WO2000006529A1 - Diketoacid-derivatives as inhibitors of polymerases - Google Patents

Diketoacid-derivatives as inhibitors of polymerases Download PDF

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Publication number
WO2000006529A1
WO2000006529A1 PCT/GB1999/002446 GB9902446W WO0006529A1 WO 2000006529 A1 WO2000006529 A1 WO 2000006529A1 GB 9902446 W GB9902446 W GB 9902446W WO 0006529 A1 WO0006529 A1 WO 0006529A1
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WIPO (PCT)
Prior art keywords
groups
optionally substituted
group
compound
ester
Prior art date
Application number
PCT/GB1999/002446
Other languages
French (fr)
Inventor
Sergio Altamura
Licia Tomei
Uwe Koch
Philippe Jean Siegfried Neuner
Vincenzo Summa
Original Assignee
Istituto Di Ricerche Di Biologia Molecolare P Angeletti S.P.A.
Nicholls, Kathryn, Margaret
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GBGB9816358.7A external-priority patent/GB9816358D0/en
Application filed by Istituto Di Ricerche Di Biologia Molecolare P Angeletti S.P.A., Nicholls, Kathryn, Margaret filed Critical Istituto Di Ricerche Di Biologia Molecolare P Angeletti S.P.A.
Priority to US09/744,795 priority Critical patent/US6492423B1/en
Priority to AT99934986T priority patent/ATE298317T1/en
Priority to CA002338490A priority patent/CA2338490A1/en
Priority to DE69925918T priority patent/DE69925918T2/en
Priority to AU50595/99A priority patent/AU756627B2/en
Priority to JP2000562336A priority patent/JP2003525200A/en
Priority to EP99934986A priority patent/EP1100763B8/en
Publication of WO2000006529A1 publication Critical patent/WO2000006529A1/en
Priority to US10/238,246 priority patent/US7022736B2/en

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    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compounds useful as enzyme inhibitors, in particular as inhibitors of enzymes involved in the transfer of phosphoryl groups and, especially as inhibitors of polymerases.
  • the invention further relates to pharmaceutical compositions containing such compounds, and to their use in the treatment of viral infections.
  • Polymerases are the enzymes which catalyse the formation of phosphodiester bonds in RNA and DNA. They play an essential role in viral replication and, therefore, are an important target in the fight against viral diseases such as human immunodeficiency virus (HIV) , hepatitis, and poliomyelitis.
  • HIV human immunodeficiency virus
  • diketoacids have utility as enzyme inhibitors and, in particular, as polymerase inhibitors and more particularly as inhibitors of hepatitis C NS5 RNA- dependent RNA polymerase, HBV DNA-dependent RNA polymerase and HIV DNA- dependent DNA polymerase. Their investigations indicate that these compounds may act by interfering with the binding of phosporyl groups at the active site of the enzyme and may, therefore, have broad application in inhibiting enzymes involved in the transfer of phosphoryl groups.
  • a compound of formula A shown below is suitable for therapeutic use, for instance as an enzyme inhibitor.
  • the compound may be in the form of a pharmaceutically acceptable salt or ester, which can be hydrolysed in vivo to the corresponding diketoacid.
  • the group R is an organic moiety which contains from 2 to 24, preferably 4 to 20, most preferably 6 to 17 carbon atoms in total.
  • R includes an optionally substituted cyclic or heterocyclic group in which the atom directly bonded to the adjacent carbonyl in the diketoacid is part of the ring structure.
  • this atom is a carbon atom.
  • the ring which is thus bonded to the carbonyl group is preferably a 3 to 8 membered ring, particularly a 4 to 6 membered ring.
  • R may be selected from:
  • aromatic groups especially those including six membered rings, such as phenyl and naphthyl;
  • heteroaryl groups especially those including five and six membered rings such as thiophene, pyrrole, furan, imidazole, pyridyl, pyrimidyl, and pyridazyl; the heteroaryl ring may, optionally be fused to another ring;
  • cycloalkyl groups especially those including five or six membered rings such as cyclopentyl, cyclohexyl and adamantyl ;
  • cycloalkenyl groups especially those including five or six numbered rings such as cyclohexenyl, cyclopentenyl;
  • cyclic heteroalkyl groups especially those including five or six numbered rings such as piperidyl, pyrrolidyl, tetrahydrofuranyl, and tetrahydropyranyl; in this class 4- piperidyl rings substituted with an aryl group at carbon 4 and on acyl or sulfonyl substituent at Nl are preferred.
  • substituents may be present and a wide variety of substituents are possible.
  • Preferred optional substituents for all compounds of the present invention are set out in the following list:
  • each of R x and R 2 is selected from H and lower alkyl groups having 1 to 6 carbon atoms; or R 1 and R 2 together form a ring including 4 to 6 carbon atoms;
  • each R 3 independently is H or lower alkyl of 1 to 6 carbon atoms
  • R 4 is an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group as such groups are defined above at (j), (k) and (1) ;
  • each of optional substituents (j) to (t) above may optionally itself be substituted by one or more groups selected from (j) to (t) .
  • a preferred class of compounds of formula A is represented by formula E:
  • Ar is an optionally substituted aryl or heteroaryl group.
  • Optional substituents may be selected from the list of preferred substituents set out above. Within this class of preferred compounds two especially preferred groups are set out below (formulas F and G)
  • R 5 , R 6 ⁇ R 7 and R 8 are, independently H or are selected from the optional substituents listed above and R 7 and R 8 taken together may form a 4 to 7, preferably 5 or 6 membered ring; and X is 0, S, NH, or NR 4 where R 4 is as defined above.
  • substituents there is a single substituent, preferably at the position which is ortho- or meta- to the diketoacid group.
  • Substitution at the meta-position is especially preferred. Where two substituents are present, then preferably the phenyldiketoacid is 2, 5-substituted; 3, 5-substitution is also possible, as is 2, 4-substitution provided, in the latter case, that the substituent at the 4-position is relatively small (e.g. methyl). Disubstitution at the 2,3- and 2, 6-positions is, in general, not preferred.
  • Preferred substituents are ether groups of formula (o) above (i.e. -OR 4 ) , hydroxyl, and -NHS0 2 R 4 . It is generally preferred that no more than one substituent be -OR 4 and/or - NHS0 2 R 4 .
  • Preferred examples of -OR 4 groups which may be found at the ortho and meta positions and particularly at the meta position include:
  • -OCH 2 Ar or, less preferably -0(CH 2 ) 2 Ar
  • Ar is an optionally substituted aryl or heteroaryl group and is particularly preferably an optionally substituted phenyl group.
  • preferred substituents on the aryl group, and especially on the phenyl ring include halogens, especially fluorine and chlorine, and electron- withdrawing groups such as -CN, -C0 2 H, and -CF 3 as well as ether and aryl groups; -0-(CH 2 ) 3 -CN; and -0- (CH 2 ) 3 -C ⁇ CH.
  • Preferred sulfonamide groups which may be found at the ortho- and meta- positions, particularly at the meta- position are those of formula:
  • Ar is an optionally substituted aryl or heteroaryl group, preferably an optionally substituted phenyl group.
  • Preferred optional substituents for the aryl, preferably phenyl group include: -CN; halogens, especially chlorine and fluorine, -CF 3 , lower (C ⁇ g) alkyl (especially methyl), hydroxy-, ether, and -N0 2 groups.
  • substituents at the ortho and meta positions are lower (eg C ⁇ - 6 ) alkyl groups, especially C ⁇ alkyl, such as methyl and ethyl, but in particular methyl, aralkyl groups, especially phenylmethyl groups, optionally substituted in the phenyl ring, especially by a halogen, and nitrogen-containing substituents such as primary, secondary or tertiary amine groups, optionally in protonated form, amide, urethane, or urea groups in each of which examples there is a nitrogen atom bonded to the phenyl ring.
  • lower alkyl groups especially C ⁇ alkyl, such as methyl and ethyl, but in particular methyl, aralkyl groups, especially phenylmethyl groups, optionally substituted in the phenyl ring, especially by a halogen
  • nitrogen-containing substituents such as primary, secondary or tertiary amine groups, optionally in protonated form, amide,
  • R 5 and R 6 is selected from H, HO-, R 4 0-, and -NHS0 2 R 4 provided that no more than one of R 5 and R 6 is R 4 0- or -NHS0 2 R 4 .
  • the diketoacid group may be at the 2- or 3- position of the ring. In many cases substitution at the 2-position is preferred.
  • Preferred examples of compounds of formula G are those in which the five membered aromatic ring,
  • R 7 and R e may both be hydrogen and in many cases that is preferred. If R 7 and R 8 correspond to substituent groups, then these may be at any of the positions not already occupied by the diketoacid group. Examples of possible substituents include alkyl (especially methyl) , halogen, and aralkyl (especially benzyl) groups.
  • pyrrole substituted diketoacid is that in which the diketoacid group is at the 2- position of the ring and where the only other substituent in the ring is on the nitrogen atom.
  • substituent R 4 present on the nitrogen atom include alkyl, aryl or aralkyl groups, particularly aralkyl (such as benzyl) groups. Where an aryl or aralkyl group is present these are preferably substituted with halogen atoms, such as fluorine or chlorine, or by cyano-groups .
  • thiophene-substituted diketoacids a wide range of substituents R 7 and R 8 may be employed in various positions as will be evident from the tables infra.
  • Preferred thiophenes have an aralkyl (such as optionally substituted benzyl) or aryl (such as optionally substituted phenyl) substituent, e.g. at the 5-position of the thiophene ring.
  • furanyl rings may also be useful, especially for inhibiting HIV reverse transcriptase.
  • Preferred substituents are optionally substituted aryl groups (especially optionally substituted phenyl) . Substitution is preferably at the 5-position of the ring.
  • the compounds of the present invention having formula A may be prepared by a process which comprises reaction of a compound of formula B with a dialkyloxalate of formula C followed by hydrolysis of the resulting diketo-ester of formula D:
  • R ' is an alkyl group, typically having 1-6 carbon atoms.
  • R ' in formula C may be selected accordingly, and the step of hydrolysing the compound of formula D omitted, since in vivo hydrolysis can render the compounds active.
  • Preferred enzymes for inhibition by the compounds of the invention are those involved in phosphate transfer, in particular polymerases such as DNA polymerases, and RNA polymerases both of which may be either RNA dependent or DNA dependant.
  • Compounds of the invention may particularly preferably be employed in the inhibition of viral enzymes. Examples of viral enzymes include RNA - dependent RNA polymerase and reverse transcriptases .
  • the compounds of the invention may be used as inhibitors of plant or animal (including human) viruses.
  • the viruses may be RNA viruses, which may, for example, be positive single stranded viruses of which polio virus, hepatitis C virus and encephalomyocarditis are examples, negative single stranded viruses such as orthomyxoviruses, and paramyxoviruses, and retroviruses of which HIV is a prominent example.
  • the viruses may be DNA viruses, especially double stranded DNA viruses such as hepatitis B virus.
  • compounds of the present invention may inhibit one or more of the following enzymes: hepatitis C virus RNA dependent RNA polymerase (HCV RdRp) , hepatitis B virus polymerase (HBV pol) and reverse transcriptase of human immunodeficiency virus (HIV RT) .
  • HCV RdRp hepatitis C virus RNA dependent RNA polymerase
  • HBV pol hepatitis B virus polymerase
  • HIV RT reverse transcriptase of human immunodeficiency virus
  • Especially preferred compounds of the invention will be suitable for use as HCV RdRp inhibitors.
  • phosphatases Other classes of enzyme involved in phosphate transfer which may be susceptible to inhibition by compounds of the present invention include phosphatases, Rnases, integrases and ribozymes.
  • compounds of the invention may be of utility in agriculture and horticulture for treating plants infected with or susceptible to plant virus.
  • the use of a compound of formula A or of a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for treatment of a viral illness in a human or animal may be used to treat viral illness by inhibiting one or more viral polymerase.
  • the medicament is for treatment of hepatitis, such as hepatitis B or C, particularly hepatitis C, and human immunodeficiency virus.
  • a still further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula A, or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, diluent or carrier.
  • the composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally .
  • compositions optionally also include one or more other agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as -, ⁇ -, or ⁇ - interferon.
  • agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as -, ⁇ -, or ⁇ - interferon.
  • a still further aspect of the invention provides a method of inhibiting an enzyme, especially a viral polymerase and/or of treating or preventing a viral illness, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described above or of a compound of formula A or salt or ester thereof.
  • Effective amount means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
  • the dosage rate at which the compound, salt or ester is administered will depend on the nature of the subject, the nature and severity of the condition, the administration method used, etc. Appropriate values are selectable by routine testing.
  • the compound, salt or ester may be administered alone or in combination with other treatments, either simultaneously or sequentially. For instance, it may be administered in combination with effective amounts of antiviral agents, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art. It may be administered by any suitable route, including orally, intravenously, cutaneously, subcutaneously, etc. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell. Suitable targeting methods are already known.
  • a further aspect of the invention provides a method of preparation of a pharmaceutical composition, involving admixing one or more compound of formula A or salt or ester thereof with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.
  • the methanol is removed in vacuo.
  • the aqueous residue is washed with diethyl ether (Et20) .
  • the aqueous fraction is acidified by addition of IN aqueous hydrochloric acid solution (HCl) and the milky mixture is extracted with two portions of ethyl acetate (EtOAc) .
  • the combined organic fractions are washed with brine.
  • the organic layer is dried over sodium sulfate (Na2S04), filtered and solvent is removed in vacuo leaving the desired dioxobutanoic acid product.
  • the Tables include IC 50 data and the methods for assay are explained after the Tables.
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,5-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 3,5- substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,4-substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,3- substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of 2,6- substituted phenyldiketoacids
  • HCV-polymerase inhibitors examples of pyrroles- substituted diketoacids
  • HCV-polymerase inhibitors examples of pyrroles- substituted diketoacids
  • HCV-polymerase inhibitors examples of pyrrole-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of pyrrole-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of thiophene-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of thiophene-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of thiophene-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of thiophene-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of furan-2- substituted diketoacids
  • HCV-polymerase inhibitors examples of pyrroles-substituted diketoacids o OH
  • HCV-polymerase inhibitors examples of thiophene-3-substituted diketoacids
  • HCV-polymerase inhibitors examples of thiophene-3-substituted diketoacids
  • HCV-polymerase inhibitors examples of thiophene-3-substituted diketoacids
  • HCV-polymerase inhibitors examples of furan-3- substituted diketoacids
  • HCV-polymerase inhibitors examples of alkyl-diketoacids
  • HCV-polymerase inhibitors examples of alkyl-diketoacids
  • HCV-polymerase inhibitors examples of alkyl- diketoacids
  • the HCV NS5B protein is the viral RdRp; compounds capable of interfering with the activity of this enzyme are thus expected to block viral replication.
  • W096/37619 describes the production of recombinant HCV RdRp from insect cells infected with recombinant baculovirus encoding the enzyme.
  • the purified enzyme was shown to possess in vitro RNA polymerase activity using RNA as template.
  • the reference describes a polymerisation assay using poly (A) as a template and oligo (U) as a primer.
  • Incorporation of tritiated UTP is quantified by measuring acid-insoluble radioactivity.
  • the present inventors have employed this assay to screen the various compounds described above as inhibitors of HCV RdRp and other virally encoded polymerases. Incorporation of radioactive UMP was measured as follows.
  • the standard reaction (100 ⁇ l) was carried out in a buffer containing 20mM tris/HCl pH 7.5, 5mM MgCl 2 , ImM DTT,50mM NaCl, ImM EDTA, 20U Rnasin (Promega), 0.05% Triton X-100, l ⁇ Ci [ 3 H] UTP (40 Ci/mmol,NEN) , lO ⁇ M UTP and 10 ⁇ g/ml poly(A). Oligo (U) 12 (l ⁇ g/ml, Genset) was added as a primer. The final NSSB enzyme concentration was 20 nM.
  • % residual activity 100/ (1+ [I] /IC S0 ) s where [I] is the inhibitor concentration and "s" is the slope of the inhibition curve.
  • Analogous assays employed the polymerase of hepatitis B virus (HBV pol), obtained in the form of viral particles from the sera of HBV positive patients. These particles contain a polymerase bound to an incomplete double stranded DNA template. In the assay the incorporation of 32 P-dNTP is measured as radioactivity incorporated in acid insoluble precipitate.
  • HBV pol hepatitis B virus
  • the standard reaction (100 ⁇ l) was carried out in a buffer containing 50mM tris/HCl pH 7.5, 30mM MgCl 2 , ImM DTT, 100 mM KCl, 0.02% Triton X-100, 1 ⁇ Ci [ 32 P] dCTP (300 Ci/mmol, NEN), 1 ⁇ M dATP,dTTP, dGTP.
  • a buffer containing 50mM tris/HCl pH 7.5, 30mM MgCl 2 , ImM DTT, 100 mM KCl, 0.02% Triton X-100, 1 ⁇ Ci [ 32 P] dCTP (300 Ci/mmol, NEN), 1 ⁇ M dATP,dTTP, dGTP.
  • the present inventors hypothesize that the diketoacid fragment of the compounds of the present invention inhibits RNA dependent polymerase activity by providing an "active site anchor" and interacting with divalent metal cations (Mg 2+ , Mn 2+ ) required for polymerase activity.
  • the ring system found on the left hand side of the molecule can apparently be modified in order to build specificity towards a given polymerase.

Abstract

Diketoacids of Formula (A) are useful as inhibitors of viral polymerases. In particular hepatitis C virus RNA dependent RNA polymerase (HCV RdRp), hepatitis B virus polymerase (HBV pol) and reverse transcriptase of human immunodeficiency virus (HIV RT). The group R may be broadly chosen and is an organic moiety which contains 2 to 24 carbon atoms and includes an optionally cyclic or heterocyclic group in which the atom directly bonded to the adjacent carbonyl in the diketoacid is part of the ring structure.

Description

DIKETOACID-DERIVATIVES AS INHIBITORS OF POLYMERASES
Technical Field
The present invention relates to compounds useful as enzyme inhibitors, in particular as inhibitors of enzymes involved in the transfer of phosphoryl groups and, especially as inhibitors of polymerases. The invention further relates to pharmaceutical compositions containing such compounds, and to their use in the treatment of viral infections.
Polymerases are the enzymes which catalyse the formation of phosphodiester bonds in RNA and DNA. They play an essential role in viral replication and, therefore, are an important target in the fight against viral diseases such as human immunodeficiency virus (HIV) , hepatitis, and poliomyelitis.
Background Art
US 5 475 109 describes dioxobutanoic acids substituted with piperidine or similar N-substituted saturated cycloalkyls as inhibitors of the cap-dependent endonuclease of influenza virus.
Disclosure of the Invention The present inventors have discovered that a range of diketoacids have utility as enzyme inhibitors and, in particular, as polymerase inhibitors and more particularly as inhibitors of hepatitis C NS5 RNA- dependent RNA polymerase, HBV DNA-dependent RNA polymerase and HIV DNA- dependent DNA polymerase. Their investigations indicate that these compounds may act by interfering with the binding of phosporyl groups at the active site of the enzyme and may, therefore, have broad application in inhibiting enzymes involved in the transfer of phosphoryl groups.
According to a first aspect of the present invention there is provided a compound of formula A shown below. This compound is suitable for therapeutic use, for instance as an enzyme inhibitor.
Figure imgf000004_0001
FORMULA A Optionally, the compound may be in the form of a pharmaceutically acceptable salt or ester, which can be hydrolysed in vivo to the corresponding diketoacid. In formula A, the group R is an organic moiety which contains from 2 to 24, preferably 4 to 20, most preferably 6 to 17 carbon atoms in total. R includes an optionally substituted cyclic or heterocyclic group in which the atom directly bonded to the adjacent carbonyl in the diketoacid is part of the ring structure. Preferably, this atom is a carbon atom.
The ring which is thus bonded to the carbonyl group is preferably a 3 to 8 membered ring, particularly a 4 to 6 membered ring.
Thus, for example, R may be selected from:
(i) optionally substituted aromatic groups, especially those including six membered rings, such as phenyl and naphthyl;
(ii) optionally substituted heteroaryl groups especially those including five and six membered rings such as thiophene, pyrrole, furan, imidazole, pyridyl, pyrimidyl, and pyridazyl; the heteroaryl ring may, optionally be fused to another ring;
(iii) optionally substituted cycloalkyl groups, especially those including five or six membered rings such as cyclopentyl, cyclohexyl and adamantyl ;
(iv) optionally substituted cycloalkenyl groups, especially those including five or six numbered rings such as cyclohexenyl, cyclopentenyl;
(v) optionally substituted cyclic heteroalkyl groups, especially those including five or six numbered rings such as piperidyl, pyrrolidyl, tetrahydrofuranyl, and tetrahydropyranyl; in this class 4- piperidyl rings substituted with an aryl group at carbon 4 and on acyl or sulfonyl substituent at Nl are preferred.
In the case of optional substitution, one or more substituents may be present and a wide variety of substituents are possible. Preferred optional substituents for all compounds of the present invention are set out in the following list:
(a) -OH;
(b) -SH;
(c) - halogen, such as fluorine, chlorine or bromine, (d) - CO 2 H; ( e ) - CN;
( f ) - NO 2 ;
(g) - NR j R 2 wherein each of R x and R 2 is selected from H and lower alkyl groups having 1 to 6 carbon atoms; or R 1 and R 2 together form a ring including 4 to 6 carbon atoms;
(h) - SO 2 NR j R 2 where R x and R 2 are as defined above; (i) -CONH2, - NHC02H, or -NHCOCOOH;
(j) an alkyl (or alkenyl or alkynyl group) group having 1 to 12 (2 to 12) carbon atoms, preferably 1 to 7 (2 to 7) carbon atoms optionally substituted by any one or more of the groups (a) - (i) above and/or optionally interrupted by a group selected from -0-, -S-, -NR 3 -/ 0 -C u- , -CO 2 -, -0C0-, -CONR 3 -, -NR3CONR3-, -S02 -, -
NR3S02-, and -SO 2 NR 3 -; where each R3 independently is H or lower alkyl of 1 to 6 carbon atoms;
(k) an aryl or heteroaryl group having 2 to 10 carbon atoms optionally substituted with any one or more of groups (a) to (j) above;
(1) an aralkyl or heteroaralkyl group having 3 to 16 carbon atoms optionally substituted with any one or more of groups (a) - (j) above and/or in which the alkyl part of the group is optionally interrupted by a group selected from
0
II -0-, -S-, -NR 3 -, -C- - CO 2 -, -OCO-, -CONR 3 -, -
NR3CONR3-, -SO 2 ~ , -NR3S02-, and - SO 2 NR 3 - ; where R3 is as defined above;
0 w (m) -C- R 4 where R 4 is an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group as such groups are defined above at (j), (k) and (1) ;
0 0 (n) -C W-O-R 4 or -O-CII-R 4 where R 4 is as defined above;
(o) -OR 4 where R4 is as defined above; 0 0 0 n ii a
(p) -CNHR 4, -NH-C-R 4 or -NH-C-NHR4 where R 4 is as defined above;
(q) -S02R4 where R4 is as defined above;
-NHR4 or -N(R4)2 where R4 is as defined above; (s) -NHS02R4 or -S02NHR4, where R4 is as defined above;
(t) -SR4
and each of optional substituents (j) to (t) above may optionally itself be substituted by one or more groups selected from (j) to (t) .
A preferred class of compounds of formula A is represented by formula E:
Figure imgf000009_0001
FORMULA E
in which Ar is an optionally substituted aryl or heteroaryl group. Optional substituents may be selected from the list of preferred substituents set out above. Within this class of preferred compounds two especially preferred groups are set out below (formulas F and G)
Figure imgf000010_0001
FORMULA F
Figure imgf000010_0002
FORMULA G
R 5 , R 6ι R 7 and R8 are, independently H or are selected from the optional substituents listed above and R7 and R8 taken together may form a 4 to 7, preferably 5 or 6 membered ring; and X is 0, S, NH, or NR4 where R4 is as defined above.
In compounds of formula F, (which are optionally substituted phenyl diketoacids) ortho, meta and para substitution are possible.
In general, it is preferred that there is a single substituent, preferably at the position which is ortho- or meta- to the diketoacid group. Substitution at the meta-position is especially preferred. Where two substituents are present, then preferably the phenyldiketoacid is 2, 5-substituted; 3, 5-substitution is also possible, as is 2, 4-substitution provided, in the latter case, that the substituent at the 4-position is relatively small (e.g. methyl). Disubstitution at the 2,3- and 2, 6-positions is, in general, not preferred.
Preferred substituents, especially at the ortho and meta positions, are ether groups of formula (o) above (i.e. -OR 4) , hydroxyl, and -NHS02R4. It is generally preferred that no more than one substituent be -OR 4 and/or - NHS02R4.
Preferred examples of -OR4 groups which may be found at the ortho and meta positions and particularly at the meta position include:
-OCH2Ar or, less preferably -0(CH2)2Ar where Ar is an optionally substituted aryl or heteroaryl group and is particularly preferably an optionally substituted phenyl group. Examples of preferred substituents on the aryl group, and especially on the phenyl ring include halogens, especially fluorine and chlorine, and electron- withdrawing groups such as -CN, -C02H, and -CF3 as well as ether and aryl groups; -0-(CH2)3-CN; and -0- (CH2)3-C≡CH.
Preferred sulfonamide groups which may be found at the ortho- and meta- positions, particularly at the meta- position are those of formula:
-NH-S02-Ar, where Ar is an optionally substituted aryl or heteroaryl group, preferably an optionally substituted phenyl group. Preferred optional substituents for the aryl, preferably phenyl group, include: -CN; halogens, especially chlorine and fluorine, -CF3, lower (C^g) alkyl (especially methyl), hydroxy-, ether, and -N02 groups.
For both the -OCH2Ar and -NHS02Ar substituted compounds, another preferred example of Ar is naphthyl .
Other preferred substituents at the ortho and meta positions are lower (eg Cτ-6 ) alkyl groups, especially C^ alkyl, such as methyl and ethyl, but in particular methyl, aralkyl groups, especially phenylmethyl groups, optionally substituted in the phenyl ring, especially by a halogen, and nitrogen-containing substituents such as primary, secondary or tertiary amine groups, optionally in protonated form, amide, urethane, or urea groups in each of which examples there is a nitrogen atom bonded to the phenyl ring.
One particularly preferred sub class of compounds of formula F is those in which each of R 5 and R 6 is selected from H, HO-, R 4 0-, and -NHS02R4 provided that no more than one of R 5 and R 6 is R 4 0- or -NHS02R4.
In compounds of formula G the diketoacid group may be at the 2- or 3- position of the ring. In many cases substitution at the 2-position is preferred.
Preferred examples of compounds of formula G are those in which the five membered aromatic ring,
Figure imgf000013_0001
is a pyrrole or thiophene ring. In the case of the pyrrole-substituted diketoacids, the groups R7 and Re may both be hydrogen and in many cases that is preferred. If R7 and R8 correspond to substituent groups, then these may be at any of the positions not already occupied by the diketoacid group. Examples of possible substituents include alkyl (especially methyl) , halogen, and aralkyl (especially benzyl) groups.
One embodiment of pyrrole substituted diketoacid is that in which the diketoacid group is at the 2- position of the ring and where the only other substituent in the ring is on the nitrogen atom. In this case, preferred examples of the substituent R4 present on the nitrogen atom, include alkyl, aryl or aralkyl groups, particularly aralkyl (such as benzyl) groups. Where an aryl or aralkyl group is present these are preferably substituted with halogen atoms, such as fluorine or chlorine, or by cyano-groups .
In the case of the thiophene-substituted diketoacids a wide range of substituents R7 and R8 may be employed in various positions as will be evident from the tables infra. Preferred thiophenes have an aralkyl (such as optionally substituted benzyl) or aryl (such as optionally substituted phenyl) substituent, e.g. at the 5-position of the thiophene ring.
Compounds containing furanyl rings may also be useful, especially for inhibiting HIV reverse transcriptase. Preferred substituents are optionally substituted aryl groups (especially optionally substituted phenyl) . Substitution is preferably at the 5-position of the ring.
The formulae of numerous preferred specific compounds of the present invention are presented later below.
The compounds of the present invention having formula A may be prepared by a process which comprises reaction of a compound of formula B with a dialkyloxalate of formula C followed by hydrolysis of the resulting diketo-ester of formula D:
Figure imgf000015_0001
FORMULA B FORMULA C FORMULA D
where R ' is an alkyl group, typically having 1-6 carbon atoms. In the case where the target molecule is a pharmaceutically acceptable ester of the compound of formula A then R ' in formula C may be selected accordingly, and the step of hydrolysing the compound of formula D omitted, since in vivo hydrolysis can render the compounds active.
Preferred enzymes for inhibition by the compounds of the invention are those involved in phosphate transfer, in particular polymerases such as DNA polymerases, and RNA polymerases both of which may be either RNA dependent or DNA dependant. Compounds of the invention may particularly preferably be employed in the inhibition of viral enzymes. Examples of viral enzymes include RNA - dependent RNA polymerase and reverse transcriptases .
The compounds of the invention may be used as inhibitors of plant or animal (including human) viruses.
The viruses may be RNA viruses, which may, for example, be positive single stranded viruses of which polio virus, hepatitis C virus and encephalomyocarditis are examples, negative single stranded viruses such as orthomyxoviruses, and paramyxoviruses, and retroviruses of which HIV is a prominent example. Alternatively, the viruses may be DNA viruses, especially double stranded DNA viruses such as hepatitis B virus. In particular, compounds of the present invention may inhibit one or more of the following enzymes: hepatitis C virus RNA dependent RNA polymerase (HCV RdRp) , hepatitis B virus polymerase (HBV pol) and reverse transcriptase of human immunodeficiency virus (HIV RT) .
Especially preferred compounds of the invention will be suitable for use as HCV RdRp inhibitors.
Other classes of enzyme involved in phosphate transfer which may be susceptible to inhibition by compounds of the present invention include phosphatases, Rnases, integrases and ribozymes.
According to a further aspect of the invention there is provided the non-therapeutic use of compound of formula A or suitable salt or ester as an enzyme inhibitor, especially as an inhibitor of polymerases, especially viral polymerases. For instance, compounds of the invention may be of utility in agriculture and horticulture for treating plants infected with or susceptible to plant virus.
According to a further aspect of the invention there is provided the use of a compound of formula A or of a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for treatment of a viral illness in a human or animal. For instance, the medicament may be used to treat viral illness by inhibiting one or more viral polymerase. Preferably the medicament is for treatment of hepatitis, such as hepatitis B or C, particularly hepatitis C, and human immunodeficiency virus.
A still further aspect of the invention provides a pharmaceutical composition comprising a compound of formula A, or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, diluent or carrier. The composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally .
The pharmaceutical compositions optionally also include one or more other agents for the treatment of viral infections such as an antiviral agent, or an immunomodulatory agent such as -, β-, or γ- interferon.
A still further aspect of the invention provides a method of inhibiting an enzyme, especially a viral polymerase and/or of treating or preventing a viral illness, the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of the pharmaceutical composition described above or of a compound of formula A or salt or ester thereof. "Effective amount" means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
The dosage rate at which the compound, salt or ester is administered will depend on the nature of the subject, the nature and severity of the condition, the administration method used, etc. Appropriate values are selectable by routine testing. The compound, salt or ester may be administered alone or in combination with other treatments, either simultaneously or sequentially. For instance, it may be administered in combination with effective amounts of antiviral agents, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art. It may be administered by any suitable route, including orally, intravenously, cutaneously, subcutaneously, etc. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell. Suitable targeting methods are already known.
A further aspect of the invention provides a method of preparation of a pharmaceutical composition, involving admixing one or more compound of formula A or salt or ester thereof with one or more pharmaceutically acceptable adjuvants, diluents or carriers and/or with one or more other therapeutically or prophylactically active agents.
Modes for Carrying Out the Invention Embodiments of the invention are described below by the way of example only.
EXAMPLES (1) Synthesis
The synthesis of the 2, 4-dioxobutanoic acids consists of a Claisen condensation reaction between a methyl ketone substrate and diethyl oxalate in the presence of sodium ethoxide in tetrahydrofuran (Scheme 1A) and the subsequent hydrolysis of the ethyl ester with sodium hydroxide in methanol (Scheme IB) Scheme 1A
Figure imgf000020_0001
Reagents: (i) diethyl oxalate/NaOEt in THF Scheme IB
Figure imgf000021_0001
Reagents: (i) 5eg. NaOH/MeOH
Exemplary procedure for the synthesis of the 2, 4 -dioxobutanoate ethyl esters (Scheme 1A)
In a 50 ml round bottom flask with a stirring bar and under an inert atmosphere, the methyl ketone compound (1.0 mmole) in 10 ml of dry tetrahydrofuran (THF) is reacted with 2 equivalents of diethyl oxalate and 2 equivalents of sodium ethoxide (NaOEt) at ambient temperature for 3 hours. When reaction is completed, the reaction mixture is poured into a IN aqueous hydrochloric acid (HCl) and extracted with ethyl acetate (EtOAc) . The organic phase is separated, washed first with water and then with brine. The organic layer is dried over sodium sulfate (Na2S04), filtered and solvent is removed in vacuo leaving the desired dioxobutanoate ethyl ester in quantitative yield. Exemplary procedure for hydrolysis of the ethyl ester ( Scheme IB)
In a 50 ml round bottom flask with a stirring bar, the 2, 4-dioxobutanoate ethyl ester compound (1.0 mmole) in 10 ml of methanol (MeOH) is reacted with 5 equivalents of sodium hydroxide (NaOH) at ambient temperature for 2 hours.
The methanol is removed in vacuo. The aqueous residue is washed with diethyl ether (Et20) . The aqueous fraction is acidified by addition of IN aqueous hydrochloric acid solution (HCl) and the milky mixture is extracted with two portions of ethyl acetate (EtOAc) . The combined organic fractions are washed with brine. The organic layer is dried over sodium sulfate (Na2S04), filtered and solvent is removed in vacuo leaving the desired dioxobutanoic acid product.
Using this or analogous methods, compounds were produced as set out in the following Tables, which are categorised according to their R" group.
The Tables include IC50 data and the methods for assay are explained after the Tables.
Notes to Table: NA = not active as an inhibitor at concentrations up to that stated. ND = not done .
In the tables, where nitrogen atoms appear to be divalent, the presence of a hydrogen atom is implied.
Table Z
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000024_0001
Figure imgf000024_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000025_0001
Figure imgf000025_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000026_0001
Figure imgf000026_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000027_0001
Figure imgf000027_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000028_0001
Figure imgf000028_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000029_0001
Figure imgf000029_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000030_0001
Figure imgf000030_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000031_0001
Figure imgf000031_0002
Table X
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000032_0001
Figure imgf000032_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000033_0001
Figure imgf000033_0002
Table Z
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000034_0001
Figure imgf000034_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000035_0001
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000036_0001
Figure imgf000036_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000037_0001
Figure imgf000037_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000038_0001
Figure imgf000038_0002
Table Z
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000039_0001
Figure imgf000039_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000040_0001
Figure imgf000040_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000041_0001
Figure imgf000041_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000042_0001
Figure imgf000042_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000043_0001
Figure imgf000043_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000044_0001
Figure imgf000044_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000045_0001
Figure imgf000045_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000046_0001
Figure imgf000046_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000047_0001
Figure imgf000047_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000048_0001
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000049_0001
Figure imgf000049_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000050_0001
Figure imgf000050_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000051_0001
Figure imgf000051_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000052_0001
Figure imgf000052_0002
Table I
HCV-polymerase inhibitors: examples of 2,5-substituted phenyldiketoacids
Figure imgf000053_0001
Figure imgf000053_0002
Table II
HCV-polymerase inhibitors: examples of 3,5- substituted phenyldiketoacids
Figure imgf000054_0001
Figure imgf000054_0002
TABLE III
HCV-polymerase inhibitors: examples of 2,4-substituted phenyldiketoacids
Figure imgf000055_0001
Figure imgf000055_0002
Table IV
HCV-polymerase inhibitors: examples of 2,3- substituted phenyldiketoacids
Figure imgf000056_0001
Figure imgf000056_0002
Table V
HCV-polymerase inhibitors: examples of 2,6- substituted phenyldiketoacids
Figure imgf000057_0001
Figure imgf000057_0002
Table Via
HCV-polymerase inhibitors: examples of pyrroles- substituted diketoacids
OH
R1 X VH
Figure imgf000058_0001
Table Via
HCV-polymerase inhibitors: examples of pyrroles- substituted diketoacids
Figure imgf000059_0001
Figure imgf000059_0002
Table Via
HCV-polymerase inhibitors: examples of pyrrole-2- substituted diketoacids
OH
R1 X VH
Figure imgf000060_0001
Table Via
HCV-polymerase inhibitors: examples of pyrrole-2- substituted diketoacids
Figure imgf000061_0001
Figure imgf000061_0002
Table VIb
HCV-polymerase inhibitors: examples of thiophene-2- substituted diketoacids
OH
R1 XJ m
Figure imgf000062_0001
Table VIb
HCV-polymerase inhibitors: examples of thiophene-2- substituted diketoacids
Figure imgf000063_0001
Table VIb
HCV-polymerase inhibitors: examples of thiophene-2- substituted diketoacids
Figure imgf000064_0001
Table VIb
HCV-polymerase inhibitors: examples of thiophene-2- substituted diketoacids
OH
R1 λ
Figure imgf000065_0001
Table Vic
HCV-polymerase inhibitors: examples of furan-2- substituted diketoacids
Figure imgf000066_0001
Figure imgf000066_0002
Table Vila
HCV-polymerase inhibitors: examples of pyrroles-substituted diketoacids o OH
R1 AA Y0B
Figure imgf000067_0001
Table Vllb
HCV-polymerase inhibitors: examples of thiophene-3-substituted diketoacids
OH
R1 AX Y°"
Figure imgf000068_0001
Table Vllb
HCV-polymerase inhibitors: examples of thiophene-3-substituted diketoacids
OH
R1 X
Figure imgf000069_0001
Table Vl b
HCV-polymerase inhibitors: examples of thiophene-3-substituted diketoacids
Figure imgf000070_0001
Figure imgf000070_0002
Table VI Ic
HCV-polymerase inhibitors: examples of furan-3- substituted diketoacids
Figure imgf000071_0001
Figure imgf000071_0002
Table VIII
HCV-polymerase inhibitors: examples of alkyl-diketoacids
Figure imgf000072_0001
Figure imgf000072_0002
Table VIII
HCV-polymerase inhibitors: examples of alkyl-diketoacids
Figure imgf000073_0001
Figure imgf000073_0002
Table VIII
HCV-polymerase inhibitors: examples of alkyl- diketoacids
Figure imgf000074_0001
Figure imgf000074_0002
Table IXa most active HCV-inhibitors
OH
R1 X Y0H
Figure imgf000075_0001
Table IXa most active HCV-inhibitors
OH
B,AX Y0H
Figure imgf000076_0001
Table IXa most active HCV-inhibitors
OH
R1 AX
Figure imgf000077_0001
Table IXa most active HCV-inhibitors
Figure imgf000078_0001
Figure imgf000078_0002
Table IXa most active HCV-inhibitors
OH
R1 AX Yoκ
Figure imgf000079_0001
Table IXa most active HCV-inhibitors
OH
R1 λ
Figure imgf000080_0001
Table IXa most active HCV-inhibitors
OH
R1 AX Υ∞
Figure imgf000081_0001
Table IXa most active HCV-inhibitors
OH
R1 AX Y°"
Figure imgf000082_0001
Table IXa most active HCV-inhibitors
Figure imgf000083_0001
Figure imgf000083_0002
Table IXa most active HCV-inhibitors
OH mAX Y°"
Figure imgf000084_0001
Table IXb most active HBV-Pol-inhibitors
Figure imgf000085_0001
Figure imgf000085_0002
Table IXc most active HIV-RT-inhibitors
Figure imgf000086_0001
Figure imgf000086_0002
Table IXc most active HIV-RT-inhibitors
OH
R1 λ Y0H
Figure imgf000087_0001
2. Measurement of Inhibitory Activity
The effectiveness of the compounds set out above as polymerase inhibitors, stated above as IC50 values, was assessed in screening assays as follows.
In initial tests, the compounds were tested to see if they were effective as inhibitors of the RNA-dependent RNA polymerase (RdRp) of hepatitis C virus (HCV) . The HCV NS5B protein is the viral RdRp; compounds capable of interfering with the activity of this enzyme are thus expected to block viral replication.
Test for Inhibition of Hepatatis C Virus RdRp
W096/37619 describes the production of recombinant HCV RdRp from insect cells infected with recombinant baculovirus encoding the enzyme. The purified enzyme was shown to possess in vitro RNA polymerase activity using RNA as template. The reference describes a polymerisation assay using poly (A) as a template and oligo (U) as a primer. Incorporation of tritiated UTP is quantified by measuring acid-insoluble radioactivity. The present inventors have employed this assay to screen the various compounds described above as inhibitors of HCV RdRp and other virally encoded polymerases. Incorporation of radioactive UMP was measured as follows. The standard reaction (100 μl) was carried out in a buffer containing 20mM tris/HCl pH 7.5, 5mM MgCl 2 , ImM DTT,50mM NaCl, ImM EDTA, 20U Rnasin (Promega), 0.05% Triton X-100, lμCi [ 3H] UTP (40 Ci/mmol,NEN) , lOμM UTP and 10 μg/ml poly(A). Oligo (U) 12 (lμg/ml, Genset) was added as a primer. The final NSSB enzyme concentration was 20 nM. After 1 hour incubation at 22 °C the reaction was stopped by adding 100 μl of 20% TCA and applying samples to DE81 filters. The filters were washed thoroughly with 5% TCA containing 1M Na 2 HPO 4 /NaH 2 PO 4 , pH 7.0, rinsed with water and then ethanol, air dried, and the filter- bound radioactivity was measured in the scintillation counter. By carrying out the reaction in the presence of various concentrations of each of the compounds set out above it was possible to determine IC50 values for each compound with the formula:
% residual activity = 100/ (1+ [I] /ICS0) s where [I] is the inhibitor concentration and "s" is the slope of the inhibition curve.
Test for Inhibition of Hepatitis B Virus Polymerase
Analogous assays employed the polymerase of hepatitis B virus (HBV pol), obtained in the form of viral particles from the sera of HBV positive patients. These particles contain a polymerase bound to an incomplete double stranded DNA template. In the assay the incorporation of 32P-dNTP is measured as radioactivity incorporated in acid insoluble precipitate.
The standard reaction (100 μl) was carried out in a buffer containing 50mM tris/HCl pH 7.5, 30mM MgCl 2 , ImM DTT, 100 mM KCl, 0.02% Triton X-100, 1 μCi [ 32P] dCTP (300 Ci/mmol, NEN), 1 μM dATP,dTTP, dGTP. After 1 hour incubation at 37 °C the reaction was stopped by adding 100 μl of 20% TCA and applying samples to DE81 filters. The filters were processed and IC50 values calculated as described above.
Test for Inhibition of Human Immunodeficiency Virus-1 Reverse Transcriptase
Analogous assays employed the reverse transcriptase of HIV (HIV -1RT) from Boehringer Mannhium.
Incorporation of radioactive dTTP was measured as follows. The standard reaction (100 μl) was carried out in a buffer containing 50mM tris/HCl pH 8.2, 2.5mM MgCl 2, ImM DTT, 80 mM KCl, 5mM EGTA, 0.05% Triton X-100, lμCi[3H] dTTP (40 Ci/mmol, NEN), 10 μM UTP and 10 μg/ml poly(A)/dT (from Pharmacia). The final HIV-1RT ( enzyme concentration was 1 nM. After 1 hour incubation at 37 °C the reaction was stopped by adding 100 μl of 20% TCA and applying samples to DE81 filters. The filters were processed and IC50 values calculated as described above.
The results demonstrate that the compounds of the present invention are effective as inhibitors of viral polymerases at low micromolar concentrations.
It is apparent from the tables above that a compound of the present invention which is effective in the inhibition of one of the RNA dependent polymerases tested may not necessarily be as effective in inhibiting the other RNA dependent polymerases. The results shown in the tables above indicate a general trend, although this is not without exception. Generally, the most active inhibitors of HCV RdRp contained a phenyl ring attached to the diketoacid, whereas the HIV-RT inhibitors contained a furanyl group and those of HBV polymerase a thiophene group.
While not wishing to be bound by any particular theory, the present inventors hypothesize that the diketoacid fragment of the compounds of the present invention inhibits RNA dependent polymerase activity by providing an "active site anchor" and interacting with divalent metal cations (Mg 2+ , Mn 2+) required for polymerase activity. The ring system found on the left hand side of the molecule can apparently be modified in order to build specificity towards a given polymerase.

Claims

The use of a compound of formula A, or of a pharmaceutically acceptable salt or ester thereof, wherein the group R is an organic moiety containing 2 to 24 carbon atoms which includes an optionally substituted cyclic or heterocyclic group, and wherein one of the atoms in the ring of the cyclic or heterocyclic group is directly bonded to the adjacent carbonyl in the diketoacid, in the manufacture of a medicament for treatment or prophylaxis of a viral illness in a human or animal by inhibition of a viral polymerase.
Figure imgf000093_0001
FORMULA A
2. The use according to claim 1 wherein the medicament is for the inhibition of a DNA polymerase or RNA polymerase .
3. The use according to claim 1 or claim 2 wherein the medicament is for treatment or prevention of infection by an RNA virus, such as a positive single-stranded virus, negative single stranded virus or retrovirus, or a DNA virus.
4. The use according to claim 3 wherein the virus is selected from polio virus, hepatitis C virus, encephalomyocarditis, orthomyxoviruses, paramyxoviruses, HIV, and hepatitis B.
5. The use according to claim 3 wherein the medicament is for the inhibition of hepatitis C virus RNA dependent RNA polymerase (HCV RdRp) , hepatitis B virus polymerase (HBV pol) , or reverse transcriptase of human immunodeficiency virus (HIV RT) .
6. The use according to any one of the following claims wherein the group R is selected from:
(i) optionally substituted aromatic groups;
(ii) optionally substituted heteroaryl groups;
(iii) optionally substituted cycloalkyl groups;
(iv) optionally substituted cycloalkenyl groups; and (v) optionally substituted cyclic heteroalkyl groups .
7. A compound of formula A, as set out in claim 1, or a pharmaceutically acceptable salt or ester thereof, for pharmaceutical use, wherein the group R is selected from:
(i) optionally substituted aromatic groups;
(ii) optionally substituted heteroaryl groups;
(iii) optionally substituted cycloalkyl groups; (iv) optionally substituted cycloalkenyl groups; and
(v) optionally substituted cyclic heteroalkyl groups, other than those containing a single nitrogen in the ring.
8. A compound, ester or salt according to claim 7 wherein the group R is an optionally substituted phenyl group of formula:
wherein R5 and R6 independently are selected from hydrogen and the following substituent groups:
(a) -OH;
(b) -SH; (c) - halogen, such as fluorine, chlorine or bromine,
(d) - CO 2 H;
(e) - CN;
(f) - NO 2 ; (g) - NR ! R 2 wherein each of R 1 and R 2 is selected from H and lower alkyl groups having 1 to 6 carbon atoms; or R τ and R 2 together form a ring including 4 to 6 carbon atoms; (h) - SO 2 NR ! R 2 where R x and R 2 are as defined above;
( i ) -CONR^ , - RiCOsH, or -NRiCOCOOH where Rx and R2 are as defined above; (j) an alkyl (or alkenyl or alkynyl group) group having 1 to 12 (2 to 12) carbon atoms, preferably 1 to 7 (2 to 7) carbon atoms optionally substituted by any one or more of the groups (a) - (i) above and/or optionally interrupted by a group selected from -0-, -S-, -NR 3 - 0
-C II- , -CO 2 -, -OCO-, -CONR 3 -, -NR3CONR3-, -S02 -, -NR3S02-, and -SO 2 NR 3 -; where each R3 independently is H or lower alkyl of 1 to 6 carbon atoms;
(k) an aryl or heteroaryl group having 2 to 10 carbon atoms optionally substituted with any one or more of groups (a) to (j) above;
(1) an aralkyl or heteroaralkyl group having 3 to
16 carbon atoms optionally substituted with any one or more of groups (a) - (j) above and/or in which the alkyl part of the group is optionally interrupted by a group selected from
0
I!
-0-, -S-, -NR 3 -, -C- - CO 2 -, -OCO-, -CONR 3 , -NR3CONR3-, -SO 2 - , -NR3SO2-, and - SO 2 NR 3 - ; where R3 is as defined above;
0
( ) -C II- R 4 where R 4 is an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group as such groups are defined above at (j), (k) and (1); 0 0
W II
(n) -C-O-R 4 or -O-C-R 4 where R 4 is as defined above;
(o) -OR 4 where R4 is as defined above; 0 0 0
(p) -C *NHR 4, -NH-CII-R 4 or -NH-Cll-NHR4 where R 4 is as defined above;
(q) -S02R4 where R4 is as defined above;
(r) -NHR4 or -N(R4)2 where R4 is as defined above;
(s) -NHS02R4 or -S02NHR4, where R4 is as defined above; and
(t; -SR
and each of optional substituents (j) to (t) above may optionally itself be substituted by one or more groups selected from (j) to (t) .
9. A compound, ester or salt according to claim 8 wherein the substituents R5 and R6 are independently selected from H-, -OH, -OR4, -NHS02R4, lower alkyl, aralkyl, amino, amide, urethane or urea groups.
10. A compound, salt or ester according to claim 8 wherein the substituents R5 and R6 are independently selected from H-, -OH, -OR4, and -NHS02R4.
11. A compound, salt or ester according to claim 9 or claim 10 containing only one substituent either of formula -OR4 or -NHS02R4.
12. A compound, salt or ester of any one of claims 9 to 11 containing a group of formula -OR4 and/or -NHS02R4 selected from:
-0CH2Ar;
-0(CH2)2Ar;
-0(CH2)3CN;
-0(CH2)3CΓëíCH; and -NHS02Ar; wherein Ar is an optionally substituted aryl or heteroaryl group.
13. A compound, salt or ester, according to any one of claims 8 to 12 having a single substituent at a position ortho- or meta- to the diketoacid group.
14. A compound, salt or ester according to any one of claims 8 to 12 having two substituents at the 2,5-; 3,5-; or 2, -positions .
15. A compound, salt or ester according to claim 7 wherein the group of formula R has the formula:
Figure imgf000100_0001
and each of R7 and R8 is independently selected from hydrogen or from the list of substituent groups set out at claim 8, and X is 0, S, NH or NR4, where R4 is as defined above.
16. A compound, salt or ester according to claim 15 which is a pyrrole-2-substituted diketoacid, a pyrrole-3-substituted diketoacid, a thiophene-2- substituted diketoacid, or a thiophene-3-substituted diketoacid.
17. A compound, salt or ester according to claim 16 which is a pyrrole substituted diketoacid in which each of R7 and R8 is hydrogen.
18. A compound, salt or ester according to any one of claims 15 to 17 which is a pyrrole substituted diketoacid having X=NR4 and wherein R4 is selected from optionally substituted or interrupted, alkyl aryl or aralkyl groups.
19. A compound, salt or ester according to claim 7 wherein R is selected from cyclopropyl-, cyclopentyl-, cyclohexyl-, cyclopentenyl-, cyclohexenyl and adamantyl groups, any of which may, optionally, be substituted.
20. A pharmaceutical composition comprising a compound, salt or ester of any one of claims 7 to 19 in combination with a pharmaceutically acceptable excipient, diluent or carrier.
21. Use, according to any one of claims 1 to 6, of a compound, salt or ester according to any one of claims 7 to 19.
22. A use according to any one of claims 1 to 6 or 21 wherein the medicament further comprises one or more other agents for the treatment of viral infections.
23. A method of inhibiting a viral polymerase and/or of treating or preventing a viral illness by inhibiting a viral polymerase, the method comprising administering to a human or animal subject suffering from the condition a therapeutically or prophylactically effective amount of the compound of formula A set out in claim 1, or of a pharmaceutically acceptable salt or ester thereof.
24. A compound of formula A, as set out in claim 1 or a pharmaceutically acceptable salt or ester thereof wherein the group R is selected from: (i) optionally substituted aromatic groups; (ii) optionally substituted heteroaryl groups; (iii) optionally substituted cycloalkyl groups;
(iv) optionally substituted cycloalkenyl groups; and (v) optionally substituted cyclic heteroalkyl groups, other than those containing a single nitrogen in the ring.
PCT/GB1999/002446 1998-07-27 1999-07-27 Diketoacid-derivatives as inhibitors of polymerases WO2000006529A1 (en)

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US09/744,795 US6492423B1 (en) 1998-07-27 1999-07-27 Diketoacid-derivatives as inhibitors of polymerases
AT99934986T ATE298317T1 (en) 1998-07-27 1999-07-27 DIKETO ACID DERIVATIVES AS INHIBITORS OF POLYMERASES
CA002338490A CA2338490A1 (en) 1998-07-27 1999-07-27 Diketoacid-derivatives as inhibitors of polymerases
DE69925918T DE69925918T2 (en) 1998-07-27 1999-07-27 DIKETIC ACID DERIVATIVES AS POLYMERASES INHIBITORS
AU50595/99A AU756627B2 (en) 1998-07-27 1999-07-27 Diketoacid-derivatives as inhibitors of polymerases
JP2000562336A JP2003525200A (en) 1998-07-27 1999-07-27 Diketoacid derivatives as polymerase inhibitors
EP99934986A EP1100763B8 (en) 1998-07-27 1999-07-27 Diketoacid-derivatives as inhibitors of polymerases
US10/238,246 US7022736B2 (en) 1998-07-27 2002-09-10 Enzyme inhibitors

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US60/096,528 1998-08-13

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Cited By (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262055B1 (en) 1998-06-03 2001-07-17 Merck & Co., Inc. HIV integrase inhibitors
WO2001077091A2 (en) * 2000-04-05 2001-10-18 Tularik Inc. Ns5b hcv polymerase inhibitors
US6306891B1 (en) 1998-06-03 2001-10-23 Merck & Co., Inc. HIV integrase inhibitors
WO2002004425A3 (en) * 2000-07-06 2002-04-25 Boehringer Ingelheim Ca Ltd Viral polymerase inhibitors
US6380249B1 (en) 1998-06-03 2002-04-30 Merck & Co., Inc. HIV integrase inhibitors
WO2003007945A1 (en) 2001-07-20 2003-01-30 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US6803374B2 (en) 2001-09-26 2004-10-12 Bristol-Myers Squibb Company Compounds useful for treating hepatitis C virus
US6869964B2 (en) 2002-05-20 2005-03-22 Bristol-Myers Squibb Company Heterocyclicsulfonamide hepatitis C virus inhibitors
US6878722B2 (en) 2002-05-20 2005-04-12 Bristol-Myers Squibb Company Substituted cycloalkyl P1′ hepatitis C virus inhibitors
WO2005034850A2 (en) 2003-09-11 2005-04-21 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis c virus
WO2005037214A2 (en) 2003-10-14 2005-04-28 Intermune, Inc. Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication
US6930106B2 (en) 2002-07-01 2005-08-16 Pharmacia & Upjohn Company Inhibitors of HCV NS5B polymerase
WO2005080388A1 (en) 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US6995174B2 (en) 2002-05-20 2006-02-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7018796B2 (en) 2000-04-07 2006-03-28 Shionogi & Co., Ltd. Preincubation assay methods
US7026339B2 (en) 2003-11-07 2006-04-11 Fan Yang Inhibitors of HCV NS5B polymerase
US7041698B2 (en) 2002-05-20 2006-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7041690B2 (en) 2002-07-01 2006-05-09 Pharmacia & Upjohn Company, Llc Inhibitors of HCV NS5B polymerase
US7132504B2 (en) 2003-11-12 2006-11-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2006117306A1 (en) 2005-05-04 2006-11-09 F. Hoffmann-La Roche Ag Heterocyclic antiviral compounds
US7135462B2 (en) 2003-11-20 2006-11-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2006119646A1 (en) 2005-05-13 2006-11-16 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
US7141574B2 (en) 2001-07-25 2006-11-28 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
WO2006083553A3 (en) * 2005-01-31 2007-04-19 Univ Georgia Res Found Diketo acids with nucleobase scaffolds: anti-hiv replication inhibitors targeted at hiv integrase
US7223785B2 (en) 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
WO2007119889A1 (en) 2006-04-18 2007-10-25 Japan Tobacco Inc. Novel piperazine compound, and use thereof as hcv polymerase inhibitor
US7309708B2 (en) 2003-11-20 2007-12-18 Birstol-Myers Squibb Company Hepatitis C virus inhibitors
WO2008043704A1 (en) 2006-10-10 2008-04-17 Medivir Ab Hcv nucleoside inhibitor
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
WO2008121634A2 (en) 2007-03-30 2008-10-09 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
EP2033654A1 (en) 2003-04-16 2009-03-11 Bristol-Myers Squibb Company Macrocyclic isoquinoline peptide inhibitors of hepatitis c virus
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
WO2009076747A1 (en) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2093235A1 (en) 2006-02-08 2009-08-26 Alios Biopharma Inc. Hyperglycosylated variants of interferon alfacon-1
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
WO2010075554A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
WO2010075549A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside phosphoramidates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
US7749961B2 (en) 2004-01-21 2010-07-06 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2206715A1 (en) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Fused heterotetracyclic compounds and use thereof as hcv polymerase inhibitor
WO2010080874A1 (en) 2009-01-07 2010-07-15 Scynexis, Inc. Cyclosporine derivative for use in the treatment of hcv and hiv infection
US7776883B2 (en) 2004-03-10 2010-08-17 The United States Of America As Represented By The Department Of Health And Human Services Quinolin-4-ones as inhibitors of retroviral integrase for the treatment of HIV, AIDS and AIDS related complex (ARC)
WO2010107739A2 (en) 2009-03-18 2010-09-23 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions of treating a flaviviridae family viral infection
WO2010135569A1 (en) 2009-05-20 2010-11-25 Pharmasset, Inc. N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production
WO2011058084A1 (en) 2009-11-14 2011-05-19 F. Hoffmann-La Roche Ag Biomarkers for predicting rapid response to hcv treatment
WO2011068715A1 (en) 2009-11-25 2011-06-09 Vertex Pharmaceuticals Incorporated 5-alkynyl-thiophene-2-carboxylic acid derivatives and their use for the treatment or prevention of flavivirus infections
WO2011067195A1 (en) 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Biomarkers for predicting sustained response to hcv treatment
WO2011079327A1 (en) 2009-12-24 2011-06-30 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
EP2351560A1 (en) 2005-01-04 2011-08-03 Novartis AG Treatment Of HCV infections with FTY720
WO2011119860A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119853A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119870A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119858A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011123645A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Nucleoside phosphoramidates
WO2011123672A1 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Purine nucleoside phosphoramidate
WO2011159826A2 (en) 2010-06-15 2011-12-22 Vertex Pharmaceuticals Incorporated Hcv ns5b protease mutants
EP2399988A2 (en) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Cell culture system for replication of HCV through the farnesoid X receptor (FXR) activation or inhibition and diagnostic method for HCV infection
WO2012006055A2 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006060A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006070A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012024363A2 (en) 2010-08-17 2012-02-23 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flaviviridae viral infections
US8178491B2 (en) 2007-06-29 2012-05-15 Gilead Sciences, Inc. Antiviral compounds
WO2012107589A1 (en) 2011-02-11 2012-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment and prevention of hcv infections
WO2012123298A1 (en) 2011-03-11 2012-09-20 F. Hoffmann-La Roche Ag Antiviral compounds
WO2012175581A1 (en) 2011-06-24 2012-12-27 F. Hoffmann-La Roche Ag Antiviral compounds
WO2013016501A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Formulations of thiophene compounds
WO2013016499A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Methods for preparation of thiophene compounds
EP2559691A1 (en) 2006-11-15 2013-02-20 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of Flavivirus infections
WO2013053657A1 (en) 2011-10-10 2013-04-18 F. Hoffmann-La Roche Ag Antiviral compounds
WO2013087743A1 (en) 2011-12-16 2013-06-20 F. Hoffmann-La Roche Ag Inhibitors of hcv ns5a
WO2013092447A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 4'-azido, 3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication
WO2013092481A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication
US8513186B2 (en) 2007-06-29 2013-08-20 Gilead Sciences, Inc. Antiviral compounds
WO2013124335A1 (en) 2012-02-24 2013-08-29 F. Hoffmann-La Roche Ag Antiviral compounds
US8618151B2 (en) 2008-12-03 2013-12-31 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2014006066A1 (en) 2012-07-06 2014-01-09 F. Hoffmann-La Roche Ag Triazole compounds as antivirals
WO2014114573A1 (en) 2013-01-23 2014-07-31 F. Hoffmann-La Roche Ag Antiviral triazole derivatives
WO2014134251A1 (en) 2013-02-28 2014-09-04 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
EP2774927A1 (en) 2008-12-03 2014-09-10 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2014135422A1 (en) 2013-03-05 2014-09-12 F. Hoffmann-La Roche Ag Antiviral compounds
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
WO2014148949A1 (en) 2013-03-22 2014-09-25 Асави, Ллс Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2н-pyrimidin-1-yl)-3-hydroxy- tetrahydro-furan-2-yl-methoxy]-phenoxy-phosphoryl-amino}-propionates, nucleoside inhibitors of hcv ns5b rna-polymerase, and methods for producing and use thereof
US8877707B2 (en) 2010-05-24 2014-11-04 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
WO2014186637A1 (en) 2013-05-16 2014-11-20 Riboscience Llc 4'-fluor0-2'-methyl substituted nucleoside derivatives
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
US9150554B2 (en) 2009-03-27 2015-10-06 Presidio Pharmaceuticals, Inc. Fused ring inhibitors of hepatitis C
US9186369B2 (en) 2003-07-25 2015-11-17 Idenix Pharmaceuticals, Llc Purine nucleoside analogues for treating flaviviridae including hepatitis C
US9249176B2 (en) 2013-05-16 2016-02-02 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9284342B2 (en) 2009-05-20 2016-03-15 Gilead Pharmasset Llc Nucleoside phosphoramidates
EP3025727A1 (en) 2008-10-02 2016-06-01 The J. David Gladstone Institutes Methods of treating liver disease
US9364484B2 (en) 2011-12-06 2016-06-14 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating viral diseases
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US10953030B2 (en) 2013-05-16 2021-03-23 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
WO2023161427A1 (en) 2022-02-24 2023-08-31 Eisbach Bio Gmbh Viral combination therapy

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089560A1 (en) * 2000-05-24 2001-11-29 The Board Of Trustees Of The Leland Stanford Junior University Inhibitors of viral infection
WO2006023893A2 (en) * 2004-08-23 2006-03-02 Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for modulating angiogenesis and apoptosis with apelin compositions
AU2007275805A1 (en) * 2006-07-19 2008-01-24 University Of Georgia Research Foundation, Inc. Pyridinone diketo acids: Inhibitors of HIV replication in combination therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4337258A (en) * 1980-12-29 1982-06-29 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butanoic acid derivatives useful in treating urinary tract calcium oxalate lithiasis
DE3214082A1 (en) * 1981-04-17 1982-11-04 Roussel-Uclaf, 75007 Paris NEW DERIVATIVES OF PHENYL ALIPHATIC CARBONIC ACIDS, THEIR PRODUCTION, THEIR USE AS MEDICINAL PRODUCTS AND THE COMPOSITIONS CONTAINING THEM
US5475109A (en) * 1994-10-17 1995-12-12 Merck & Co., Inc. Dioxobutanoic acid derivatives as inhibitors of influenza endonuclease

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3772336A (en) 1972-04-25 1973-11-13 Upjohn Co 4h-(1)benzothieno(3,2-beta)pyran-4-one-2-carboxylic acids and related compounds
US3899508A (en) 1974-04-12 1975-08-12 Lilly Co Eli 5-(2-Aminophenyl)pyrazole-3-carboxylic acids and esters thereof
JPS56100784A (en) 1980-01-16 1981-08-12 Yoshitomi Pharmaceut Ind Ltd Indolizine derivative
US4423063A (en) 1980-12-29 1983-12-27 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butaoic acid derivatives useful in treating urinary track calcium oxalate lithiasis
US4336397A (en) 1980-12-29 1982-06-22 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butanoic acid derivatives useful in treating urinary tract calcium oxalate lithiasis
JPS61134346A (en) 1984-12-03 1986-06-21 Shionogi & Co Ltd 4-oxocarboxylic acid derivative and antiulcer agent
PH27357A (en) 1989-09-22 1993-06-21 Fujisawa Pharmaceutical Co Pyrazole derivatives and pharmaceutical compositions comprising the same
US5192773A (en) 1990-07-02 1993-03-09 Vertex Pharmaceuticals, Inc. Immunosuppressive compounds
GB9522617D0 (en) 1995-11-03 1996-01-03 Pharmacia Spa 4-Phenyl-4-oxo-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity
GB9522615D0 (en) 1995-11-03 1996-01-03 Pharmacia Spa 4-Phenyl-4-oxo-butanoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity
CA2333771A1 (en) 1998-06-03 1999-12-09 Mark W. Embrey Hiv integrase inhibitors
US6262055B1 (en) 1998-06-03 2001-07-17 Merck & Co., Inc. HIV integrase inhibitors
JP2002516858A (en) 1998-06-03 2002-06-11 メルク エンド カムパニー インコーポレーテッド HIV integrase inhibitor
US6306891B1 (en) 1998-06-03 2001-10-23 Merck & Co., Inc. HIV integrase inhibitors
AU4225499A (en) 1998-06-03 1999-12-20 Merck & Co., Inc. Hiv integrase inhibitors
JP3929244B2 (en) 1998-12-25 2007-06-13 塩野義製薬株式会社 Aromatic heterocyclic derivatives having HIV integrase inhibitory activity

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4337258A (en) * 1980-12-29 1982-06-29 Merck & Co., Inc. 2,4-Dioxo-4-substituted-1-butanoic acid derivatives useful in treating urinary tract calcium oxalate lithiasis
DE3214082A1 (en) * 1981-04-17 1982-11-04 Roussel-Uclaf, 75007 Paris NEW DERIVATIVES OF PHENYL ALIPHATIC CARBONIC ACIDS, THEIR PRODUCTION, THEIR USE AS MEDICINAL PRODUCTS AND THE COMPOSITIONS CONTAINING THEM
US5475109A (en) * 1994-10-17 1995-12-12 Merck & Co., Inc. Dioxobutanoic acid derivatives as inhibitors of influenza endonuclease

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BEILSTEIN INFORMATION SERVICE: FILE: XFIRE, XP002119720 *
TOMASSINI ET AL.: "Inhibition of ....", ANTIMICROB. AGENTS CHEMOTHERAP., vol. 38, no. 12, 1994, pages 2827 - 2837, XP002119719 *

Cited By (168)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6306891B1 (en) 1998-06-03 2001-10-23 Merck & Co., Inc. HIV integrase inhibitors
US6380249B1 (en) 1998-06-03 2002-04-30 Merck & Co., Inc. HIV integrase inhibitors
US6262055B1 (en) 1998-06-03 2001-07-17 Merck & Co., Inc. HIV integrase inhibitors
WO2001077091A2 (en) * 2000-04-05 2001-10-18 Tularik Inc. Ns5b hcv polymerase inhibitors
WO2001077091A3 (en) * 2000-04-05 2002-03-21 Tularik Inc Ns5b hcv polymerase inhibitors
US6727267B2 (en) 2000-04-05 2004-04-27 Tularik Inc. NS5B HVC polymerase inhibitors
US7018796B2 (en) 2000-04-07 2006-03-28 Shionogi & Co., Ltd. Preincubation assay methods
WO2002004425A3 (en) * 2000-07-06 2002-04-25 Boehringer Ingelheim Ca Ltd Viral polymerase inhibitors
WO2003007945A1 (en) 2001-07-20 2003-01-30 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US6841566B2 (en) 2001-07-20 2005-01-11 Boehringer Ingelheim, Ltd. Viral polymerase inhibitors
US7157486B2 (en) 2001-07-25 2007-01-02 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US7141574B2 (en) 2001-07-25 2006-11-28 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
EP1891951A1 (en) 2001-07-25 2008-02-27 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
EP2335700A1 (en) 2001-07-25 2011-06-22 Boehringer Ingelheim (Canada) Ltd. Hepatitis C virus polymerase inhibitors with a heterobicylic structure
US7803944B2 (en) 2001-07-25 2010-09-28 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US6803374B2 (en) 2001-09-26 2004-10-12 Bristol-Myers Squibb Company Compounds useful for treating hepatitis C virus
US6869964B2 (en) 2002-05-20 2005-03-22 Bristol-Myers Squibb Company Heterocyclicsulfonamide hepatitis C virus inhibitors
US7041698B2 (en) 2002-05-20 2006-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US6878722B2 (en) 2002-05-20 2005-04-12 Bristol-Myers Squibb Company Substituted cycloalkyl P1′ hepatitis C virus inhibitors
US6995174B2 (en) 2002-05-20 2006-02-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US6930106B2 (en) 2002-07-01 2005-08-16 Pharmacia & Upjohn Company Inhibitors of HCV NS5B polymerase
US7041690B2 (en) 2002-07-01 2006-05-09 Pharmacia & Upjohn Company, Llc Inhibitors of HCV NS5B polymerase
US7504378B2 (en) 2002-10-25 2009-03-17 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7223785B2 (en) 2003-01-22 2007-05-29 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7507754B2 (en) 2003-01-29 2009-03-24 Asterand Uk Limited EP4 receptor antagonists
US7858644B2 (en) 2003-01-29 2010-12-28 Asterand Uk Limited EP4 receptor antagonists
US7528157B2 (en) 2003-01-29 2009-05-05 Asterand Uk Limited EP4 receptor antagonists
US7196089B2 (en) 2003-01-29 2007-03-27 Asterand Uk Limited EP4 receptor antagonists
EP2033654A1 (en) 2003-04-16 2009-03-11 Bristol-Myers Squibb Company Macrocyclic isoquinoline peptide inhibitors of hepatitis c virus
US9186369B2 (en) 2003-07-25 2015-11-17 Idenix Pharmaceuticals, Llc Purine nucleoside analogues for treating flaviviridae including hepatitis C
US7112601B2 (en) 2003-09-11 2006-09-26 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis C virus
WO2005034850A2 (en) 2003-09-11 2005-04-21 Bristol-Myers Squibb Company Cycloalkyl heterocycles for treating hepatitis c virus
US7642235B2 (en) 2003-09-22 2010-01-05 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
EP2407470A2 (en) 2003-10-14 2012-01-18 F. Hoffmann-La Roche Ltd. Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of HCV replication
WO2005037214A2 (en) 2003-10-14 2005-04-28 Intermune, Inc. Macrocyclic carboxylic acids and acylsulfonamides as inhibitors of hcv replication
US7569602B2 (en) 2003-10-16 2009-08-04 Asterand Uk Limited Furan derivatives as EP4 receptor antagonists
US7417068B2 (en) 2003-10-16 2008-08-26 Asterand Uk Limited EP4 receptor antagonists
US7026339B2 (en) 2003-11-07 2006-04-11 Fan Yang Inhibitors of HCV NS5B polymerase
US7132504B2 (en) 2003-11-12 2006-11-07 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7135462B2 (en) 2003-11-20 2006-11-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US7309708B2 (en) 2003-11-20 2007-12-18 Birstol-Myers Squibb Company Hepatitis C virus inhibitors
US7749961B2 (en) 2004-01-21 2010-07-06 Boehringer Ingelheim International Gmbh Macrocyclic peptides active against the hepatitis C virus
US7879851B2 (en) 2004-02-20 2011-02-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US8030309B2 (en) 2004-02-20 2011-10-04 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP2626354A1 (en) 2004-02-20 2013-08-14 Boehringer Ingelheim International GmbH Viral polymerase inhibitors
WO2005080388A1 (en) 2004-02-20 2005-09-01 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
EP2206715A1 (en) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Fused heterotetracyclic compounds and use thereof as hcv polymerase inhibitor
US7776883B2 (en) 2004-03-10 2010-08-17 The United States Of America As Represented By The Department Of Health And Human Services Quinolin-4-ones as inhibitors of retroviral integrase for the treatment of HIV, AIDS and AIDS related complex (ARC)
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
EP2351560A1 (en) 2005-01-04 2011-08-03 Novartis AG Treatment Of HCV infections with FTY720
US7250421B2 (en) 2005-01-31 2007-07-31 University Of Georgia Research Foundation, Inc. Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase
US7569573B2 (en) 2005-01-31 2009-08-04 The University Of Georgia Research Foundation, Inc. Diketo acids with nucleobase scaffolds: anti-HIV replication inhibitors targeted at HIV integrase
WO2006083553A3 (en) * 2005-01-31 2007-04-19 Univ Georgia Res Found Diketo acids with nucleobase scaffolds: anti-hiv replication inhibitors targeted at hiv integrase
WO2006117306A1 (en) 2005-05-04 2006-11-09 F. Hoffmann-La Roche Ag Heterocyclic antiviral compounds
EP2543664A1 (en) 2005-05-13 2013-01-09 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
EP2546246A2 (en) 2005-05-13 2013-01-16 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
WO2006119646A1 (en) 2005-05-13 2006-11-16 Virochem Pharma Inc. Compounds and methods for the treatment or prevention of flavivirus infections
EP2093235A1 (en) 2006-02-08 2009-08-26 Alios Biopharma Inc. Hyperglycosylated variants of interferon alfacon-1
WO2007119889A1 (en) 2006-04-18 2007-10-25 Japan Tobacco Inc. Novel piperazine compound, and use thereof as hcv polymerase inhibitor
EP2399988A2 (en) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Cell culture system for replication of HCV through the farnesoid X receptor (FXR) activation or inhibition and diagnostic method for HCV infection
EP2399575A2 (en) 2006-08-11 2011-12-28 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods, uses and compositions for treatment of an infection by a virus of the family of flaviviridae through the farnesoid X receptor (FXR) inhibition
WO2008043704A1 (en) 2006-10-10 2008-04-17 Medivir Ab Hcv nucleoside inhibitor
EP2361922A1 (en) 2006-10-10 2011-08-31 Medivir AB Intermediate to HCV-Nucleoside Inhibitors
EP2559691A1 (en) 2006-11-15 2013-02-20 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of Flavivirus infections
EP2559692A1 (en) 2006-11-15 2013-02-20 Virochem Pharma Inc. Thiophene analogues for the treatment or prevention of Flavivirus infections
US9585906B2 (en) 2007-03-30 2017-03-07 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US10183037B2 (en) 2007-03-30 2019-01-22 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8580765B2 (en) 2007-03-30 2013-11-12 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US11642361B2 (en) 2007-03-30 2023-05-09 Gilead Sciences, Inc. Nucleoside phosphoramidate prodrugs
US8906880B2 (en) 2007-03-30 2014-12-09 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8957046B2 (en) 2007-03-30 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
DE202008018643U1 (en) 2007-03-30 2017-03-16 Gilead Pharmasset Llc Nucleosidphosphoramidat prodrugs
US9085573B2 (en) 2007-03-30 2015-07-21 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
US8735372B2 (en) 2007-03-30 2014-05-27 Gilead Pharmasset Llc Nucleoside phosphoramidate prodrugs
WO2008121634A2 (en) 2007-03-30 2008-10-09 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US8809266B2 (en) 2007-06-29 2014-08-19 Gilead Sciences, Inc. Antiviral compounds
US8809267B2 (en) 2007-06-29 2014-08-19 Gilead Sciences, Inc. Antiviral compounds
US8178491B2 (en) 2007-06-29 2012-05-15 Gilead Sciences, Inc. Antiviral compounds
US8513186B2 (en) 2007-06-29 2013-08-20 Gilead Sciences, Inc. Antiviral compounds
WO2009076747A1 (en) 2007-12-19 2009-06-25 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
EP3025727A1 (en) 2008-10-02 2016-06-01 The J. David Gladstone Institutes Methods of treating liver disease
EP2682393A1 (en) 2008-12-03 2014-01-08 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A comprising a bicyclic core.
EP2774927A1 (en) 2008-12-03 2014-09-10 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
US8618151B2 (en) 2008-12-03 2013-12-31 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
US8865756B2 (en) 2008-12-03 2014-10-21 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
EP3222628A1 (en) 2008-12-23 2017-09-27 Gilead Pharmasset LLC Nucleoside phosphoramidates
US8716262B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8957045B2 (en) 2008-12-23 2015-02-17 Gilead Pharmasset Llc Nucleoside phosphoramidates
WO2010075549A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside phosphoramidates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
EP2671888A1 (en) 2008-12-23 2013-12-11 Gilead Pharmasset LLC 3',5'-cyclic nucleoside phosphate analogues
US9045520B2 (en) 2008-12-23 2015-06-02 Gilead Pharmasset Llc Synthesis of purine nucleosides
WO2010075554A1 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Synthesis of purine nucleosides
US8551973B2 (en) 2008-12-23 2013-10-08 Gilead Pharmasset Llc Nucleoside analogs
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
WO2010080874A1 (en) 2009-01-07 2010-07-15 Scynexis, Inc. Cyclosporine derivative for use in the treatment of hcv and hiv infection
WO2010107739A2 (en) 2009-03-18 2010-09-23 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions of treating a flaviviridae family viral infection
US9150554B2 (en) 2009-03-27 2015-10-06 Presidio Pharmaceuticals, Inc. Fused ring inhibitors of hepatitis C
US9637512B2 (en) 2009-05-20 2017-05-02 Gilead Pharmasset Llc Nucleoside phosphoramidates
EP3321275A1 (en) 2009-05-20 2018-05-16 Gilead Pharmasset LLC Crystalline form of sofosbuvir
EP2610264A2 (en) 2009-05-20 2013-07-03 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production
US8633309B2 (en) 2009-05-20 2014-01-21 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9284342B2 (en) 2009-05-20 2016-03-15 Gilead Pharmasset Llc Nucleoside phosphoramidates
US8629263B2 (en) 2009-05-20 2014-01-14 Gilead Pharmasset Llc Nucleoside phosphoramidates
EP2910562A1 (en) 2009-05-20 2015-08-26 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2 '-fluoro-2'-methyl-p-phenyl-5 '-uridylyl]-l-alanine 1-methylethyl ester in crystalline form
WO2010135569A1 (en) 2009-05-20 2010-11-25 Pharmasset, Inc. N- [ (2 ' r) -2 ' -deoxy-2 ' -fluoro-2 ' -methyl-p-phenyl-5 ' -uridylyl] -l-alanine 1-methylethyl ester and process for its production
US8642756B2 (en) 2009-05-20 2014-02-04 Gilead Pharmasset Llc Nucleoside phosphoramidates
US9206217B2 (en) 2009-05-20 2015-12-08 Gilead Pharmasset Llc Nucleoside phosphoramidates
EP2913337A1 (en) 2009-05-20 2015-09-02 Gilead Pharmasset LLC N-[(2'r)-2'-deoxy-2'-fluoro-2'-methyl-p-phenyl-5'-uridylyl]-l-alanine 1-methylethyl ester and process for its production
WO2011058084A1 (en) 2009-11-14 2011-05-19 F. Hoffmann-La Roche Ag Biomarkers for predicting rapid response to hcv treatment
WO2011068715A1 (en) 2009-11-25 2011-06-09 Vertex Pharmaceuticals Incorporated 5-alkynyl-thiophene-2-carboxylic acid derivatives and their use for the treatment or prevention of flavivirus infections
WO2011067195A1 (en) 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Biomarkers for predicting sustained response to hcv treatment
WO2011079327A1 (en) 2009-12-24 2011-06-30 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119860A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119858A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119870A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011119853A1 (en) 2010-03-24 2011-09-29 Vertex Pharmaceuticals Incorporated Analogues for the treatment or prevention of flavivirus infections
WO2011123668A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Stereoselective synthesis of phosphorus containing actives
EP2752422A1 (en) 2010-03-31 2014-07-09 Gilead Pharmasset LLC Stereoselective synthesis of phosphorus containing actives
WO2011123645A2 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Nucleoside phosphoramidates
EP2609923A2 (en) 2010-03-31 2013-07-03 Gilead Pharmasset LLC Nucleoside Phosphoramidates
WO2011123672A1 (en) 2010-03-31 2011-10-06 Pharmasset, Inc. Purine nucleoside phosphoramidate
EP3290428A1 (en) 2010-03-31 2018-03-07 Gilead Pharmasset LLC Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
US8859756B2 (en) 2010-03-31 2014-10-14 Gilead Pharmasset Llc Stereoselective synthesis of phosphorus containing actives
US8877707B2 (en) 2010-05-24 2014-11-04 Presidio Pharmaceuticals, Inc. Inhibitors of HCV NS5A
WO2011159826A2 (en) 2010-06-15 2011-12-22 Vertex Pharmaceuticals Incorporated Hcv ns5b protease mutants
WO2012006055A2 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006060A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012006070A1 (en) 2010-06-28 2012-01-12 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flavivirus infections
WO2012024363A2 (en) 2010-08-17 2012-02-23 Vertex Pharmaceuticals Incorporated Compounds and methods for the treatment or prevention of flaviviridae viral infections
US8841275B2 (en) 2010-11-30 2014-09-23 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
US9394331B2 (en) 2010-11-30 2016-07-19 Gilead Pharmasset Llc 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections
WO2012107589A1 (en) 2011-02-11 2012-08-16 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment and prevention of hcv infections
WO2012123298A1 (en) 2011-03-11 2012-09-20 F. Hoffmann-La Roche Ag Antiviral compounds
WO2012175581A1 (en) 2011-06-24 2012-12-27 F. Hoffmann-La Roche Ag Antiviral compounds
WO2013016501A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Formulations of thiophene compounds
WO2013016491A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013016490A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013016492A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Thiophene compounds
WO2013016499A1 (en) 2011-07-26 2013-01-31 Vertex Pharmaceuticals Incorporated Methods for preparation of thiophene compounds
WO2013053657A1 (en) 2011-10-10 2013-04-18 F. Hoffmann-La Roche Ag Antiviral compounds
US9549941B2 (en) 2011-11-29 2017-01-24 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US9364484B2 (en) 2011-12-06 2016-06-14 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating viral diseases
US10869873B2 (en) 2011-12-06 2020-12-22 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating viral diseases
WO2013087743A1 (en) 2011-12-16 2013-06-20 F. Hoffmann-La Roche Ag Inhibitors of hcv ns5a
WO2013092447A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 4'-azido, 3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication
WO2013092481A1 (en) 2011-12-20 2013-06-27 F. Hoffmann-La Roche Ag 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication
US9108999B2 (en) 2011-12-20 2015-08-18 Riboscience Llc 2′, 4′-difluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9708357B2 (en) 2011-12-20 2017-07-18 Riboscience, LLC 4′-azido, 3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2013124335A1 (en) 2012-02-24 2013-08-29 F. Hoffmann-La Roche Ag Antiviral compounds
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog
WO2014006066A1 (en) 2012-07-06 2014-01-09 F. Hoffmann-La Roche Ag Triazole compounds as antivirals
WO2014114573A1 (en) 2013-01-23 2014-07-31 F. Hoffmann-La Roche Ag Antiviral triazole derivatives
WO2014134251A1 (en) 2013-02-28 2014-09-04 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions
WO2014135422A1 (en) 2013-03-05 2014-09-12 F. Hoffmann-La Roche Ag Antiviral compounds
WO2014148949A1 (en) 2013-03-22 2014-09-25 Асави, Ллс Alkyl 2-{[(2r,3s,5r)-5-(4-amino-2-oxo-2н-pyrimidin-1-yl)-3-hydroxy- tetrahydro-furan-2-yl-methoxy]-phenoxy-phosphoryl-amino}-propionates, nucleoside inhibitors of hcv ns5b rna-polymerase, and methods for producing and use thereof
US9895442B2 (en) 2013-05-16 2018-02-20 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9694028B2 (en) 2013-05-16 2017-07-04 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2014186637A1 (en) 2013-05-16 2014-11-20 Riboscience Llc 4'-fluor0-2'-methyl substituted nucleoside derivatives
US10953030B2 (en) 2013-05-16 2021-03-23 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US9249176B2 (en) 2013-05-16 2016-02-02 Riboscience Llc 4′-azido, 3′-deoxy-3′-fluoro substituted nucleoside derivatives as inhibitors of HCV RNA replication
US11116783B2 (en) 2013-08-27 2021-09-14 Gilead Pharmasset Llc Combination formulation of two antiviral compounds
US11707479B2 (en) 2013-08-27 2023-07-25 Gilead Sciences, Inc. Combination formulation of two antiviral compounds
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
US11351186B2 (en) 2017-09-21 2022-06-07 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
WO2023161427A1 (en) 2022-02-24 2023-08-31 Eisbach Bio Gmbh Viral combination therapy

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