WO2007039143A1 - Composes de c (2) -heteroarylmethyl-c (4) -pyrazin-2-yl acyl pyrrolidine et leur utilisation pour traiter des infections virales, en particulier le vhc - Google Patents

Composes de c (2) -heteroarylmethyl-c (4) -pyrazin-2-yl acyl pyrrolidine et leur utilisation pour traiter des infections virales, en particulier le vhc Download PDF

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WO2007039143A1
WO2007039143A1 PCT/EP2006/009235 EP2006009235W WO2007039143A1 WO 2007039143 A1 WO2007039143 A1 WO 2007039143A1 EP 2006009235 W EP2006009235 W EP 2006009235W WO 2007039143 A1 WO2007039143 A1 WO 2007039143A1
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formula
thiazol
butyl
compounds
tert
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PCT/EP2006/009235
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English (en)
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David Haigh
Charles David Hartley
Peter David Howes
Linos Lazarides
Fabrizio Nerozzi
Stephen Allan Smith
Richard Lewis Jarvest
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Glaxo Group Limited
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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

Definitions

  • the present invention relates to novel C(4)-pyrazine acyl pyrrolidine derivatives useful as 5 anti-viral agents. Specifically, the present invention involves novel Hepatitis C Virus (HCV) inhibitors.
  • HCV Hepatitis C Virus
  • HCV infection is responsible for 40-60% of all chronic liver disease 5 and 30% of all liver transplants.
  • Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U.S.
  • the CDC estimates that the number of deaths due to HCV will minimally increase to 38,000/year by the year 2010.
  • Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection.
  • adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia 5 induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1 ): 71 S-77S).
  • hepatitis C virus HCV
  • NNBH non-B hepatitis
  • flaviviruses e.g. yellow fever virus and Dengue virus types 1-4
  • pestiviruses e.g.
  • HCV bovine viral diarrhea virus, border disease virus, and classic swine fever virus
  • the HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5' noncoding region' RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • ORF long open reading frame
  • this RNA Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.
  • This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2 nd Edition, p931- 960; Raven Press, N. Y.).
  • 3' NTR which roughly consists of three regions: an ⁇ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3" X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261).
  • the 3 1 NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.
  • the NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases.
  • the NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1b isolates) and inter-typically (-85% aa identity between genotype 1a and 1 b isolates).
  • the essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4), p.2046-2051 ).
  • inhibition of NS5B RdRp activity is predicted to cure HCV infection.
  • genotype 1 Although the predominant HCV genotype worldwide is genotype 1 , this itself has two main subtypes, denoted 1a and 1b. As seen from entries into the Los Alamos HCV database (www.hcv.lanl.gov) (Table 1 ) there are regional differences in the distribution of these subtypes: while genotype 1a is most abundant in the United States, the majority of sequences in Europe and Japan are from genotype 1 b. Table 1
  • genotype 1a makes it highly desirable to identify an anti-viral agent that is able to inhibit both genotype 1a and genotype 1b. This means a wider patient pool would be able to benefit from treatment with the same agent.
  • A represents OR 1 , NR 1 R 2 , or R 1 wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • B represents C(O)R 3 wherein R 3 is selected from the group consisting of C ⁇ alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; C represents C 1-6 alkyl, aryl, heteroaryl or heterocyclyl; D represents a saturated or unsaturated 6-membered heterocyclic ring comprising three or more carbon atoms, each of which may independently be optionally substituted by R 4 and R 5 , and one to three heteroatoms independently selected from N, optionally substituted by hydrogen, C 1-6 alkyl, C(O)R 3 , SO 2 R 3 , aryl, heteroaryl, arylalkyl, or heteroarylalkyl; O; and S, optionally substituted by one or two oxygen atoms; wherein the 6 membered ring may be attached at any endocyclic carbon atom, and may be optionally fused to a saturated or unsaturated 5 or 6 membered carbocyclic or heterocyclic ring which may itself
  • R 6 and R 7 are independently selected from hydrogen, C 1-6 alkyl, aryl and heteroaryl; and R 8 represents hydrogen, Ci -6 alkyl, arylalkyl, or heteroarylalkyl; E represents hydrogen or C 1-6 alkyl; F represents hydrogen, C h alky!, aryl or heteroaryl; and G represents hydrogen, C 1-6 alkyl, heterocyclylalkyl, arylalkyl or heteroarylalkyl; and salts, solvates and esters thereof, provided that when A is OR 1 then R 1 is other than terf-butyl.
  • the present invention involves C(2)-heteroarylmethyl-C(4)-pyrazin-2-yl acyl pyrrolidine compounds represented hereinbelow, pharmaceutical compositions comprising such compounds and use of the compounds in treating viral infection, especially HCV infection.
  • the present invention provides at least one chemical entity chosen from compounds of Formula (Ia) :
  • A represents hydroxy
  • B represents -C(O)R 3 ;
  • D represents 1 ,3-thiazol-2-yl
  • E represents pyrazin-2-yl
  • G represents 1 ,3-thiazol-4-ylmethyl or 1 H-pyrazol-1-ylmethyl
  • R 3 represents 4-tert-butyl-3-ethenylphenyl or 4-tert-butyl-5-ethenyl-2-fluorophenyl; and salts, solvates and esters thereof; provided that when A is esterified to form -OR where R is selected from branched chain alkyl, then R is other than tert-butyl.
  • A is hydroxy (that is, not esterified).
  • the compounds of Formula (Ia) are represented by compounds of Formula (Ip)-
  • the compounds of Formula (Ia) are represented by compounds of Formula (Ia).
  • the chemical entities of the present invention exhibit an improved genotype-1a/1 b profile against HCV polymerase, and therefore have the potential to achieve efficacy in man over a broad patient population.
  • 'genotype-1a/1 b profile' means potency as an inhibitor of HCV polymerase enzyme in wildtype HCV of the 1 a genotype and of the 1 b genotype. High potency in both genotypes is considered to be advantageous.
  • references herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.
  • a method for the treatment of a human or animal subject with viral infection, particularly HCV infection comprises administering to said human or animal subject an effective amount of at least one chemical entity chosen from compounds of Formula (Ia) and pharmaceutically acceptable salts, solvates or esters thereof.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms.
  • chemical entities useful in the present invention may be chosen from compounds of Formula (Ia) selected from the group consisting of: re/-(2R,4S,5R)-1-(3-ethenyl-4-tert-butylbenzoyl)-4-(pyrazin-2-yl)-2-(1 ,3-thiazol-4-ylmethyl)-
  • Suitable pharmaceutically acceptable salts of the compounds of formula (Ia) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-tolu
  • the present invention also relates to solvates of the compounds of Formula (Ia), for example hydrates.
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (Ia), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl
  • alkoxycarbonylalkyl e.g. methoxycarbonylmethyl
  • any alkyl moiety present in such esters preferably contains 1 to 18 carbon atoms, particularly 1 to 4 carbon atoms. Any aryl moiety present in such esters preferably comprises a phenyl group.
  • the compound of Formula (Ia) is in the form of the parent compound, or a salt or a solvate.
  • the term "pharmaceutically acceptable” used in relation to an ingredient (active ingredient such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation for administration to a patient refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.
  • A' is a protected hydroxy group, for example an alkoxy, benzyloxy or silyloxy, for example tri-(C 1-4 alkyl)-silyloxy group
  • B, D, E and G are as defined above for Formula (Ia), by deprotection.
  • Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3 rd Ed (1999), J Wiley and Sons.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 0 to 50 0 C, more preferably 20 to 30 0 C.
  • a suitable catalyst for example palladium-on- carbon.
  • the reaction is carried out in a solvent, for example ethanol.
  • the temperature is in the range 0 to 50 0 C.
  • A' is allyloxy
  • B, D, E and G are as defined above for Formula (Ia)
  • a suitable catalyst for example tetrakis(triphenylphosphine)palladium(0) and a suitable proton source, for example phenylsilane.
  • the reaction is carried out in a suitable solvent, for example dichloromethane.
  • a suitable fluoride source for example tetrabutylammonium fluoride.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran.
  • A" is hydroxy or an alkoxy, benzyloxy or a silyloxy, for example a trKC ⁇ alkyl)- silyloxy, group, and D, E and G are as defined above for Formula (Ia); with a suitable acylating agent, for example R 3 -C(O)-hal, wherein hal is a halo atom, preferably chloro or bromo, and R 3 is as defined above for Formula (Ia).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • the temperature is in the range 0 to 50 0 C, more preferably 20 to 30 0 C.
  • the reaction may be carried out at the reflux temperature of the solvent.
  • the reaction is carried out in a suitable solvent, for example THF or acetonitrile, optionally in the presence of a Lewis acid catalyst, such as lithium bromide or silver acetate, and a base, such as triethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or tetramethyl guanidine.
  • a Lewis acid catalyst such as lithium bromide or silver acetate
  • a base such as triethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or tetramethyl guanidine.
  • DBU triethylamine
  • tetramethyl guanidine tetramethyl guanidine.
  • the temperature is in the range 0 to 5O 0 C, more preferably 20 to 3O 0 C.
  • reaction is carried out in a suitable solvent, for example THF or acetonitrile, in the presence of an acid, such as acetic acid, or the reaction may be carried out by heating compounds of Formula (IV) and Formula (V) in a suitable solvent, for example toluene, xylene or acetonitrile in the absence of a catalyst.
  • a suitable solvent for example THF or acetonitrile
  • an acid such as acetic acid
  • the reaction is carried out in a suitable solvent, for example THF or acetonitrile, optionally in the presence of a Lewis acid catalyst, such as lithium bromide or silver acetate, and a base, such as triethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or tetramethyl guanidine.
  • a Lewis acid catalyst such as lithium bromide or silver acetate
  • a base such as triethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or tetramethyl guanidine.
  • DBU triethylamine
  • tetramethyl guanidine tetramethyl guanidine
  • the reaction is carried out at a temperature in the range 0 to 5O 0 C, more preferably 20 to 30 0 C.
  • a drying agent is used in the process, for example molecular sieves.
  • Compounds of Formula (IV) may be prepared by reaction of a compound of Formula (Vl) in which G is as defined above for Formula (Ia) and A" is as defined above for Formula (III) with a compound of Formula D-CHO in which D is as defined above for Formula (Ia) optionally in the presence of a suitable drying agent, for example magnesium sulphate, in a suitable solvent, for example dichloromethane.
  • a suitable drying agent for example magnesium sulphate
  • a suitable solvent for example dichloromethane.
  • the reaction is carried out at a temperature in the range 0 to 50 0 C.
  • G is 1 H-pyrazol-1-ylmethyl and M is a metal cation, for example potassium, with a suitable acid, for example 10% aqueous hydrochloric acid, in the presence of an ion exchange resin, such as AmberlystTM 120 (H + ).
  • a suitable acid for example 10% aqueous hydrochloric acid
  • an ion exchange resin such as AmberlystTM 120 (H + ).
  • Compounds of Formula (Vl) in which G is 1 H-pyrazol-1-ylmethyl, and A" is an alkoxy, benzyloxy or a silyloxy, for example a tri-(C 1-4 alkyl)-silyloxy, group may be prepared by treatment of a compound of Formula (Vl) in which G is 1H-pyrazol-1-ylmethyl, and A" is hydroxy, by conventional esterification or protecting group procedures.
  • a compound of Formula (Vl) in which G is 1 H-pyrazol-1-ylmethyl, and A" is tert-butoxy may be prepared by treatment of a compound of Formula (Vl) in which G is 1 H-pyrazol-1- ylmethyl, and A" is hydroxy, with an appropriate tert-butyl transfer agent, such as tert- butylacetate in the presence of a suitable acid catalyst, such as 70% perchloric acid.
  • an appropriate tert-butyl transfer agent such as tert- butylacetate in the presence of a suitable acid catalyst, such as 70% perchloric acid.
  • reaction is carried out at a temperature in the range 50-70 0 C, more preferably 60 0 C.
  • G is 1 ,3-thiazol-4-ylmethyl and A" is an alkoxy, benzyloxy or a silyloxy, for example a tri-(C 1-4 alkyl)-silyloxy, group with an acid, for example 15% aqueous citric acid.
  • the reaction is carried out in a suitable solvent, for example THF.
  • reaction is carried out in the presence of a suitable base, such as potassium f-butoxide.
  • a suitable solvent for example THF.
  • reaction is carried out in the presence of a suitable catalyst, for example lithium iodide.
  • the reaction is carried out at a temperature in the range -10 0 C to room temperature, suitably at 0 0 C.
  • A" is hydroxy or an alkoxy, benzyloxy or a silyloxy, for example a tri-(C 1-4 alkyl)- silyloxy, group, and B, D and E are as defined above for Formula (Ia); with a compound of Formula G-hal in which G is as defined above for Formula (I) and hal is a halo atom, preferably chloro or bromo.
  • a suitable solvent for example THF
  • a suitable base for example lithium hexamethyldisilazide (LHMDS).
  • reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example triethylamine.
  • a suitable solvent for example dichloromethane
  • a suitable base for example triethylamine
  • the temperature is in the range 0 to 50 0 C, suitably 20 to 30 0 C.
  • the reaction may be carried out at the reflux temperature of the solvent.
  • reaction in which A" is as defined above for Formula (III), with a compound of Formula (V) and a compound of Formula D-CHO.
  • a suitable solvent for example THF or acetonitrile
  • a Lewis acid catalyst such as lithium bromide or silver acetate
  • a base such as triethylamine, 1 ,8- diazabicyclo[5,4,0]undec-7-ene (DBU) or tetramethyl guanidine.
  • DBU triethylamine
  • DBU triethylamine
  • a drying agent is used in the process, for example molecular sieves.
  • a suitable acid halide forming reagent for example oxalyl chloride or thionyl chloride.
  • the reaction is carried out in the presence of a suitable catalyst, for example dimethylformamide or diethylformamide.
  • a suitable solvent for example dichloromethane, at a temperature in the range 0 to 50 0 C, for example 20 to 30 0 C.
  • the reaction is carried out using thionyl chloride under reflux.
  • the compound of Formula (XIV) may be prepared by reaction of a compound of Formula
  • the temperature is in the range 0 to 50 0 C, suitably 20 to 3O 0 C.
  • P' is a suitable protecting group, for example tert-butyl, with a suitable olefinating reagent, for example methyltriphenylphosphonium bromide.
  • the reaction is carried out in the presence of a suitable base, for example potassium terf-butoxide.
  • a suitable solvent for example THF.
  • the temperature is in the range 0 to 50°C, suitably 20 to 30 0 C.
  • P' is a suitable protecting group, for example tert-butyl, with a suitable formylating reagent, for example DMF.
  • the reaction is carried out in the presence of a suitable base, for example n-butyl lithium in hexane.
  • a suitable solvent for example THF.
  • the temperature is in the range 0 to -78°C, suitably -78 0 C.
  • reaction is carried out in the presence of a suitable base, for example DBU.
  • a suitable base for example DBU.
  • an activating agent for example 1 ,1 '-carbonyldiimidazole.
  • the reaction is carried out in a suitable solvent, for example DMF.
  • the temperature is in the range 0 to 5O 0 C, suitably 40 0 C.
  • the compound of Formula (XIV) may also be prepared by reaction of a compound of Formula (XVIII) with an ethenyl transfer reagent, for example potassium ethenyltrifluoroborate.
  • an ethenyl transfer reagent for example potassium ethenyltrifluoroborate.
  • the reaction is carried out in the presence of a suitable catalyst, for example [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with CH 2 CI 2 .
  • a suitable base for example caesium carbonate.
  • the reaction is carried in a suitable solvent, for example a mixture of THF and water.
  • the reaction is carried out under reflux.
  • a suitable acid halide forming reagent for example oxalyl chloride or thionyl chloride.
  • the reaction is carried out in the presence of a suitable catalyst, for example dimethylformamide or diethylformamide.
  • a suitable solvent for example dichloromethane, at a temperature in the range 0 to 5O 0 C, for example 20 to 30 0 C.
  • the reaction is carried out using thionyl chloride under reflux.
  • the compound of Formula (XIX) may be prepared by reaction of the compound of Formula (XX)
  • the reaction is carried out in the presence of a suitable catalyst, for example [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with CH 2 CI 2 .
  • a suitable catalyst for example [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with CH 2 CI 2 .
  • the reaction is carried out in the presence of a suitable base for example caesium carbonate.
  • the reaction is carried in a suitable solvent, for example a mixture of THF and water.
  • the reaction is carried out under reflux.
  • the compound of Formula (XX) may be prepared by reaction of the compound of Formula (XX)
  • reaction is carried in the presence of a suitable acid, for example trifluoroacetic acid and concentrated sulphuric acid. In one aspect, the reaction is carried out at a temperature in the range 20-50 0 C.
  • the compound of Formula (XXI) may be prepared by treatment of the compound of Formula (XXII)
  • the compound of Formula (XXII) may be prepared by reaction of the compound of Formula (XXIII)
  • reaction is carried out in a suitable solvent, for example dimethylformamide. In one aspect, the reaction is carried out at a temperature in the range 50-80°C.
  • the compound of Formula (XXIII) may be prepared by reaction of the compound of
  • reaction is carried out in a suitable solvent, for example dimethylformamide.
  • the compound of Formula (XXIV) may be prepared by reaction of the compound of Formula (XXV)
  • the reation is carried out at a temperature in the range 50-80 0 C.
  • the present invention provides a method for the interconversion of the rel-(2R, 4S, 5R)-diastereoisomer of a compound of formula (I) or (II) wherein A is other than hydroxy, into the rel-(2R, 4R, 5R)-diastereoisomer.
  • a suitable base such as aqueous sodium hydroxide
  • a suitable solvent such as methanol
  • Compounds of Formula (Ia) in which A is an ester may be prepared by esterification of compounds of Formula (Ia) in which A is hydroxy by standard literature procedures for esterification.
  • racemic compounds of Formula (Ia), (II), (III), (Xl) and (XII) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of Formula (Ia), (II), (III), (Xl) and (XII) may be resolved by chiral preparative HPLC. Alternatively, racemic compounds of Formula (Ia), (II), (III), (Xl) and (XII) which contain an appropriate acidic or basic group, such as a carboxylic acid group or amine group may be resolved by standard diastereoisomeric salt formation with a chiral base or acid reagent respectively as appropriate.
  • an appropriate acidic or basic group such as a carboxylic acid group or amine group
  • a racemic compound of Formula (III) may be resolved by treatment with a chiral acid such as (R)-(-)-1 ,1 '-binaphthyl-2,2'-diyl-hydrogen phosphate, in a suitable solvent, for example dichloromethane, isopropanol or acetonitrile.
  • the enantiomer of Formula (III) may then be obtained by treating the salt with a suitable base, for example triethylamine, in a suitable solvent, for example methyl terf-butyl ether.
  • Individual enantiomers of Formula (II) and/or (III) may then be progressed to an enantiomeric compound of Formula (Ia) by the chemistry described above in respect of racemic compounds.
  • individual enantiomeric compounds of Formula (III) and/or (XII) may be prepared by general methods of asymmetric synthesis using, where appropriate, chiral auxiliaries or chiral catalytic reagents and additionally performing any suitable functional group interconversion step as hereinbefore described, including the addition or removal of any such chiral auxiliary.
  • chiral auxiliaries include chiral alcohols such as menthol or 1-phenylethanol; chiral oxazolidinones such as
  • Suitable general chiral catalytic reagents include chiral basic amines and chiral ligands such as N-methylephedrine, 1-phenyl-2-(1-pyrrolidinyl)-1-propanol, 3-(dimethylamino)-
  • the reaction is carried out in the presence of a suitable chiral catalytic reagent, for example (-)-N-methylephedrine, and a suitable metal salt, for example manganese (II) bromide, in a suitable solvent, for example acetonitrile.
  • a suitable chiral catalytic reagent for example (-)-N-methylephedrine
  • a suitable metal salt for example manganese (II) bromide
  • a suitable solvent for example acetonitrile.
  • the reaction is carried out at a temperature in the range -30 c C to room temperature, suitably at -20 0 C.
  • the reaction may be carried out in the presence of a suitable chiral catalytic reagent, for example S-BINAP, and a suitable metal salt, for example silver acetate, in the presence of a suitable base, for example diisopropylethylamine, in a suitable solvent, for example acetonitrile optionally co-solvated with toluene.
  • a suitable chiral catalytic reagent for example S-BINAP
  • a suitable metal salt for example silver acetate
  • a suitable base for example diisopropylethylamine
  • a suitable solvent for example acetonitrile optionally co-solvated with toluene.
  • the reaction is carried out at a temperature in the range -15 0 C to room temperature, suitably at -5 0 C.
  • the major chiral diastereoisomer of a compound of Formula (Ilia) arising from such an asymmetric reaction may be further enantioenriched by conventional purification techniques well known in the art, for example by chromatography, or by fractional crystallisation.
  • a favourable crystallisation method is the fractional crystallisation of a salt of the major chiral diastereoisomer, for example the hydrochloride salt or the (R)-(-)-1,1'- binaphthyl-2,2'-diyl-hydrogen phosphate salt.
  • the hydrochloride salt of a compound of Formula (Ilia) may be prepared by treating a compound of Formula (Ilia) with anhydrous hydrogen chloride in a suitable solvent, for example diethyl ether. Preferably the reaction is carried out at a temperature in the range -10 to 10°C.
  • the (R)-(-)-1 ,1 '-binaphthyl-2,2'-diyl-hydrogen phosphate salt of a compound of Formula (Ilia) may be prepared as herein before described for the resolution of a racemic compound of Formula (III).
  • chiral compounds of Formula (Ia), (II) and/or (Xl) may be prepared from chiral compounds of Formula (III), such as (Ilia), or of Formula (XII).
  • Methyltriphenylphosphonium bromide (1.35 g) in dry THF (25 mL) was stirred at room temperature under nitrogen. A 1.0 M solution of potassium te/f-butoxide in THF (3.8 mL) was added and the resulting solution was stirred for 30 minutes at room temperature. To this was added 3-fomnyl-4-tert-butylbenzoic acid, tert-butyl ester (Intermediate 2; 0.50 g) and the mixture was stirred for a further 2 hours. The reaction mixture was quenched with water and extracted with diethyl ether. The combined extracts were dried (MgSO 4 ), filtered and concentrated in vacuo.
  • Alternative method B A mixture of 3-bromo-4-tert-butylbenzoic acid (9.52 g), potassium ethenyltrifluoroborate (5.95 g), [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with CH 2 CI 2 (2.43 g) and caesium carbonate (48.2 g) in THF-water (10:1 v/v; 500 mL) was degassed for 15 minutes by bubbling nitrogen through the mixture. The mixture was then heated under reflux for 4.5 hours. The cooled mixture was diluted with ether and then washed with 0.5 M hydrochloric acid.
  • the 4-(chloromethyl)-1 ,3-thiazole (formed in Part B) was dissolved in THF (100 mL) and added dropwise (dropping funnel) over 30 minutes to the reaction mixture from Part A, keeping the reaction at ice-bath temperature. Solid anhydrous lithium iodide (1 g, 7.5 mmol) was added directly to the reaction mixture 5 minutes after addition of the alkylating agent had started. The dropping funnel was rinsed with further dry THF (50 mL) which was added to the reaction.
  • the reaction was stirred at ice-bath temperature for 45 minutes, allowed to warm to room temperature over 30 minutes and was stirred at room temperature for an additional 2.5 hours before being partitioned between a mixture of saturated brine (400 mL), water (200 mL) and ethyl acetate (800 mL). The organic layer was separated and the aqueous layer re-extracted with further ethyl acetate (2 x 300 mL). The combined organic layers were dried over sodium sulphate and evaporated to give the title compound (57.8 g, crude) which was used without further purification.
  • Re/-(2R,4S,5R) stereochemistry shown (R)-Absolute stereochemistry shown re/-(2R,4S,5R)-4-(Pyrazin-2-yl)-2-(1 ,3-thiazol-4-ylmethyl)-5-(1 ,3-thiazol-2-yl)-pyrrolidine-2- carboxylic acid, tert-butyl ester (Intermediate 9; 10.8 g, 25.1 mmol) and (R)-1 ,1'- binaphthyl-2,2'-diyl-hydrogen phosphate (8.76 g, 25.1 mmol) were suspended in acetonitrile (55 mL) and heated to reflux with stirring to give a clear solution.
  • the crude product was purified by column chromatography on silica gel, eluting initially with dichloromethane, followed by cyclohexane-ethyl acetate (50:50 v/v), followed by ethyl acetate and finally with ethyl acetate-methanol (90:10 v/v) to give the title compound as a gum.
  • compositions for use in therapy comprising at least one chemical entity chosen from compounds of formula (Ia) and pharmaceutically acceptable salts, solvates and esters thereof in admixture with at least one pharmaceutically acceptable diluent or carrier.
  • the chemical entities of the present invention can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.
  • injection parenteral administration
  • the chemical entities of the invention are formulated in liquid solutions, preferably, in pharmaceutically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the chemical entities may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the chemical entities of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various chemical entities to be administered can be determined by standard procedures taking into account factors such as the compound (IC 50 ) potency, (EC 50 ) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present compounds.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (Ia).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (Ia).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • compositions comprising a compound of Formula (Ia) and/or a pharmaceutically acceptable salt, solvate or ester thereof, which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • composition is in the form of a capsule
  • any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional non-CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • a conventional non-CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • a typical suppository formulation comprises a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa- butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non- aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • ASSAYS The potential for chemical entities of the invention to inhibit NS5B wildtype HCV polymerase activity, genotype 1a and genotype 1b, may be demonstrated, for example, using the following in vitro assays:
  • HCV RNA Polymerase [Recombinant NS5B with C-terminal 21 amino acid deletion and C- terminal 6His-tag (Ferrari et al. J. Virol. 73(2), 1999, 1649. 'Characterization of soluble hepatitis C virus RNA-dependent RNA polymerase expressed in Escherichia coli.') expressed in E. coli and purified to homogeneity] was added to 25 nM final concentration. Polymerase of genotype 1a was from strain H77 (Yanagi, M., Purcell, R. H., Emerson, S. U. & Bukh, J. (1997), Proceedings of the National Academy of Sciences, USA 94, 8738- 8743) containing a sequence change from valine to isoleucine at position 180.
  • Reaction Conditions were 25 nM enzyme, 1.5 ⁇ g/ml oligo-rG13/poly-rC and 0.2 ⁇ Ci ⁇ - 33 P- GTP in 0.5 ⁇ M GTP (20 Ci/mMol) , 20 rtiM Tris pH 7.5, 23 mM NaCI, 3 mM DTT, 5 mM MgCI 2 , 1 mM MnCI 2 .
  • Enzyme was diluted to 500 nM concentration in 20 mM Tris-HCI, pH 7.5, 25 mM NaCI and 3 mM DTT.
  • 4x concentrated assay buffer mix was prepared using 1 M Tris-HCI, pH7.5 (1 ml_), 5M NaCI (0.25 mL), 1 M DTT (0.12 mL) and Water (8.63 ml_), Total 10 mL
  • 2x concentrated first reagent was prepared using 4x concentrated assay buffer mix (5 ⁇ L), 40 u/ ⁇ L RNasin (0.1 ⁇ L), 20 ⁇ g/mL polyrC/biotinylated-oligorG (1.6 ⁇ l_), 500 nM enzyme (1 ⁇ L ) and Water (2.3 ⁇ L), Total 10 ⁇ L/well.
  • 2x concentrated second reagent was prepared using 1M MgCI 2 (0.1 ⁇ L), 1 M MnCI 2 (0.02 ⁇ L), 25 ⁇ M GTP (0.4 ⁇ L), Q-[ 33 P]- GTP (10 ⁇ Ci/ ⁇ L, 0.02 ⁇ L) and water (9.5 ⁇ L), Total 10 ⁇ L/well.
  • the assay was set up using compound (1 ⁇ L in 100% DMSO), first reagent (10 ⁇ L), and second reagent (10 ⁇ L), Total ' 21 ⁇ L.
  • the reaction was performed in a U-bottomed, white, 96-well plate.
  • the reaction was mixed on a plate-shaker, after addition of the Enzyme, and incubated for 1h at 22°C. After this time, the reaction was stopped by addition of 60 ⁇ L 1.5 mg/ml streptavidin SPA beads
  • Reaction Conditions were 0.5 ⁇ M [ 33 P]-GTP (20 Ci/mMol), 1 mM Dithiothreitol, 20 mM MgCI 2 , 5mM MnCI 2 , 20 mM Tris-HCI, pH7.5, 1.6 ⁇ g/mL polyC/0.256 ⁇ M biotinylated oligoG13, 10% glycerol, 0.01 % NP-40, 0.2 u/ ⁇ L RNasin and 50 mM NaCI.
  • HCV RNA Polymerase Recombinant full-length NS5B (Lohmann et al, J. Virol. 71 (11 ), 1997, 8416. 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 4 nM final concentration.
  • 5x concentrated assay buffer mix was prepared using 1M MnCI 2 (0.25 mL), glycerol (2.5mL), 10% NP-40 (0.025 mL) and Water (7.225 mL), Total 10 mL.
  • 2x concentrated enzyme buffer contained 1 M-Tris-HCI, pH7.5 (0.4 mL), 5M NaCI (0.2 mL), 1 M-MgCI 2 (0.4 mL), glycerol (1 mL), 10% NP-40 (10 ⁇ L), 1 M DTT (20 ⁇ L) and water (7.97 mL), Total 1O mL
  • Substrate Mix was prepared using 5x Concentrated assay Buffer mix (4 ⁇ L), [ 33 P]-GTP (10 ⁇ Ci/ ⁇ L, 0.02 ⁇ L), 25 ⁇ M GTP (0.4 ⁇ L), 40 u/ ⁇ L RNasin (0.1 ⁇ L), 20 ⁇ g/mL polyrC/biotinylated-oligorG (1.6 ⁇ L), and Water (3.94 ⁇ L), Total 10 ⁇ L.
  • Enzyme Mix was prepared by adding 1mg/ml full-length NS5B polymerase (1.5 ⁇ L) to 2.81 mL 2x-concentrated enzyme buffer.
  • the Assay was set up using compound (1 ⁇ L), Substrate Mix (10 ⁇ L), and Enzyme Mix (added last to start reaction) (10 ⁇ L), Total 21 ⁇ L.
  • the reaction was performed in a U-bottomed, white, 96-well plate.
  • the reaction was mixed on a plate-shaker, after addition of the Enzyme, and incubated for 1h at 22°C. After this time, the reaction was stopped by addition of 40 ⁇ l_ 1.875 mg/ml streptavidin SPA beads in 0.1 M EDTA.
  • the beads were incubated with the reaction mixture for 1 h at 22°C after which 120 ⁇ l_ 0.1 M EDTA in PBS was added.
  • the plate was sealed, mixed centrifuged and incorporated radioactivity determined by counting in a Trilux (Wallac) or Topcount (Packard) Scintillation Counter.
  • genotype 1a and genotype 1b may be demonstrated, for example, using the following cell based assays:
  • test compound 100 ⁇ L of medium containing 10% FCS were added to each well of clear, flat-bottomed 96 well microplates, excepting wells in the top row.
  • Test compound was diluted in assay medium to twice the final required starting concentration from a 40 mM stock solution in DMSO. 200 ⁇ L of the starting dilution were introduced into two wells each in the top row and doubling dilutions made down the plate by the sequential transfer of 100 ⁇ L aliquots with thorough mixing in the wells; the final 100 ⁇ L were discarded. The two bottom rows were not used for compound dilutions.
  • Huh-7 HCV replicon cell monolayers nearing confluency were stripped from growth flasks with versene-trypsin solution and the cells were resuspended in assay medium at either 2 x 10 5 cells/mL (sub-line 5-15; genotype 1 b; Lohmann, V., Korner, F., Koch, J-O., Herian, U., Thielmann, L. And Bartenschlager, R., 1999, Science, 285, pp 110-113) or at 3 x 10 5 cells/mL (genotype 1a; Gu, B., Gates, AT., Isken, O., Behrens, S.E.and Sarisky, R.T., J. Virol., 2003, 77, 5352-5359). 100 ⁇ L of cell suspension were added to all wells and the plates incubated at 37°C for 72 hours in a 5% CO 2 atmosphere.
  • the assay medium was aspirated from the plates.
  • the cell sheets were washed by gentle immersion in phosphate buffered saline (PBS), which was then aspirated off, and fixed with acetone:methanol (1 :1 ) for 5 minutes.
  • PBS phosphate buffered saline
  • 100 ⁇ L of ELISA diluent PBS + 0.05% v/v Tween 20 + 2% w/v skimmed milk powder
  • the diluent was removed and each well then received 50 ⁇ L of a 1/200 dilution of anti-HCV specific, murine, monoclonal antibody (either Virostat #1872 or #1877), except for wells in one of the compound-free control rows which received diluent alone to act as negative controls.
  • the plates were incubated at 37 0 C for 2 hours and washed 3 times with PBS/0.05% Tween 20, then 50 ⁇ l_ of horseradish peroxidase conjugated, anti-mouse, rabbit polyclonal serum (Dako #P0260), diluted 1/1000, were added to all wells.
  • the plates were incubated for a further hour, the antibody removed and the cell sheets washed 5 times with PBS/Tween and blotted dry.
  • the assay was developed by the addition of 50 ⁇ l_ of ortho-phenylenediamine/peroxidase substrate in urea/citrate buffer (SigmaFast, Sigma #P-9187) to each well, and colour allowed to develop for up to 15 minutes.
  • the reaction was stopped by the addition of 25 ⁇ l_ per well of 2 M sulphuric acid and the plates were read at 490 nm on a Fluostar Optima spectrophotometer.
  • the substrate solution was removed and the plates were washed in tap water, blotted dry and the cells stained with 5 % carbol fuchsin in water for 30 minutes. The stain was discarded and the cell sheets washed, dried and examined microscopically to assess cytotoxicity. Data analysis t
  • the absorbance values from all compound-free wells that had received both primary and secondary antibodies were averaged to obtain a positive control value.
  • the mean absorbance value from the compound-free wells that had not received the primary antibody was used to provide the negative (background) control value.
  • the readings from the duplicate wells at each compound concentration were averaged and, after the subtraction of the mean background from all values, were expressed as a percentage of the positive control signal.
  • the quantifiable and specific reduction of expressed protein detected by the ELISA in the presence of a drug can be used as a measure of replicon inhibition.
  • GraFit software was used to plot the curve of percentage inhibition against compound concentration and derive the 50% inhibitory concentration (IC 50 ) for the compound.
  • Genotype 1a Genotype 1 b enzyme ⁇ 0.15 ⁇ M # ⁇ 0.10 ⁇ M
  • Compound A corresponds to the racemate of the enantiomeric compound disclosed as Example 19 in WO03/037895, re/-(2S,4S,5R)-2-lsobutyl-1-(4-tert-butyl-3- methoxybenzoyl)-4-(pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid.
  • Compound B corresponds to the enantiomeric compound disclosed as Example 19 in WO03/037895, Enantiomer A of re/-(2S,4S,5R)-2-lsobutyl-1-(4-tert-butyl-3- methoxybenzoyl)-4-(pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid.
  • Compound C corresponds to the racemic compound disclosed as Example 40 in WO03/037895, re/-(2R,4S,5R)-1-(4-tert-Butyl-3-methoxybenzoyl)-2-(pyridin-2-ylmethyl)-4- (pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid.
  • Compound D corresponds to the racemic compound disclosed as Example 49 in WO03/037895, re/-(2R,4S,5R)-1 -(4-tert-Butyl-3-methoxybenzoyl)-2-(1 H-imidazol-4-yl- methyl)-4-(pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)-pyrrolidine-2-carboxylic acid.
  • Compound E corresponds to the racemic compound disclosed as Example 51 in WO03/037895, re/-(2R,4S,5R)-1-(4-tert-Butyl-3-methoxybenzoyl)-2-(2-(methylthio)ethyl)- 4-(pyrazin-2-yl)-5-(1 ,3-thiazol-5-yl)-pyrrolidine-2-carboxylic acid.
  • Compound F corresponds to the racemic compound disclosed as Example 57 in WO03/037895, re/-(2R,4S,5R)-1-(4-fert-Butyl-3-methoxybenzoyl)-2-(2-(methylsulphonyl)- ethyl)-4-pyrazin-2-yl-5-(1 ,3-thiazol-2-yl)-pyrrolidine-2-carboxylic acid.
  • Compound G corresponds to the enantiomeric compound disclosed as Example 59 in WO03/037895, Enantiomer A of re/-(2S,4S,5R)-1-(4-tert-Butyl-3-methylbenzoyl)-2- isobutyl-4-(pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid.
  • Compound H corresponds to the enantiomeric compound disclosed as Example 65 in WO03/037895, Enantiomer A of re/-(2S,4S,5R)-1-(4-terf-Butyl-3-ethylbenzoyl)-2-isobutyl- 4-(pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid.
  • Compound I corresponds to the racemic compound disclosed as Example 67 in WO03/037895, re/-(2R,4S,5R)-1-(4-tert-Butyl-3-methoxybenzoyl)-2-(phenylmethyl)-4- (pyrazin-2-yl)-5-(1 ,3-thiazol-2-yl)pyrrolidine-2-carboxylic acid.
  • Compound A may be prepared as described above in the Examples section as 'preparation of racemate of example 19 from WO2003/037895A1 '
  • the compounds of the present invention which have been tested demonstrate a surprisingly superior genotype-1a/1b profile, as shown by the IC 50 values in the enzyme and cell-based assays across both of the 1a and 1 b genotypes of HCV, compared to Compounds A - I. Accordingly, the compounds of the present invention are of great potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • compositions according to the invention may also be used in combination with at least one other therapeutic agents, for example immune therapies
  • compositions according to the invention may also be used in combination with gene replacement therapy.
  • antifibrotic agents e.g. interferon, therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (eg ribavirin and amantidine).
  • the compositions according to the invention may also be used in combination with gene replacement therapy.
  • the invention thus provides, in a further aspect, a combination comprising at least one chemical entity chosen from compounds of formula (Ia) and pharmaceutically acceptable salts, solvates or esters thereof, together with at least one other therapeutically active agent.
  • compositions comprising a combination as defined above together with at least one pharmaceutically acceptable diluent or carrier thereof represent a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

Abstract

L'invention porte sur des agents antiviraux de formule (Ia) dans laquelle A représente hydroxy; B représente -C(O)R3, D représente 1,3-thiazol-2-yl; E représente pyrazin-2-yl; G représente 1,3-thiazol-4-ylméthyle ou 1H-pyrazol-1-ylméthyle; R3 représente 4-tert-butyl-3-éthénylphényle ou 4-tert-butyl-5-éthényl-2-fluorophényle; et sur des sels, solvates et esters desdits composés, à condition que, lorsque A est estérifié pour former un groupe OR, R étant choisi dans un groupe alkyle à chaîne ramifiée, alors R est différent de tert-butyl; l'invention concerne également des procédés de préparation et d'utilisation desdits composés dans le traitement du VHC.
PCT/EP2006/009235 2005-09-23 2006-09-21 Composes de c (2) -heteroarylmethyl-c (4) -pyrazin-2-yl acyl pyrrolidine et leur utilisation pour traiter des infections virales, en particulier le vhc WO2007039143A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2326253A1 (es) * 2008-04-02 2009-10-05 Universidad De Alicante Procedimiento para la obtencion de pirrolidinas polisustituidas inhibidoras del virus de la hepatitis c.

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037895A1 (fr) * 2001-11-02 2003-05-08 Glaxo Group Limited Derives d'heteroaryl acyl pyrrolidine a 4 a 6 chainons utilises comme inhibiteurs de hcv
WO2004037818A1 (fr) * 2002-10-24 2004-05-06 Glaxo Group Limited Derives de 1-acyl-pyrrolidine destines au traitement d'infections virales
WO2006045615A1 (fr) * 2004-10-25 2006-05-04 Glaxo Group Limited Composes d'acide 4- (pyrazine-2-yl) -pyrrolidine-2-carboxylique et derives associes servant d'inhibiteurs du virus de l'hepatite c

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037895A1 (fr) * 2001-11-02 2003-05-08 Glaxo Group Limited Derives d'heteroaryl acyl pyrrolidine a 4 a 6 chainons utilises comme inhibiteurs de hcv
WO2004037818A1 (fr) * 2002-10-24 2004-05-06 Glaxo Group Limited Derives de 1-acyl-pyrrolidine destines au traitement d'infections virales
WO2006045615A1 (fr) * 2004-10-25 2006-05-04 Glaxo Group Limited Composes d'acide 4- (pyrazine-2-yl) -pyrrolidine-2-carboxylique et derives associes servant d'inhibiteurs du virus de l'hepatite c

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2326253A1 (es) * 2008-04-02 2009-10-05 Universidad De Alicante Procedimiento para la obtencion de pirrolidinas polisustituidas inhibidoras del virus de la hepatitis c.
WO2009121989A1 (fr) * 2008-04-02 2009-10-08 Universidad De Alicante Procédé permettant d'obtenir des pyrrolidines polysubstituées inhibitrices du virus de l'hépatite c

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