate or a prodrug moiety at the 5'-position to yield a nucleotide or a 5'-nucleoside prodrug respectively, or alternatively, the 3'- and amino-protecting groups can be removed by treatment with acid such as with HCI in THF or methanol, or with TFA in CH 2 CI 2 or the like, to yield the 3',5'-dihydroxy derivative (2f).
  • phosphoramidate i.e. a prodrug moiety of formula (ii)
  • advantage can be taken of the higher reactivity of the primary 5'-hydroxy group compared to the secondary 3- hydroxy group, and the phosphoramidate can be introduced directly on the 3',5-diol without need of any special protecting group strategy.
  • This method is illustrated in Scheme 3 for the preparation of a compound of formula I wherein R 22 and R 22 are both H, and the phosphoramidate moiety is of formula iib.
  • nucleoside derivative (3a) prepared as described above, with a desired chlorophosphoramidate in an inert solvent such as an ether, e.g. diethyl ether or TH F, or a halogenated hydrocarbon, e.g. dichloromethane, in the presence of a base such as a N- methylimidazole (NMI) or the like, followed by removal of Boc group and the 3'-hydroxy protecting group using standard conditions, provides the phosphoramidate derivative (3b).
  • a base such as a N- methylimidazole (NMI) or the like
  • NMI N- methylimidazole
  • Compounds of formula I wherein R 3 is CH 3 will be achieved using the same strategy but starting from the 3'-protected derivative (2e).
  • the chlorophosphoramidate used in the above scheme can be prepared in a two-step reaction starting from phosphorus oxychloride (POCI 3 ), the thus formed phosphorus ester is then further reacte
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene.
  • N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like;
  • carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxy-carbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
  • cyclopentyloxycarbonyl adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
  • Favoured N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl (Bz), t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).
  • Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl,
  • silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsilyl, triphenylsilyl, t- butyldiphenylsilyl, triisopropyl silyl and the like, substituted ethyl ethers such as 1 -ethoxymethyl, 1 -methyl-1 -methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, diphenylmethyl,
  • Ester hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate,
  • Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like.
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount in this context is an amount sufficient to stabilize or to reduce viral infection, and in particular HCV infection, in infected subjects (e.g. humans).
  • the "therapeutically effective amount” will vary depending on individual requirements in each particular case. Features that influence the dose are e.g. the severity of the disease to be treated, age, weight, general health condition etc. of the subject to be treated, route and form of administration.
  • the invention relates to the use of a compound of formula I, for the treatment of "treatment naive" patients, i.e. patients infected with HCV that are not previously treated against the infection.
  • the invention relates to the use of a compound of formula I, the treatment of "treatment experienced” patients, i.e. patients infected with HCV that are previously treated against the infection and have subsequently relapsed.
  • the invention relates to the use of a compound of formula I, the treatment of "non-responders", i.e. patients infected with HCV that are previously treated but have failed to respond to the treatment.
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically effective amount of a compound of formula I as specified herein, and a pharmaceutically acceptable carrier.
  • a prophylactically effective amount in this context is an amount sufficient to act in a prophylactic way against HCV infection, in subjects being at risk of being infected.
  • this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically or prophylactically effective amount of a compound of formula I, as specified herein. Therefore, the compounds of the present invention may be formulated into various
  • compositions for administration purposes As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form or solvate, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • the compounds of the present invention may also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any art-known delivery system.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the compounds of formula I show activity against HCV and can be used in the treatment and/or prophylaxis of HCV infection or diseases associated with HCV. Typically the compounds of formula I can be used in the treatment of HCV infection or diseases associated with HCV.
  • HCV diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC.
  • a number of the compounds of this invention may be active against mutated strains of HCV. Additionally, many of the compounds of this invention may show a favourable pharmacokinetic profile and have attractive properties in terms of bioavailability, including an acceptable half-life, AUC (area under the curve) and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
  • the in vitro antiviral activity against HCV of the compounds of formula I can be tested in a cellular HCV replicon system based on Lohmann et al. (1999) Science 285:1 10-1 13, with the further modifications described by Krieger et al.
  • cellular counter screens exist for the evaluation of non-selective inhibition of linked reporter gene activity, such as firefly luciferase.
  • Appropriate cell types can be equipped by stable transfection with a luciferase reporter gene whose expression is dependent on a constitutively active gene promoter, and such cells can be used as a counter-screen to eliminate non-selective inhibitors.
  • the compounds of formula I are useful in the treatment of warm-blooded animals, in particular humans, infected with HCV.
  • the compounds of formula I are further useful for the prophylaxis of HCV infections.
  • the present invention furthermore relates to a method of treating a warm-blooded animal, in particular human, infected by HCV, or being at risk of infection by HCV, said method comprising the administration of an anti-HCV effective amount of a compound of formula I.
  • the compounds of the present invention may therefore be used as a medicine, in particular as an anti HCV medicine.
  • Said use as a medicine or method of treatment comprises the systemic administration to HCV infected subjects or to subjects susceptible to HCV infection of an amount effective to combat the conditions associated with HCV infection.
  • the present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or the prevention of HCV infection.
  • the present invention relates to the use of the compounds of formula I in the manufacture of a medicament for the treatment of HCV infection.
  • an antiviral effective daily amount would be from about 0.01 to about 700 mg/kg, or about 0.5 to about 400 mg/kg, or about 1 to about 250 mg/kg, or about 2 to about 200 mg/kg, or about 10 to about 150 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing about 1 to about 5000 mg, or about 50 to about 3000 mg, or about 100 to about 1000 mg, or about 200 to about 600 mg, or about 100 to about 400 mg of active ingredient per unit dosage form.
  • the invention also relates to a combination of a compound of formula I, a pharmaceutically acceptable salt or solvate thereof, and another antiviral compound, in particular another anti- HCV compound.
  • the term "combination” may relate to a product containing (a) a compound of formula I and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections.
  • HCV polymerase inhibitors include, NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371 , HCV-086, HCV-796 and R-1479, R-7128, MK-0608, VCH-759, PF-868554, GS9190, XTL-2125, NM-107, GSK625433, R-1626, BILB-1941 , ANA-598, IDX-184, IDX-375, INX-189, MK-3281 , MK-1220, ABT-333, PSI-7851 , PSI-6130, GS-7977, VCH-916.
  • Inhibitors of HCV proteases include BILN-2061
  • TMC435350 also referred to as TMC435, Simeprevir
  • An example of an HCV NS5A inhibitor is BMS790052, A-831 , A-689, NIM-81 1 and DEBIO-025 are examples of NS5B cyclophilin inhibitors.
  • Inhibitors of other targets in the HCV life cycle including NS3 helicase; metalloprotease inhibitors; antisense oligonucleotide inhibitors, such as ISIS-14803 and AVI-4065; siRNA's such as SIRPLEX-140-N; vector-encoded short hairpin RNA (shRNA); DNAzymes; HCV specific ribozymes such as heptazyme, RPI.13919; entry inhibitors such as HepeX-C, HuMax-HepC; alpha glucosidase inhibitors such as celgosivir, UT-231 B and the like; KPE-02003002; and BIVN 401 .
  • siRNA's such as SIRPLEX-140-N
  • shRNA vector-encoded short hairpin RNA
  • DNAzymes HCV specific ribozymes such as heptazyme, RPI.13919
  • entry inhibitors such as HepeX-C, HuMax-HepC
  • Immunomodulatory agents include, natural and recombinant interferon isoform compounds, including ointerferon, ⁇ -interferon, ⁇ -interferon, and ⁇ -interferon, such as Intron A®, Roferon- A®, Canferon-A300®, Advaferon®, Infergen®, Humoferon®, Sumiferon MP®, Alfaferone®, IFN- beta®, and Feron®; polyethylene glycol derivatized (pegylated) interferon compounds, such as PEG interferon-a-2a (Pegasys®), PEG interferon-a-2b (PEG-lntron®), and pegylated IFN- oconl ; long acting formulations and derivatizations of interferon compounds such as the albumin-fused interferon albuferon a; compounds that stimulate the synthesis of interferon in cells, such as resiquimod; interleukins; compounds that enhance the development of type 1
  • antiviral agents include, ribavirin, amantadine, viramidine, nitazoxanide; telbivudine; NOV- 205; taribavirin; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors, and mycophenolic acid and derivatives thereof, and including, but not limited to, VX-497 (merimepodib), VX-148, and/or VX-944); or combinations of any of the above.
  • interferon-a IFN-a
  • pegylated interferon- ⁇ or ribavirin therapeutics based on antibodies targeted against HCV epitopes
  • small interfering RNA Si RNA
  • ribozymes DNAzymes
  • antisense RNA small molecule antagonists of for instance NS3 protease, NS3 helicase and NS5B polymerase.
  • combinations of a compound of formula I as specified herein and an anti-HIV compound preferably are those HIV inhibitors that have a positive effect on drug metabolism and/or pharmacokinetics that improve bioavailability.
  • An example of such an HIV inhibitor is ritonavir.
  • this invention further provides a combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; and (b) ritonavir or a pharmaceutically acceptable salt thereof.
  • the compound ritonavir, its pharmaceutically acceptable salts, and methods for its preparation are described in WO 94/14436. US 6,037,157, and references cited therein: US 5,484,801 , US 08/402,690, WO 95/07696, and WO 95/09614, disclose preferred dosage forms of ritonavir.
  • the invention also concerns a process for preparing a combination as described herein, comprising the step of combining a compound of formula I and another agent, such as an antiviral, including an anti-HCV or anti-HIV agent, in particular those mentioned above.
  • the said combinations may find use in the manufacture of a medicament for treating HCV infection in a mammal infected therewith, said combination in particular comprising a compound of formula I, as specified above and interferon-a (IFN-a), pegylated interferon-a, or ribavirin.
  • the invention provides a method of treating a mammal, in particular a human, infected with HCV comprising the administration to said mammal of an effective amount of a combination as specified herein.
  • said treating comprises the systemic administration of the said combination, and an effective amount is such amount that is effective in treating the clinical conditions associated with HCV infection.
  • the above-mentioned combinations are formulated in the form of a pharmaceutical composition that includes the active ingredients described above and a carrier, as described above.
  • Each of the active ingredients may be formulated separately and the formulations may be co-administered, or one formulation containing both and if desired further active ingredients may be provided.
  • the combinations may also be formulated as a combined preparation for simultaneous, separate or sequential use in HCV therapy.
  • the said composition may take any of the forms described above.
  • both ingredients are formulated in one dosage form such as a fixed dosage combination.
  • the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula I, including a possible stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof, or a
  • the individual components of the combinations of the present invention can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is meant to embrace all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the separate dosage forms are administered simultaneously.
  • the combinations of the present invention contain an amount of ritonavir, or a pharmaceutically acceptable salt thereof, that is sufficient to clinically improve the
  • the combinations of the present invention contains an amount of ritonavir, or a pharmaceutically acceptable salt thereof, which is sufficient to increase at least one of the pharmacokinetic variables of the compound of formula I selected from t 1/2 , Cmin, Cmax, C ss , AUC at 12 hours, or AUC at 24 hours, relative to said at least one
  • the combinations of this invention can be administered to humans in dosage ranges specific for each component comprised in said combinations, e.g. the compound of formula I as specified above, and ritonavir or a pharmaceutically acceptable salt, may have dosage levels in the range of 0.02 to 5.0 g/day.
  • the weight ratio of the compound of formula I to ritonavir may be in the range of from about 30:1 to about 1 :15, or about 15: 1 to about 1 : 10, or about 15: 1 to about 1 : 1 , or about 10: 1 to about 1 : 1 , or about 8: 1 to about 1 : 1 , or about 5: 1 to about 1 : 1 , or about 3: 1 to about 1 :1 , or about 2:1 to 1 :1.
  • the compound formula I and ritonavir may be co-administered once or twice a day, preferably orally, wherein the amount of the compound of formula I per dose is as described above; and the amount of ritonavir per dose is from 1 to about 2500 mg, or about 50 to about 1500 mg, or about 100 to about 800 mg, or about 100 to about 400 mg, or 40 to about 100 mg of ritonavir.
  • Phenyl dichlorophosphate (12.4 ml, 83.1 mmol) was added to a cooled (-20 °C) slurry of the pTs salt of (S)-butyl 2-aminopropanoate (26.4 g, 83.1 mmol) in dichloromethane (DCM) (200 ml). The mixture was stirred for 10 min then triethylamine (25.5 ml, 183 mmol) was added drop wise during 15 min. The mixture was stirred at -20 °C for 1 h then at 0 °C for 30 min.
  • Phenyl dichlorophosphate (7.4 mL, 49.5 mmol) was added at -30°C under argon in one portion to a solution of the hydrochloride of (S)-butyl 2-aminopropanoate (9.0 g, 49.5 mmol) in CH 2 CI 2 (100 mL). After 10 min triethylamine (15 ml, 109 mmol) was added dropwise and the reaction mixture was allowed to attain room temperature and was stirred for 5h under Ar.
  • Phenyl dichlorophosphate (3.2 g, 15 mmol) was added under nitrogen at -30 °C to a solution of (S)-3,3-dimethylbutyl 2-aminopropanoate (5.2 g, 15 mmol) in DCM (80 ml), followed by dropwise addition of triethylamine (3.0 mg, 30 mmol).
  • step a The amine from step a (95.5 g, 276.4 mmol) and CH 2 CI 2 (100 ml) was added and the slurry was cooled with ice/H 2 0/NaCI keeping the inner temperature of the flask was to—12 °C. After 45 min, triethylamine (848 ml, 608.2 mmol) in CH 2 CI 2 (200 ml) was added slowly over 65 minutes. After the addition the temperature is slowly raised to 20 °C.
  • 1 b To a solution of 1 a (100 g, 609.7 mmol) in DMF (1 .5 L), sodium hydride (150 g, 3.71 mol) was added in portions at 0°C and allowed to stir at same temperature for 45 min. Benzyl bromide (450 mL, 3.71 mol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16 h.
  • trifluoromethanesulphonate (0.6 mL, 3.3 mmol) was added and the reaction mixture was heated to 80 °C for 5 h. An additional lot of trimethylsilyl trifluoromethanesulphonate (0.6 mL, 3.3 mmol) was added and heating was continued for 16 h. After completion of the reaction (TLC), the solvent was removed under reduced pressure and the residue was taken in EtOAc (50 mL), washed with 10% aqueous NaHC0 3 solution (25 mL) and dried over sodium sulphate. After removal of the solvent the crude was purified by column chromatography on silica gel (230-400 mesh, 30% EtOAc in p.
  • the uracil-nucleoside 1 (291 mg, 1 .13mmol) was dissolved in acetonitrile/water: 1/1 (3 mL) and triethylamine (2.50 mmol) was added. To the stirred solution was then added di-tert-butyl dicarbonate in portions of 1 .13 mmol every 5 hours. Upon completion (2 to 3 days) the mixture was evaporated onto silica-gel and the residue purified by flash chromatography using gradient DCM/MeOH: 98/2 to 92/8, which gave the title compound (324 mg, 80%). MS: 358.3 [M+H].
  • the 5'-0-unprotected nucleoside 2a (0.15 mmol) was dissolved in a mixture of
  • the intermediate 2b (0.094 mmol) was dissolved in dry dimethyl formamide (1.5 ml_), tributylamine pyrophosphate (0.19 mmol)) was added under nitrogen and the solution stirred overnight at room temperature. The solvent was removed in vacuum and the residue taken into 15% ammonia (12 ml.) and stirred at room temperature for 2h 30 min. Solvents were removed by evaporation and the residue re-dissolved in water containing 5% acetonitrile (4 ml.) and washed with DCM (3x2 ml_). The organic extracts were discarded, the water layer filtered to remove any insoluble material and the solution concentrated in vacuum.
  • Solvent B 10mM ammonium acetate, 10% water, 90% acetonitrile) to yield an inseparable mixture of the nucleoside phosphates. This mixture was freeze-dried and the residue purified by preparative HPLC on Dionex DNAPac using a gradient (4 mL/min) from 0% B to 60% B over 30 min (Solvent A: 0.05M ammonium bicarbonate, 90% water, 10% acetonitrile; Solvent B: 0.8M ammonium bicarbonate, 90% water, 10% acetonitrile) to yield, after freeze drying twice the desired tri-phosphate in its ammonium salt form (4 mg, 7.5% yield) in 99.2% purity.
  • Step b) ((2R,3S,4R,5RV4-amino-5-(2,4-dioxo-3,4-dihvdropyrimidin-1 (2H vn-3-hvdroxy-4- methyltetrahvdrofuran-2-yl)methyl dihvdroqen phosphate (29b)
  • Step b) (2SVcvclopentyl 2-(((((2R.3S.4R.5RV4-amino-5-(2.4-dioxo-3.4-dihvdropyrimidin-1 (2HV yl)-3-hvdroxy-4-methyltetrahvdrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-amino)propanoate (5b-A & 5b-B)
  • Step b) (2SV3.3-Dimethylbutyl 2-(((((2R.3S.4R.5RV4-amino-5-(2.4-dioxo-3.4-dihvdroDyrimidin- 1 (2H)-yl)-3-hvdroxy-4-methyltetrahvdrofuran-2-yl)methoxy)(phenoxy)- phosphoryl)amino)propanoate (6b-A & 6b-B)
  • the compounds of formula I may be examined for activity in the inhibition of HCV RNA replication in a cellular assay aimed at identifying compounds that inhibit a HCV functional cellular replicating cell line, also known as HCV replicons.
  • a suitable cellular assay is based on a bicistronic expression construct, as described by Lohmann et al. (1999), Science vol. 285 pp. 1 10-1 13 with modifications described by Krieger et al. (2001 ), Journal of Virology 75: 4614- 4624, in a multi-target screening strategy.
  • the assay utilizes the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh- Luc).
  • This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type 1 b translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL- luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase).
  • IRS Internal Ribosome Entry Site
  • EMCV encephalomyocarditis virus
  • FfL- luciferase reporter portion
  • neo R neomycine phosphotransferase
  • HCV RNA stably transfected replicon cells that express HCV RNA, which replicates autonomously and to high levels, encoding inter alia luciferase, are used for screening the antiviral compounds.
  • the replicon cells are plated in 384 well plates in the presence of the test and control compounds which are added in various concentrations. Following an incubation of three days, HCV replication is measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLuxTM ultraHTS microplate imager).
  • Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor.
  • the inhibitory activity of a compound on luciferase activity is monitored on the Huh-Luc cells, enabling a dose-response curve for each test compound.
  • EC 5 o values are then calculated, which value represents the amount of the compound required to decrease the level of detected luciferase activity by 50%, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.
  • the compounds of the invention are metabolised by cellular kinases in target tissues to the 5'-trisphosphate. It is this triphosphate which is believed to be the antivirally active species.
  • the enzyme assay described here example may be used to confirm that compounds of the invention are antivirally active as the 5'-triphosphate metabolite.
  • the enzyme assay measures the inhibitory effect of triphosphate compounds in an HCV NS5B- 21 (21 -aminoacid C-terminally truncated version) SPA assay (scintillation proximity assay).
  • the assay is performed by evaluating the amount of radiolabeled ATP incorporated by HCV NS5B- 21 into newly synthesized RNA using an heterogeneous biotinylated RNA template.
  • IC 50 values the compounds are tested at various concentrations in a final volume of 100 ⁇ of reaction mixture. The reaction is stopped by addition of 0.5M EDTA solution.
  • the samples are transferred into flashplates precoated with streptavidin.
  • the incorporated radioactivity is quantified using a scintillation counter (Wallac Microbeta Trilux).
  • Biotinylated RNA template with a sequence of
  • Enzyme HCV NS5B-21 , made up to 500Mg/ml in water. Replizyme
  • Radiolabeled 3 H-ATP (cat. no TRK747) GE Healthcare
  • the assay should include enzyme controls (about four, containing 1 ⁇ DMSO instead of inhibitor) and background control containing all ingredients except template. Compounds are serially diluted in DMSO on a separate dilution plate to 100x the final desired assay concentrations.
  • Sufficient reaction mixture for the number of wells to be used is made up according to the table below and 90 ⁇ /well is added to a 96 well polyproylene plate. 1 ⁇ of compound in DMSO from the dilution plate is added to each well, except the enzyme control wells and background control wells to which 1 ⁇ DMSO is added.
  • AverageEnzymeControlCPM - BackgroundCPM Background Reaction buffer without template.
  • IC 50 is determined using Graphpad Prism. Plot Compound concentration in Log versus percentage inhibition. Fit the curve with nonlinear regression to the Log (Inhibitor) versus Response equation.
  • Y is % Inhibition
  • X is log (inhibitor) and top and bottom are the upper and lower limits of the % Inhibition.
  • the nucleotide of Example 3 was tested in the above described enzyme assay and the IC 50 value determined to be 13 ⁇ .
  • Fresh human plated hepatocytes (Biopredic, France) in 12-well plates were used. Each well was plated with 0.76 x 10 6 cells and incubated with a 10 ⁇ DMSO solution of compound (0.1 % DMSO) in 1 ml. incubation medium in a C0 2 incubator at 37 °C for 6-8hours. The incubation was stopped by washing each well with 1 ml. ice cold Hank ' s balanced solution, pH 7.2 twice, followed by addition of 0.5 ml. ice cold 70% methanol. Immediately after the addition of methanol, the cell-layer was detached from the bottom of the well by a cell scraper and sucked up and down 5-6 times with an automatic pipet. The cell suspension was transferred to a glass vial and stored overnight at -20 °C.
  • the samples each consisting of various levels of protide, free nucleoside, and mono-, di- and triphosphate were then vortexed and centrifuged at 10 °C for 10 minutes, at 14000 rpm in an Eppendorf centrifuge 5417R.
  • the supernatants were transferred to 2 ml. glass vials with insert and subjected to bioanalysis.
  • the HPLC mobile phases for the POLAR-RP column consisted of 10 mmol/L ammonium acetate in 2 % acetonitrile (mobile phase A) and 10 mmol/L ammonium acetate in 90 % acetonitrile (mobile phase B) and for the BioBasic AX column 10 mmol/L ammonium acetate in 2 % acetonitrile (mobile phase C) and 1 % ammonium hydroxide in 2 % acetonitrile (mobile phase D).
  • the HPLC gradient for pump Y started at 0% mobile phase B and was held for 2 min. During loading phase, the mobile phase went through the POLAR-RP and BioBasic AX column, and prodrug, nucleoside and internal standard were trapped on the POLAR-RP column;
  • nucleotides (mono-, di- and triphosphates) eluted on to the BioBasic AX column and were trapped there.
  • the flow was switched from the POLAR-RP column to the MS and the mobile phase C switched from pump X to the BioBasic AX column.
  • the compounds on the POLAR-RP column were eluted with a gradient from 0 % B up to 100 % B in about two minutes and analyzed in positive or negative mode using the multiple reaction monitoring mode (MRM).
  • MRM multiple reaction monitoring mode
  • the flow from the BioBasic AX column was switched to the MS and the phosphates were eluted with a of about 7 minutes gradient up 50 % D ) and analyzed in positive or negative mode using MRM.
  • both columns are reconditioned. Triphosphate concentration for each compound was then determined by comparison with standard curves.
  • the standard curves were made by analysis of standard samples with known concentrations of triphosphate. The standards were ran in the same matrices as the test samples. Due to variations in phosphorylation levels depending on hepatocyte donor, an internal reference compound is required in each run of the assay in order to enable ranking the results from different runs to each other.

Abstract

L'invention concerne des composés de formule (I) : qui sont utiles dans le traitement ou la prophylaxie d'une infection par le virus de l'hépatite C, et des aspects associés.
PCT/IB2012/056994 2011-12-05 2012-12-05 Inhibiteurs de vhc polymérase WO2013084165A1 (fr)

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