WO2006100106A1 - Agents antiviraux de type 3-carboxypyrroles - Google Patents

Agents antiviraux de type 3-carboxypyrroles Download PDF

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WO2006100106A1
WO2006100106A1 PCT/EP2006/002833 EP2006002833W WO2006100106A1 WO 2006100106 A1 WO2006100106 A1 WO 2006100106A1 EP 2006002833 W EP2006002833 W EP 2006002833W WO 2006100106 A1 WO2006100106 A1 WO 2006100106A1
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alkyl
heterocyclyl
heteroaryl
formula
phenyl
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Richard Martin Grimes
Pritom Shah
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to novel 3-carboxy pyrrole derivatives useful as anti-viral agents. Specifically, the present invention involves novel inhibitors of Hepatitis C Virus (HCV) replication.
  • HCV Hepatitis C Virus
  • HCV infection is responsible for 40-60% of all chronic liver disease 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 induced by ribavirin (Lindsay, K.L. (1997) Hepatology 26 (suppl 1): 71S-77S).
  • HCV post-transfusion non A, non-B hepatitis
  • NANBH non-B hepatitis
  • this virus was assigned as a new genus in the Flaviviridae family.
  • 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 1 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 JuI.). 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 1 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' 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 1b 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): 2046-2051).
  • inhibition of NS5B RdRp activity is predicted to be useful to treat HCV infection.
  • the present invention involves novel 3-carboxy pyrrole 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 (I) :
  • A represents hydroxy
  • R 1 represents aryl, heteroaryl bonded through a ring carbon atom, or heterocyclyl bonded through a ring carbon atom, each of which may be optionally substituted by one or more substituents selected from -C h alky!, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(O)R D , -NR E C0 2 R D , -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, -CF 3 , -OCF 3 , NR E SO 2 R D , phenyl and heterocydyl, wherein the -C 1-6 alky( substituent itself may be optionally substituted by one or more substituents selected from
  • R 2 represents phenyl substituted by one or more substituents selected from -C 1-6 alkyl, halo, -0R A , -SR A , -C(O)NR 5 R 0 , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(0)R°, -NR E C0 2 R°, -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, and heterocyclyl; or R 2 represents -(CH 2 ) n C 5-7 cycloalkyl optionally substituted on the cycloalkyl by one or more substitutents selected from -C-,.
  • t represents O, 1 , 2, 3 or 4;
  • n O or 1 ;
  • R 3 represents heterocyclyl or heteroaryl; or phenyl optionally substituted by one or more substituents selected from -C 1-6 alkyl, halo, -0R A , -SR A , -C(O)NR 6 R 0 , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(O)R D , -NR E CO 2 R D , -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, and heterocyclyl; or R 3 represents -Ci.
  • 6 alkyl optionally substituted by one or more substituents selected from -C 1-6 alkyl, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -NR E C(O)R°, -NR E CO 2 R D , -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , fluoro, nitro, cyano, oxo, phenyl, heteroaryl and heterocyclyl;
  • R 4 represents hydrogen
  • R A represents hydrogen, -Ci -6 alkyl, arylalkyl, heteroaryialkyl, aryl, heterocyclyl or heteroaryl;
  • R B and R c independently represent hydrogen, -C 1-6 alkyl, aryl, heterocyclyl or heteroaryl; or R B and R c together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • R° is selected from the group consisting of -C 1-6 alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroaryialkyl;
  • R E represents hydrogen or -C 1-6 alkyl
  • R F and R G are independently selected from the group consisting of hydrogen, -C 1-6 alkyl, aryl, heteroaryl, arylalkyl, and heteroaryialkyl; or R F and R G together with the nitrogen atom to which they are attached form a 5 or 6 membered saturated cyclic group;
  • At least one chemical entity chosen from compounds of Formula (I) and physiologically acceptable salts, solvates and esters thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly HCV infection.
  • 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 (I) and physiologically acceptable salts, solvates and esters thereof.
  • at least one chemical entity chosen from compounds of Formula (I) and physiologically acceptable salts, solvates and esters thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.
  • the chemical entities of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. All of these racemic compounds, enantiomers and diastereoisomers are contemplated to be within the scope of the present invention.
  • R 1 represents phenyl, heteroaryl bonded through a ring carbon atom, or heterocyclyl bonded through a ring carbon atom, each of which may be optionally substituted by one or more substituents selected from -C 1-e alkyl, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R C , -SO 2 R 0 , cyano, -CF 3 , -OCF 3 , NR E SO 2 R°, phenyl and heterocyclyl, wherein the -C 1-6 alkyl substituent itself may be optionally substituted by one or more substituents selected from -C 5-9 cycloalkyl, halo, -NR B R C , -C(O)NR B R C , -NR E C(O)R°, -SR A
  • R 2 represents optionally substituted C 5-7 cycloalkyl, especially C 5-7 cycloalkyl substituted by C 1-4 alkyl. In another aspect, R 2 represents optionally substituted -C 5- 6 cycloalkyl. In yet another aspect R 2 represents -C 6 cycloalkyl substituted by -C 1-4 alkyl, especially frans-4-methylcyclohexyl.
  • R 3 represents optionally substituted heterocyclyl or C 1-4 alkyl.
  • R 3 represents 1-methylethyl, 2-methoxyethyl, 2-(methoxy)-1-[(methoxy)methyl]ethyl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-ylmethyl, tetrahydro-2H-furan-3-yl or [1- (methylsulfonyl)-4-piperidinyl].
  • R 3 represents optionally substituted heterocyclyl or unsubstituted C 1-4 alkyl.
  • R 3 represents 1-methylethyl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-furan-3-yl or [1-(methylsulfonyl)-4-piperidinyl].
  • acetyl refers to -C(O)CH 3 .
  • acetylamino refers to -N(H)C(O)CH 3 .
  • alkyl refers to an optionally substituted hydrocarbon group.
  • the alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl group is linear or branched, examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • alkyl hydrocarbon group is unsaturated, it will be understood that there will be a minimum of 2 carbon atoms in the group, for example an alkenyl or alkynyl group.
  • alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group.
  • alkyl moieties are -C 1-4 alkyl.
  • alkenyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds. In one aspect the alkenyl group has from 2 to 6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.
  • alkynyl refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds. In one aspect the alkynyl group has from 2 to 6 carbon atoms. Examples of such groups include ethyny], propyny], butynyl, pentynyl or hexynyl and the like.
  • cycloalkyl refers to an optionally substituted, cyclic hydrocarbon group.
  • the hydrocarbon group may be saturated or unsaturated, monocyclic or bridged bicyclic.
  • examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like.
  • the cycloalkyl group has from 5 to 7 carbon atoms.
  • cycloalkyl moieties are cyclohexenyl, cyclopentenyl and cyclohexyl. Unless otherwise stated, the cycloalkyl group may be substituted by one or more optional substituents including -C h alky!
  • alkoxy refers to an -O-alkyl group wherein alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
  • aryl refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • Aryl includes carbocyclic aryl and biaryl groups, all of which may be optionally substituted.
  • aryl moieties contain 6-10 carbon atoms.
  • aryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl.
  • aryl substituents are selected from the group consisting of -C 1-6 alkyl, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R G , -NR E C(O)R°, -NR E CO 2 R D , -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, heterocyclyl, -CF 3 , -OCF 3 and phenyl.
  • arylalkyl refers to an aryl group attched to the parent molecular moiety through an alkyl group.
  • carbonyl refers to -C(O)-.
  • cyano refers to -CN.
  • halogen or halo refer to a fluorine, chlorine, bromine or iodine atom. References to "fluoro”, “chloro”, “bromo” or “iodo” should be construed accordingly.
  • heteroaryl refers to an optionally substituted, 5, 6, 8, 9 or 10 membered, aromatic group comprising one to four heteroatoms selected from N, O and S, with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems.
  • heteroaryl moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted (where applicable) pyridyl, pyrazinyl, thiazolyl, thienyl, benzodioxolyl, benzofuranyl, benzodioxinyl and indolyl.
  • heteroaryl substituents are selected from the group consisting of -C 1-6 alkyl, halo, -OR A , -SR A , -C(O)NR B R C , -C(O)R 0 , -CO 2 H, -CO 2 R 0 , -NR B R G , -NR E C(O)R°, -NR E CO 2 R°, -NR E C(O)NR F R G , -SO 2 NR F R G , -SO 2 R 0 , nitro, cyano, heterocyclyl, -CF 3 and phenyl.
  • heteroarylalkyl refers to a heteroaryl group attched to the parent molecular moiety through an alkyl group.
  • heterocyclic and “heterocyclyl” refer to an optionally substituted, 5 or 6 membered, saturated or partially saturated, cyclic group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, -C 1-6 alkyl, -C(O)R 0 , -C(O)NR B R C , -C(O)OR 4 , -SO 2 R 0 , aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms.
  • Ring carbon atoms may be optionally substituted by -Ci -6 alkyl, -C(O)R 0 , or -SO 2 R 0 .
  • heterocyclic moieties are unsubstituted or monosubstituted tetrahydro-2H-pyran-4-yl, piperidinyl and 1 ,2,3,6- tetrahyd ro-4-pyrid i nyl .
  • nitro refers to -NO 2 .
  • Ac refers to “acetyl”
  • Et refers to “ethyl”
  • iPr refers to “isopropyl”
  • Me refers to “methyl”
  • OBn refers to "benzyloxy”
  • Ph refers to "phenyl”.
  • chemical entities useful in the present invention may be chosen from compounds of Formula (I) selected from the group consisting of:
  • physiologically acceptable salt complexes also covers the physiologically acceptable salts of the compounds of Formula (I).
  • suitable physiologically acceptable salts of the compounds of Formula (I) 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.
  • the present invention also relates to solvates of the compounds of Formula (I), for example hydrates.
  • the present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, -C 1-4 alkyl or -C 1-4 alkoxy or amino); or for example - CH 2 OC(O)R' or -CH 2 OCO 2 R' in which R' is alkyl (e.g.
  • R' is f-butyl
  • 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.
  • A is a protected hydroxy group, for example an alkoxy, benzyloxy or silyloxy group and R 1 , R 2 , R 3 and R 4 are as defined above for Formula (I).
  • R 1 , R 2 , R 3 and R 4 are as defined above for Formula (I)
  • an appropriate base for example aqueous sodium hydroxide or lithium hydroxide, optionally in a solvent such as methanol, tetrahydrofuran or combinations thereof.
  • the temperature is in the range 25 to 100 0 C, more preferably 50 to 100 0 C.
  • A is silyloxy
  • R 1 , R 2 , R 3 and R 4 are as defined above for Formula (I)
  • a suitable fluoride source for example tetrabutylammonium fluoride.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran.
  • the temperature is in the range 0 to 50 0 C, more preferably 15 to 30 0 C.
  • R 1 , R 2 , R 3 , R 4 and A are as defined above for Formula (II), and P 1 is an acid or ester thereof, for example -COW wherein W is alkoxy, silyloxy, aryloxy or arylalkyloxy but W and A are always different to each other.
  • P 1 is an ester
  • the group may be converted to acid in a first step.
  • W is an acid
  • the group may be decarboxylated to leave hydrogen.
  • W is silyloxy
  • the group may be converted to an acid by treatment with a suitable fluoride source for example tetrabutylammonium fluoride.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran.
  • the temperature is in the range 0 to 50 0 C, more preferably 15 to 3O 0 C.
  • the group when W is benzyloxy, the group may be converted to an acid by hydrogenolysis using hydrogen gas with a catalyst such as palladium on carbon in a suitable solvent such as ethanol, optionally in the presence of a suitable acid, for example hydrochloric acid, and optionally conducting the reaction under pressure.
  • a suitable acid for example hydrochloric acid or trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 50 to 7O 0 C.
  • Decarboxylation where W is an acid may be carried out using a suitable acid, for example hydrochloric acid or trifluoroacetic acid.
  • a suitable acid for example hydrochloric acid or trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 50 to 70 0 C.
  • R 1 , R 3 and R 4 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group, with a suitable acylating agent, for example R 2 -C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable solvent for example dichloromethane
  • a suitable base for example pyridine or triethylamine
  • a phosphine such as triphenylphosphine may be used.
  • 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.
  • R 1 , R 3 and R 4 are as defined above for Formula (I), and A is an alkoxy, benzyloxy or silyloxy group, and P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other, with a suitable acylating agent, for example R 2 -C(0)-Y, wherein Y is a halo atom, for example chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction may be carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine and thereafter removing any protecting group if desired.
  • a suitable base for example pyridine or triethylamine
  • a phosphine such as triphenylphosphine may be used.
  • 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.
  • Compounds of Formula (IVa) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared by reaction of a compound of Formula (IV) in which R 1 , R 3 and R 4 are as defined above for Formula (I), A is an alkoxy, benzyloxy or silyloxy group, and P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other.
  • the COW group may be converted to acid in a first step. Where W is an acid, the group may be decarboxylated to leave hydrogen.
  • the group may be converted to an acid by treatment with a suitable fluoride source for example tetrabutylammonium fluoride.
  • a suitable fluoride source for example tetrabutylammonium fluoride.
  • the reaction is carried out in a suitable solvent, for example tetrahydrofuran.
  • the temperature is in the range 0 to 5O 0 C, more preferably 15 to 30 0 C.
  • the group when W is benzyloxy, the group may be converted to an acid by hydrogenolysis using hydrogen gas with a catalyst such as palladium on carbon in a suitable solvent such as ethanol, optionally in the presence of a suitable acid, for example hydrochloric acid, and optionally conducting the reaction under pressure.
  • a catalyst such as palladium on carbon in a suitable solvent such as ethanol
  • a suitable acid for example hydrochloric acid
  • the group P 1 may be removed (in a single reaction) with a suitable acid, for example hydrochloric acid or trifluoroacetic acid.
  • a suitable acid for example hydrochloric acid or trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 50 to 70 0 C.
  • Decarboxylation where W is an acid may be carried out using a suitable acid, for example hydrochloric acid or trifluoroacetic acid.
  • the reaction is carried out in a solvent, for example dichloromethane.
  • the temperature is in the range 50 to 70°C. This yields a compound of Formula (IVa) in the form of the relevant acid addition salt. It is this salt which is used in the preparation of a compound of Formula (II) as described above.
  • R 1 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy and P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other, by treatment with a suitable vinyl ether, or a suitable aldehyde or a suitable ketone in the presence of a suitable acid, such as acetic acid, and a suitable reducing agent such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane.
  • a suitable vinyl ether or a suitable aldehyde or a suitable ketone
  • a suitable acid such as acetic acid
  • a suitable reducing agent such as sodium triacetoxyborohydride
  • compounds of Formula (IV) in which A is an alkoxy, benzyloxy or silyloxy group may be prepared from compounds of Formula (V) by treatment with a suitable alkylating agent R 3 -X where X is a halo group such as chloride, bromide or iodide, or X is a sulphonate ester such as methanesulfonate, in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • a suitable alkylating agent R 3 -X where X is a halo group such as chloride, bromide or iodide, or X is a sulphonate ester such as methanesulfonate, in suitable solvent such as dimethylformamide in the presence of a suitable base such as triethylamine.
  • R 1 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy
  • P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other, with a cyclisation agent, for example 1 ,8-diazobicyclo[5.4.0]undec-7-ene, in the presence of a suitable solvent, for example tetrahydrofuran.
  • the reaction is carried out at a temperature in the range 50 to 100 0 C, suitably at 60 0 C.
  • R 1 is as defined above for Formula (I) and P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other, with compounds of Formula (VIII) in which R 4 and A are as defined above for Formula (II) and R' is -C 1-4 alkyl (such as ethyl), under reflux in a suitable solvent such as toluene, in the presence of a suitable base, for example triethylamine.
  • Compounds of Formula (III) may also be prepared by reaction of a compound of Formula (IX) in which R 1 , R 2 and R 4 are as defined above for Formula (I), A is an alkoxy, benzyloxy or silyloxy group, and P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other, with a suitable alkylating agent R 3 -X in which X is a halo atom such as chloro, bromo or iodo, or X is a sulphonate ester such as methanesulfonate, in a suitable solvent such as dimethylformamide, in the presence of a suitable base such as triethylamine and sodium hydride.
  • R 1 , R 2 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy group
  • Compounds of Formula (IX) may be prepared from compounds of Formula (V) by reaction with a suitable acylating agent, for example R 2 -C(O)-Y, in which Y is a halo atom, preferably chloro or bromo, and R 2 is as defined above for Formula (I).
  • a suitable acylating agent for example R 2 -C(O)-Y, in which Y is a halo atom, preferably chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine.
  • a suitable solvent for example dichloromethane
  • a suitable base for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of an amine base.
  • R 2 , R 3 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy group
  • P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other, by treatment with an aryl, heteroaryl, cycloalkenyl or alkenyl boronic acid in the presence of a copper catalyst such as copper (II) acetate.
  • the reaction is carried out in the presence of a base, such as pyridine, in air, and in a suitable solvent such as dichloromethane or THF.
  • compounds of Formula (III) in which R 1 represents aryl or heteroaryl may be prepared by reaction of compounds of Formula (X) with an aryl or heteroaryl halide or triflate in the presence of a copper catalyst such as copper (I) iodide.
  • a copper catalyst such as copper (I) iodide.
  • the reaction is carried out in the presence of a base such as potassium carbonate or /rans-1 ,2- diaminocyclohexane or a combination thereof in a suitable solvent such as dioxan or pyridine or a combination thereof.
  • Compounds of Formula (X) may be prepared by deprotection of the ring nitrogen (P) of a compound of Formula (Xl)
  • R 2 , R 3 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy group
  • P 1 is an acid or ester thereof, for example -COW wherein W is alkyloxy, aryloxy or arylalkyloxy but W and A are always different to each other
  • P is a suitable protecting group.
  • Suitable protecting groups include, but are not restricted to, benzyl.
  • Benzyl groups can be removed by hydrogenation using hydrogen gas with a catalyst such as palladium on carbon in a suitable solvent such as ethanol, optionally in the presence of a suitable acid, for example hydrochloric acid or acetic acid, and optionally conducting the reaction under pressure.
  • a catalyst such as palladium on carbon in a suitable solvent such as ethanol
  • a suitable acid for example hydrochloric acid or acetic acid
  • compounds of Formula (Xl) may be prepared from compounds of Formulae (IV) or (V) in which the group R 1 is a protecting group (P) instead of a group as defined for Formula (I), by application of the synthetic routes described above in relation to the synthesis of compounds of Formula (III).
  • compounds of Formula (II) may be prepared from compounds of Formula (II).
  • R 1 , R 2 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy group
  • P 1 is hydrogen
  • a suitable alkylating agent R 3 -X in which X is a halo atom such as chloro, bromo or iodo, or X is a sulphonate ester such as methanesulfonate, in a suitable solvent such as dimethylformamide, in the presence of a suitable base such as triethylamine and sodium hydride.
  • R 1 and R 4 are as defined above for Formula (I)
  • A is an alkoxy, benzyloxy or silyloxy and P 1 is hydrogen
  • a suitable acylating agent for example R 2 -C(0)-Y, in which Y is a halo atom, preferably chloro or bromo, and R 2 is as defined above for Formula (I).
  • the reaction is carried out in a suitable solvent, for example dichloromethane, in the presence of a suitable base, for example pyridine or triethylamine.
  • a phosphine such as triphenylphosphine may optionally be used in place of an amine base.
  • Compounds of Formula (Va) may be prepared from compounds of Formula (V) by application of the synthetic routes described above in relation to the synthesis of compounds of Formula (IVa) from compounds of Formula (IV).
  • a compound of Formula (II) may be prepared by appropriate manipulation of another compound of Formula (II).
  • a compound of Formula (II) in which any substituent comprises -C 2-4 alkenyl may be prepared from a suitable aldehyde or ketone substituent and a phosphorous ylid generated from a phosphonium salt in the presence of a suitable base, such as potassium te/t-butoxide, in a suitable solvent such as THF.
  • a suitable base such as potassium te/t-butoxide
  • THF suitable solvent
  • the trans and cis isomers may be separated by standard techniques known in the art
  • a compound of Formula (II) in which any substituent comprises -C 2-4 alkyl may be prepared by reduction of an alkenyl substituent, for example using hydrogen, optionally under pressure, in the presence of a suitable catalyst such as palladium on carbon, in a suitable solvent such as ethanol.
  • a compound of Formula (II) in which any substituent comprises -C(O)NR A R B may be prepared by reacting a suitable acid substituent with an amine (HNR A R B ) in the presence of a coupling agent such as HATU, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a compound of Formula (II) in which any substituent comprises -C(O)NR A R B may be prepared by reacting a suitable acid chloride substituent with an amine (HNR A R B ) in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -NR E C(O)R D may be prepared by reacting a suitable amine substituent with a carboxylic acid (R 0 CO 2 H) in the presence of a coupling agent such as HATU, in the presence of a suitable base such as triethylamine, in a suitable solvent such as DMF.
  • a compound of Formula (II) in which any substituent comprises -NR E C(O)R D may be prepared by reacting a suitable amine substituent with an acid chloride in the presence of a suitable base such as triethylamine in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -NR E SO 2 R D may be prepared by reacting an amine substituent with a suitable sulfonyl chloride in the presence of a suitable base such as trietnylamine, in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -SO 2 NR F R G may be prepared by reacting a sulfonyl chloride substituent with a suitable amine (HNR F R G ) in the presence of a suitable base such as triethylamine, in a suitable solvent such as dichloromethane.
  • a compound of Formula (II) in which any substituent comprises -SO 2 R A may be prepared by oxidation of a compound in which a substituent represents -SR A , using for example oxone, sodium periodate, 3-chloro perbenzoic acid, or hydrogen peroxide.
  • a base such as
  • a suitable solvent such as dichloromethane
  • Esters of compounds of Formula (I), in which A is -OR where R is selected from straight or branched chain alkyl, arylalkyl, aryloxyalkyl, or aryl, may also be prepared by esterification of a compound of Formula (I) in which A is hydroxy by standard literature procedures for esterification.
  • (XI) which exist as diastereoisomers may optionally be separated by techniques well known in the art, for example by column chromatography or recrystallisation. For example, the formation of an ester using a chiral alcohol, separation of the resulting diastereoisomers, and subsequent hydrolysis of the ester to yield the individual enantiomeric acid of Formula (1), (II), (III), (IV), (IVa), (V), (IX), (X) and (Xl).
  • racemic compounds of Formula (I), (II), (III), (IV), (IVa), (V), (IX), (X) and (Xl) 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 (I), (II), (III), (IV), (IVa), (V), (IX), (X) and (Xl) may be resolved by chiral preparative HPLC.
  • racemic compounds of Formula (I), (II), (III), (IV), (IVa), (V), (IX), (X) and (Xl) 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. Such techniques are well established in the art.
  • a racemic compound may be resolved by treatment with a chiral acid such as (R)-(-)-1 ,1'-binaphthyl-2,2'-diyl-hydrogen phosphate or (- )-di-O,O'-p-tolyl-L-tartaric acid, in a suitable solvent, for example isopropanol.
  • a chiral acid such as (R)-(-)-1 ,1'-binaphthyl-2,2'-diyl-hydrogen phosphate or (- )-di-O,O'-p-tolyl-L-tartaric acid
  • racemic acid compounds may be resolved using a chiral base, for example (S)-alpha methylbenzylamine, (S)-alpha phenylethylamine, (1 S, 2S)-(+)-2-amino-1-phenyl-1 ,3- propane-diol, (-) ephidrine, quinine, brucine.
  • Individual enantiomers of Formula (II), (III), (IV), (IVa), (V), (IX), (X) and (Xl) may then be progressed to an enantiomeric compound of Formula (I) by the chemistry described above in respect of racemic compounds.
  • the reaction was cooled, diluted with DCM and washed with 1 N HCI and saturated sodium bicarbonate, passed through a hydrophobic and the organics concentrated.
  • the crude material was purified using a 80 g silica ISCO Companion Flash column eluting with a gradient of 5-30% EtOAc in cyclohexane to furnish the title compound.
  • the organic phase was washed with water, followed by 2N hydrochloric acid, then brine, passed through a hydrophobic frit and concentrated.
  • the crude product was purified by a 12O g silica ISCO Companion flash column eluting with 0-50% ethyl acetate in cyclohexane to furnish the title compound.
  • compositions for use in therapy comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof in admixture with one or more physiologically acceptable diluents or carriers.
  • 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 chemical entities 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 physiologically 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 compounds 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 chemical entity), 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 chemical entities with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present chemical entities.
  • 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 (I) or a pharmaceutically acceptable salt 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(l).
  • a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
  • 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.
  • Chemical entities of Formula (I) 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.
  • 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 (I) 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.
  • 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 1 M 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 1M-Tris-HCI, pH7.5 (0.4 mL), 5M NaCI (0.2 mL), 1 M-MgCl 2 (0.4 mL), glycerol (1 mL), 10% NP-40 (10 ⁇ l_), 1M DTT (20 ⁇ L) and water (7.97 mL), Tote/ 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 1 mg/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 1h 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.
  • the exemplified compounds have IC 50 values of ⁇ 35 ⁇ M. In another aspect, compounds have an IC 50 of ⁇ 5 ⁇ M; in yet another aspect, compounds have an IC 50 of ⁇ 1 ⁇ M. Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV.
  • compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies (eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys; Hoffmann-La Roche)), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g.
  • Interferon such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (
  • 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 compound of formula (I) or a physiologically acceptable salt or solvate thereof together with at least one other therapeutically active agent, especially interferon and/or ribavirin.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention.

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Abstract

La présente invention concerne de nouveaux agents antiviraux de Formule (I) : où : A représente un groupement hydroxy ; R4 représente un atome d'hydrogène et les autres substituants sont tels que définis dans les revendications ; ainsi que les sels, les solvates et les esters desdits agents, des procédés de synthèse desdits agents, des préparations pharmaceutiques les comprenant, et leur emploi dans le traitement du VHC.
PCT/EP2006/002833 2005-03-21 2006-03-20 Agents antiviraux de type 3-carboxypyrroles Ceased WO2006100106A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039146A1 (fr) * 2005-09-23 2007-04-12 Smithkline Beecham Corporation Derives de 4-carboxy pyrazole utilises en tant qu'agents antiviraux
JP2010510191A (ja) * 2006-11-17 2010-04-02 スミスクライン ビーチャム コーポレーション 抗ウイルス剤としての２−カルボキシチオフェン誘導体
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8648103B2 (en) 2008-07-08 2014-02-11 Daiichi Sankyo Company, Limited Nitrogen-containing aromatic heterocyclyl compound

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WO2002055025A2 (fr) * 2001-01-13 2002-07-18 Univ North Carolina Composes, procedes et compositions servant au traitement de l'infection par le virus de la diarrhee bovine virale (vbvd) et l'infection par le virus de l'hepatite c (vhc)
WO2003037893A1 (fr) * 2001-11-02 2003-05-08 Glaxo Group Limited Derives d'acyl-dihydro-pyrrole utilises comme inhibiteurs du vhc
WO2004092161A1 (fr) * 2003-04-11 2004-10-28 Vertex Pharmaceuticals Incorporated Inhibiteurs des serine proteases, en particulier de la protease ns3-ns4a du vhc

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WO2002055025A2 (fr) * 2001-01-13 2002-07-18 Univ North Carolina Composes, procedes et compositions servant au traitement de l'infection par le virus de la diarrhee bovine virale (vbvd) et l'infection par le virus de l'hepatite c (vhc)
WO2003037893A1 (fr) * 2001-11-02 2003-05-08 Glaxo Group Limited Derives d'acyl-dihydro-pyrrole utilises comme inhibiteurs du vhc
WO2004092161A1 (fr) * 2003-04-11 2004-10-28 Vertex Pharmaceuticals Incorporated Inhibiteurs des serine proteases, en particulier de la protease ns3-ns4a du vhc

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007039146A1 (fr) * 2005-09-23 2007-04-12 Smithkline Beecham Corporation Derives de 4-carboxy pyrazole utilises en tant qu'agents antiviraux
JP2010510191A (ja) * 2006-11-17 2010-04-02 スミスクライン ビーチャム コーポレーション 抗ウイルス剤としての２−カルボキシチオフェン誘導体
EP2494991A1 (fr) 2007-05-04 2012-09-05 Vertex Pharmaceuticals Incorporated Polythérapie pour le traitement de l'infection par VHC
US8648103B2 (en) 2008-07-08 2014-02-11 Daiichi Sankyo Company, Limited Nitrogen-containing aromatic heterocyclyl compound
US9150563B2 (en) 2008-07-08 2015-10-06 Daiichi Sankyo Company, Limited Nitrogen-containing aromatic heterocyclyl compound

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