WO2001007027A2 - Inhibiteurs d'helicase virale - Google Patents

Inhibiteurs d'helicase virale Download PDF

Info

Publication number
WO2001007027A2
WO2001007027A2 PCT/US2000/019650 US0019650W WO0107027A2 WO 2001007027 A2 WO2001007027 A2 WO 2001007027A2 US 0019650 W US0019650 W US 0019650W WO 0107027 A2 WO0107027 A2 WO 0107027A2
Authority
WO
WIPO (PCT)
Prior art keywords
viral
virus
compound
cor
halo
Prior art date
Application number
PCT/US2000/019650
Other languages
English (en)
Other versions
WO2001007027A3 (fr
Inventor
Michael Hale
Francois Maltais
Christopher Baker
James Janetka
Young Choon Moon
Jeffrey Saunders
Original Assignee
Vertex Pharmaceuticals Incorporated
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.)
Filing date
Publication date
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Priority to AU61110/00A priority Critical patent/AU6111000A/en
Publication of WO2001007027A2 publication Critical patent/WO2001007027A2/fr
Publication of WO2001007027A3 publication Critical patent/WO2001007027A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention is in the field of medicinal chemistry and relates to a method useful for inhibiting viral helicases, and in particular, the helicases of the flaviviridae, poxviridae, and papovaviridae family of viruses.
  • the method employs compounds and compositions useful for treating and preventing infections caused by these viruses which include hepatitis C, bovine viral diarrhea virus and vaccinia viruses.
  • Helicase encoding sequences have been identified in many viruses. These viral helicases have been suggested to catalyze the separation of double-stranded nucleic acid structures during transcription and genome replication [G. Kadare et al., J. Virol., 71, pp. 2583-2590 (1997)].
  • poliovirus a positive-stranded RNA virus of the Picornaviridae family
  • mutation of conserved sequence motifs in the 2C helicase inhibits virus replication and proliferation [C. Mirzayan et al . , Virology, 189, pp. 547-555 (1992)].
  • Similar mutational studies on the helicases encoded by herpes simplex virus type 1 and bovine papillo a virus also show that these enzymes are critical for virus replication [P.
  • HCV hepatitis C virus
  • the HCV genome encodes a polyprotein of 3010- 3033 amino acids [Choo, Q.-L., et al . "Genetic Organization and Diversity of the Hepatitis C Virus", Proc. Natl. Acad. Sci. USA, 88, pp. 2451- 2455 (1991); Kato, N. et al . , Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis", Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990); Takamizawa, A. et al .
  • the HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication.
  • the NS proteins are derived by proteolytic cleavage of the polyprotein [Bartentscher, R. et al . , "Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and
  • NS2 encodes a presumed metalloprotease
  • NS5B is a RNA-dependent RNA polymerase
  • NS3 is a bifunctional enzyme with a serine protease localized to the N-terminal 181 residues of the protein and a RNA helicase in the C- terminal 465 amino acids.
  • 4-Pyrimidinone derivatives covering a wide range of structures are known to have a variety of biological activities. Depending on the specific structure, compounds containing a 4-pyrimidinone moiety are reported to have immunomodulatory effects, and to be active, inter alia , against tumors, inflammatory disease, certain viruses, parasites and other pests (Wierenga, Pharmac . Ther. , 1985, 30, 67; Ram et al . , Eur. J. Med. Chem. , 1992, 27, 851; WO 98/24782; US Patent 5,149,810, and EP Publication No. 238059A3) .
  • R is methyl, CH 2 CN or CH 2 CONH 2 .
  • the present invention provides a method for inhibiting certain viral helicases and is thereby useful for controlling a virus that relies on such a helicase for viral replication.
  • the method comprises administering to a mammal infected with such virus a pharmaceutically acceptable composition comprising a compound of formula I:
  • R 1 , R 2 , R 3 , R 4 , X and T are as described below.
  • Preferred compounds are those where R 3 is an electro: withdrawing group such as halo, CN or C0 2 R. More preferred are those compounds where R 3 is an electro: withdrawing group and R 2 is OH, SH or Cl . Most preferred are those compounds where R 2 and R 3 are as just described and X is NH or S.
  • the present method is useful for inhibiting viral helicase activity in vivo and in vi tro, and is particularly useful for treating infections caused by poxviridae, papovaviridae or flaviviridae viruses such as hepatitis C, dengue, yellow fever, bovine viral diarrhea and vaccinia viruses .
  • the present invention provides a method for inhibiting certain viral helicases and is thereby useful for controlling a virus that encodes such a helicase in its genome.
  • the method is particularly useful for reducing infections in mammals caused by poxviridae, papovaviridae or flaviviridae viruses such as hepatitis C, dengue, yellow fever, bovine viral diarrhea and vaccinia viruses.
  • the method comprises administering to a mammal having such viral infection a pharmaceutically acceptable composition comprising a compound of formula I:
  • X is S or N(R 5 ) ; n is zero or 1;
  • T is a bond or a linker group
  • each R 1 is independently selected from R, phenyl, or Ht, wherein up to seven hydrogen atoms in R 1 are optionally and independently replaced by halo, R, OR, SR, OH, N0 2 , CN, N(R 5 ) 2 , NR 5 COR, NR 5 CON(R 5 ) 2 , NR 5 COR, NR 5 C0 2 R, C0 2 R, C0 2 H, COR, CON(R 5 ) 2 , S(0) 2 R, S0 2 N(R 5 ) 2 , S(0)R, or NR 5 S(0) 2 R;
  • R 3 is halo, CN, C0 2 R 1 , C0 2 H, COR 1 , CHO, C0N(R 5 ) 2 , S0 2 R 1 , S0 2 N(R ) 2 , N0 2 , or R substituted with one or more halo; each R 5 is independently selected from hydrogen, R, COR 1 , CO ⁇ R 1 , C0N(R) 2 , OR, or S(0) R 1 ; when ⁇ represents a single bond, the ring nitrogen attached to such bond is substituted by R 5 ; any N present may exist as the N oxide; and any heteroatom may be optionally substituted with a metabolically or chemically labile group for administration as a prodrug.
  • alkyl and alkoxy used alone or as part of a larger moiety shall include both straight and branched chains containing one to twelve carbon atoms.
  • alkenyl and alkynyl used alone or as part of a larger moiety shall include both straight and branched chains containing two to six carbon atoms.
  • haloalkyl means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • halogen means F, Cl, Br, or I.
  • heteroatom means N, 0 or S and shall include any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • Ht an "Ht” moiety may be attached to the rest of the compound of this invention at any endocyclic carbon or heteroatom which results in the creation of a stable structure.
  • Preferred “Ht” moieties are 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles.
  • Examples of such preferred moieties include imidazolyl, imidazolinoyl, imidazolidinyl , quinolyl, isoqinolyl, indolyl, indazolyl, indazolinolyl, perhydropyridazyl , pyridazyl, pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl , pyridazinyl, morpholinyl, thiamorpholinyl , furyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl , thiamorpholinyl sulfone, o
  • the compounds according to the invention may contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantio ers, diastereomeric mixtures and individual diastereomers . All such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereogenic carbon may be of the R or S configuration.
  • T may be a bond or a linker group.
  • a linker group is a group that connects two parts of the molecule.
  • any suitable linker having a length of one to eight atoms may be employed.
  • Suitable linkers also include, but are not limited to, straight or branched, saturated or unsaturated, hydrocarbon chains wherein up to three nonadjacent carbons and the hydrogens bound thereto are replaced by one or more W groups which may or may not be the same.
  • One embodiment of this invention relates to compounds where X is S, represented by formula IA below.
  • Preferred IA compounds are those compounds where R 1 is a phenyl substituted as described above. More preferred IA compounds are those where R 1 is a substituted phenyl and R 2 is OH, SH or Cl . Most preferred IA compounds are those where R 1 and R 2 are as just described and R 3 is halo, CN or C0 2 R 1 .
  • R 2 is OH or SH
  • keto-enol tautomerism is possible.
  • the relative amounts of specific tautomer present will vary depending on the structure of the compound and the chemical environment about the compound.
  • R 1 , R 2 , R 3 , and R 4 are as described above.
  • Examples of this embodiment are shown by compounds IB-1 and IB-2.
  • X is CH and T, R 1 , R 2 , R 3 , and R 4 are as described above.
  • An example of this embodiment is IC-1 where T is CH 2 CH 2 , R 1 is phenyl, R 2 is 0H,R 3 is CN and R 4 is 4-chlorophenyl .
  • R 2 is halo as exemplified by compound IA-21 below.
  • Preferred T groups are a bond, (CH 2 ) P , where p is one to three, CH 2 C0 2 CH 2 , or CH 2 C0NH.
  • R 3 groups are those groups that are known to be electron-withdrawing groups. Examples of such groups include CN, C0 2 R 1 , S0 2 R, COR, S0 2 N(R 5 ) , halo, and haloalkyl, preferably haloalkyl multiply substituted by fluorine such as CF 3 . Specific examples of compounds of this invention where R 3 is other than CN are IA-22 (R 3 is C0 2 CH 3 )and
  • the method of this invention may be carried out using a prodrug of any of the useful compounds described herein.
  • Prodrugs may be obtained in a number of ways that will be apparent to one skilled in the art.
  • the preparation generally involves attaching to the active compound a chemical moiety that is hydrolytically or metabolically labile in the mammalian system that will receive the compound.
  • Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds when such compounds are administered to the mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • compositions of this invention include, without limitation, carbamates, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
  • the compounds of this invention may be synthesized according to the synthetic schemes shown below and by methods analogous to those known in the art.
  • the intermediate (4) may be made through the acid catalyzed addition of an alcohol to cyanamide [F. Kurzer et al . , Org. Synth. , IV, p. 645 (1963)].
  • the compounds of this invention are designed to inhibit viral helicase, either directly or indirectly, and thereby inhibit the unwinding function of the helicase.
  • Viral helicases, and in particular the HCV NS3 helicase contain a binding site for ATP (which is cleaved by the ATPase activity of the helicase) and a separate binding site for double-stranded polynucleotide ⁇ (which are unwound by the unwinding activity of the helicase) .
  • the energy generated by cleavage of ATP is required for the unwinding activity. Therefore, the compounds of this invention can be assayed for their ability to inhibit ATP cleavage or to inhibit unwinding activity.
  • the compounds of this invention were designed to be helicase inhibitors of flaviviridae viruses, such as hepatitis C, dengue and yellow fever virus, and were found to be effective in this regard. They were also found to be particularly useful against viruses belonging to the poxviridae and papovaviridae family of viruses.
  • Poxviridae viruses include, but are not limited to, vaccinia virus.
  • Papovaviridae viruses include, but are not limited to, bovine viral diarrhea and human papilloma viruses .
  • This invention also provides a composition comprising a compound of this invention or a pharmaceutically acceptable salt thereof, as described above, and a pharmaceutically acceptable carrier.
  • salts of the compounds of this invention are preferably derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, peroxine salt, sodium sulfonate, sodium
  • Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others . Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides
  • compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial g
  • compositions of this invention are formulated for pharmaceutical administration to a mammal, preferably a human being.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3- butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as those described in Pharmacopeia Helvetica or similar alcohol .
  • the pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, beeswax and polyethylene glycols .
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs .
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents .
  • the amount of compound present in the above- described composition should be sufficient to cause a detectable decrease in ATPase activity and/or unwinding activity of a viral helicase, as measured by any of the assays described in the examples .
  • compositions of this invention may further comprise an anti-viral agent effective against hepatitis C virus infection.
  • agents include, but are not limited to, inhibitors of HCV NS3 protease, such as those described in WO 98/17679; inhibitors of HCV polymerase; IMPDH inhibitors, such as mycophenolic acid, mycophenolate mofetil, and those described in any of United States Patents 5,380,879; 5,441,953; 5,493,030; 5,633,279;
  • the amount of the anti-viral agent present in the compositions of this invention should be between 10-100% of the amount of that agent normally used in a monotherapy for anti-viral activity. Such amounts are known in the art and/or described in the patent applications referred to above.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of active ingredients will also depend upon the particular compound and anti-viral agent, if present, in the composition.
  • the invention provides a method of detecting viral helicase activity in a biological sample suspected of containing a polypeptide having viral helicase activity. This method comprising the steps of: a) contacting said biological sample with a compound of this invention; and b) detecting whether said compound binds to said biological sample.
  • biological sample includes cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • biological sample also includes living organisms, in which case "contacting a compound of this invention with a biological sample suspected of containing HCV NS3 helicase” is synonymous with the term “administrating said compound to the living organism.
  • polypeptide having viral helicase activity means any polypeptide which demonstrates activity in at least, but not limited to, the unwinding assay described below.
  • that term means a polypeptide encoded by a naturally occurring or an experimentally produced strain of virus or a polypeptide having a consensus amino acid sequence derived from polypeptides having the aforementioned activities encoded by two or more strains of the helicase-containing virus.
  • detecting viral helicase activity includes inhibiting the helicase activity, if present, in said sample; determining the presence or absence of the helicase activity in said sample; quantitating the helicase activity in said sample; and, in the case of a living organism, treating and/or reducing the severity of a viral infection caused by a virus that encodes a helicase in its genome. Each of these is clearly useful in diagnostic and therapeutic applications relating to such viruses .
  • the helicase to be detected is one encoded by the HCV genome.
  • the compounds and compositions of this invention may also be administered with one or more other anti-viral agents.
  • the patient if the patient is also administered another anti-viral agent, it may be delivered together with the compound of this invention in a single dosage form, or, as a separate dosage form.
  • the anti-viral agent may be administered prior to, at the same time as, or following administration of a pharmaceutically acceptable composition comprising a compound of this invention.
  • the compounds of this invention may be tested using the assays described in the Testing section below.
  • the standard 3 ' -tailed double-stranded RNA/RNA hybrid was prepared as described as follows. Two 32 nucleotide in length RNAs were synthesized and gel purified. The two RNA' were annealed such that the duplex RNA substrate has two 3 ' 15 nucleotide single stranded tails and a 21 base pair duplex region. Th duplex RNA substrate was 5' end-labeled with 33P? ATP on one strand with T4 polynucleotide kinase. The opposite strand contains a 5 ' -phosphate which has been incorporated during RNA synthesis. The labeled substrate was gel purified and diluted with cold duplex RNA substrate before use.
  • Standard helicase reactions (50 ⁇ l) were carried out as follows. HCV NS34A helicase (0.3 nM) was added to a mixture of 25 mM morpholinepropanesulfonic acid (MOPS) -NaOH (pH 7.5), 0.3 mM ATP, 0.3 mM MnCl2 , 1 mM dithiothreitol (DTT) , 0.05 mg of bovine serum albumin (BSA) per ml, and 18 nM of 3 ' -tailed double-stranded RNA/RNA hybrid substrate. Mixtures were incubated for 45 min at 37°C and stopped by the addition of 15 uL of 50 mM EDTA.
  • MOPS morpholinepropanesulfonic acid
  • DTT dithiothreitol
  • BSA bovine serum albumin
  • the assay conditions as outlined above may be applied to a Vaccinia virus unwinding assay by substituting the Vaccinia virus RNA helicase (NPH- II) for the HCV helicase (HCV NS34A) . See: Gross, C. H.; Shuman, S. Journal of Virology (1995) 69, 4727- 4736.
  • ATPase activity of HCV NS3 helicase in the presence or absence of inhibitor was monitored by following the rate of ADP production using a coupled enzyme assay.
  • an amount of NADH equal to ADP is oxidized to NAD + resulting in a decrease in absorbance at 340 nm.
  • a reaction mix consisting of buffer, pH 7.5, coupling enzyme components, poly(rU), and HCV NS3 helicase was prepared and aliquoted into wells. Various concentrations of inhibitor in DMSO were added to the wells and incubated for 20 minutes at 37°C.
  • reaction are as follows: 25 mM MOPS, pH 7.5, 0.3 mM MnCl 2 , 2.5mM PEP, 0.2 mM NADH, 20 ⁇ g/mL pyruvate kinase, 6.0 ⁇ g/mL lactate dehydrogenase, 0.5M poly(rU), 2 nM HCV NS34A helicase, 1.5% DMSO with varying concentrations of inhibitor, and 300 ⁇ M ATP.
  • ATPase activity of HCV helicase in the presence or absence of inhibitor was also measured by quantifying the ADP produced from ATP using an HPLC method.
  • a reaction mix consisting of buffer, pH 7.5, poly(rU) , and HCV NS34A helicase was prepared and aliquoted into wells. Various concentrations of inhibitor in DMSO were added to the wells and incubated for 20 minutes at 37°C. Reactions were initiated with ATP.
  • the final concentrations of assay components in 200 ⁇ l reaction are as follows: 25 mM MOPS, pH 7.5 , 0.3 mM MnCl 2 ,0.5 ⁇ M poly(rU), 2 nM HCV NS34A Helicase, 1.5%DMS0 with varying concentrations of inhibitor, and 300 ⁇ M ATP.
  • MDBK (ATCC CCL-22) cells are cultured as adherent monolayers in DMEM, 2mM L-glutamine, 0. ImM non-essential amino acids, ImM sodium pyruvate and 10% donor horse serum (DHS) at 37°C with approximately 5% C0 2 .
  • DHS donor horse serum
  • bovine kidney cells are used to seed 96 well flat bottom tissue culture plates at a density of 3-4 x 10 4 cells/well (100 ⁇ L/well of 3-4 x 10 5 cells/ml) .
  • One 96 well plate is seeded for each compound tested and cells are allowed to adhere overnight. This serves as the "assay plate” .
  • the cell culture media is decanted from the 96 well plates the following day and half of the total number of wells are subsequently infected with 50 ⁇ L of an appropriate dilution of Bovine Viral Diarrhea Virus, BVDV, (ATCC VR-1422) that exhibits the majority of CPE approximately 65-72 hours post infection (for the virus stock currently in use, the dilution is 1:600).
  • BVDV Bovine Viral Diarrhea Virus
  • the BVDV is diluted in a "Viral Dilution Buffer" that consists of the MDBK cell culture media lacking the DHS.
  • the uninfected wells are mock infected with 50 ⁇ L of this buffer as well. Before the addition of compound, infection is allowed to proceed for at least 1 hour at 37°C with approximately 5% CO 2 .
  • the compounds are diluted. Each compound is first serial diluted as 100 X in 100% tissue culture grade DMSO for a total of seven concentrations for each compound assayed. An eighth mock dilution, consisting of DMSO only, is also prepared for each assay plate as a no-compound control. Secondly, the 100 X 100% DMSO serial and mock dilutions are further diluted 1:13.3 in a "Compound Dilution Buffer" that consists of the MDBK cell culture media supplemented with only 2% DHS. This second and final dilution provides a series of compound concentrations existing as 7.5X in 7.5% DMSO as well as a 7.5% DMSO control.
  • both the infected and mock-infected MDBK cells are supplemented with 80 ⁇ L of "Compound Dilution Buffer". Each well at this point should have 130 ⁇ L. 20 ⁇ L of each 7.5X 7.5% DMSO compound concentrations are added to separate wells for a final IX concentration in 1% DMSO.
  • each assay plate consists of 7 compound dilutions and 1 no-compound control, in triplicate, on both infected and mock infected wells (48 wells total) .
  • the mock-infected wells serve as indicators of cytotoxicity.
  • MTS reagent Promega CellTiter 96® Aq ue0us Non-Radioactive Cell Proliferation Assay
  • 30 ⁇ L of MTS reagent is added to each well. Incubation proceeds for approximately 4 hours at 37°C with 5% C0 2 at which time absorbance is read with a Spectra MAX 190 microplate spectrophotometer at 490 nm with background correction at 650 nm.
  • IC50, CC50 and TI are determined via analysis with Softmax Pro software. 3 wells containing identical assay conditions in the absence of cells and compound serve as an absorbance background that is subtracted from all the samples prior to analysis.
  • Protocol Use sterile technique for all manipulations, following BL2 level guidelines.
  • Day 1 From a subconfluent tissue culture flask (approximately 70-90% confluent) , seed 100 ⁇ L of 3-4 x 10 5 MDBK cells/ml in a 96 well flat bottom tissue culture plate (rinse monolayer with PBS prior to trypsinization to eliminate any cell debris) .
  • This plate will serve as the 100X 100% DMSO compound dilution scheme (i.e. "dilution plate # 1").
  • This plate will serve as the 1:13.3 dilution scheme for the final 7.5X 7.5% compound concentrations (i.e. "dilution plate # 2").
  • Multiple compounds, eight readily, can be diluted in each plate simultaneously with a BIOHIT multichannel pipettor or equivalent.
  • the format used was a 6-well plate. Data points were obtained in duplicate or triplicate.
  • Vero cells per well using a medium of EMEM with 10%
  • FCS non-essential amino acids
  • pyruvate glutamine
  • HSV Cytotoxicity Assay
  • Table 3 The testing results in the BVDV Cell Culture Assay are shown in Table 3 below for selected compounds.
  • values designated "D” represent an IC 50 or CC 50 , as the case may be, of less than 20 ⁇ M;
  • E represents an IC 50 or CC 50 of between 20 and 40 ⁇ M;
  • F represents an IC 50 or CC 50 of between 40 and 80 ⁇ M;
  • G represents an IC 50 or CC 50 of > 80 ⁇ M. It is important to note the difference between the type of data presented in this table as compared to Table 2.
  • Table 3 shows the cellular potency which may be interpreted as a combination of cellular penetration and inhibition.
  • HSV-1 Herpes simplex virus-1
  • the compounds tested were found to be relatively inactive in this assay.
  • compounds IA-10, IA-11, IA-12 and IB-20 had IC50 values in this assay of greater than 20 ⁇ M. While the compounds of this invention are active against Hepatitis C virus, bovine viral diarrhea virus and/or vaccinia virus, the HSV test shows that the compounds are not active against all viruses.

Abstract

La présente invention concerne une méthode permettant d'inhiber les hélicases virales, et notamment l'hélicase NS3 du virus de l'hépatite C. Cette méthode utilise des compositions de formule (I), dans laquelle R?1, R2, R3, R4¿, X et T sont tels que définis dans le descriptif. Les composés préférés sont ceux dans lesquels R3 est un groupe preneur d'électrons, tel que halo, CN ou CO¿2R?1. De préférence, R3 est un groupe preneur d'électrons et R2 est OH. Idéalement, R2 et R3 sont tels que définis ci-dessus, X étant S. Plus particulièrement, les compositions et les méthodes de cette invention sont utilisées dans le traitement de maladies provoquées par le virus de l'hépatite C, le virus de la diarrhée virale bovine ou le virus de la vaccine.
PCT/US2000/019650 1999-07-22 2000-07-19 Inhibiteurs d'helicase virale WO2001007027A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61110/00A AU6111000A (en) 1999-07-22 2000-07-19 Inhibitors of viral helcase

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US14519399P 1999-07-22 1999-07-22
US60/145,193 1999-07-22
US15078399P 1999-08-26 1999-08-26
US60/150,783 1999-08-26

Publications (2)

Publication Number Publication Date
WO2001007027A2 true WO2001007027A2 (fr) 2001-02-01
WO2001007027A3 WO2001007027A3 (fr) 2001-08-09

Family

ID=26842750

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/019650 WO2001007027A2 (fr) 1999-07-22 2000-07-19 Inhibiteurs d'helicase virale

Country Status (2)

Country Link
AU (1) AU6111000A (fr)
WO (1) WO2001007027A2 (fr)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019225A1 (fr) * 2003-08-21 2005-03-03 Kyorin Pharmaceutical Co., Ltd. Procede de production d'un compose presentant un antagonisme par rapport au recepteur nk1 et production d'un intermediaire de celui-ci
WO2007047146A2 (fr) * 2005-10-11 2007-04-26 Intermune, Inc. Inhibiteurs de réplication virale
US7223769B2 (en) 2002-03-12 2007-05-29 Sumitomo Chemical Company, Limited Pyrimidine compounds and their use as pesticides
WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
WO2008061740A1 (fr) * 2006-11-23 2008-05-29 Novartis Ag Pyrimidines et leur utilisation comme antagonistes du récepteur cxcr2
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
WO2010022121A1 (fr) * 2008-08-20 2010-02-25 Schering Corporation Dérivés de pyridine et pyrimidine substituées et leur utilisation dans le traitement d'infections virales
US7732448B2 (en) 2003-05-12 2010-06-08 Sumitomo Chemical Company, Limited Pyrimidine compounds and pests controlling composition containing the same
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
WO2012113920A1 (fr) 2011-02-24 2012-08-30 Katholieke Universiteit Leuven Dérivés d'arylsulfone agissant contre les virus de béta-herpès humains
US8268990B2 (en) 2007-11-22 2012-09-18 Astrazeneca Ab Compounds
JP2013508299A (ja) * 2009-10-16 2013-03-07 リブ−エックス ファーマシューティカルズ，インコーポレイテッド 抗微生物性化合物および抗微生物性化合物の製造方法および使用方法
US8440681B2 (en) 2007-08-28 2013-05-14 Irm Llc 2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors
US8445505B2 (en) 2008-06-25 2013-05-21 Irm Llc Pyrimidine derivatives as kinase inhibitors
US8470834B2 (en) 2008-08-20 2013-06-25 Merck Sharp & Dohme Corp. AZO-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8476288B2 (en) 2009-05-21 2013-07-02 Astrazeneca Ab Salts 756
US8519129B2 (en) 2008-06-25 2013-08-27 Irm Llc Pyrimidine derivatives as kinase inhibitors
US8541434B2 (en) 2008-08-20 2013-09-24 Merck Sharp & Dohme Corp. Ethynyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8715638B2 (en) 2008-08-20 2014-05-06 Merck Sharp & Dohme Corp. Ethenyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
US9376398B2 (en) 2012-05-18 2016-06-28 Sumitomo Dainippon Pharma Co., Ltd Carboxylic acid compounds
US9533978B2 (en) 2009-05-21 2017-01-03 Sumitomo Dainippon Pharma Co., Ltd Pyrimidine derivatives and their use in the treatment of cancer and further diseases
CN106496190A (zh) * 2016-10-18 2017-03-15 北京瑞济善健康科技有限公司 新型ns5b抑制剂及其用途
CN107951887A (zh) * 2016-10-18 2018-04-24 李文超 一种抗病毒药物
CN107954983A (zh) * 2016-10-18 2018-04-24 陈利华 嘧啶酮类化合物及其用途
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308272A (en) * 1980-10-03 1981-12-29 The Upjohn Company Process for treating hypertension
GB2158068A (en) * 1984-04-26 1985-11-06 Aston Molecules Ltd Pyrimidine derivative solvate compounds
US5256668A (en) * 1993-03-17 1993-10-26 American Home Products Corporation Aminopyrimidine derivatives as antiviral agents for respiratory syncytial virus
WO1996010565A1 (fr) * 1994-10-04 1996-04-11 Istituto Superiore Di Sanita' 6-benzyl-4-oxopyrimidines substituees, leur procede de preparation et compositions pharmaceutiques les contenant
WO1996041634A2 (fr) * 1995-06-13 1996-12-27 Sardinian Antiviral Research Consortium - Sarc S.C.R.L. Utilisation d'un inhibiteur de transcriptase inverse non-nucleosidique en association avec des inhibiteurs de nucleosides pour le traitement d'infections a vih
WO1997006804A1 (fr) * 1995-08-19 1997-02-27 Glaxo Group Limited Analogues de nucleosides 1,3-oxathiolane utilises dans le traitement de l'hepatite c
WO2000003998A1 (fr) * 1998-07-17 2000-01-27 Novirio Pharmaceuticals Limited 6-benzyl-4-oxopyrimidines substitues, procede pour leur preparation et compositions pharmaceutiques les contenant
WO2000013708A1 (fr) * 1998-09-04 2000-03-16 Viropharma Incorporated Methodes de traitement ou de prevention des infections virales et des maladies associees

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4308272A (en) * 1980-10-03 1981-12-29 The Upjohn Company Process for treating hypertension
GB2158068A (en) * 1984-04-26 1985-11-06 Aston Molecules Ltd Pyrimidine derivative solvate compounds
US5256668A (en) * 1993-03-17 1993-10-26 American Home Products Corporation Aminopyrimidine derivatives as antiviral agents for respiratory syncytial virus
WO1996010565A1 (fr) * 1994-10-04 1996-04-11 Istituto Superiore Di Sanita' 6-benzyl-4-oxopyrimidines substituees, leur procede de preparation et compositions pharmaceutiques les contenant
WO1996041634A2 (fr) * 1995-06-13 1996-12-27 Sardinian Antiviral Research Consortium - Sarc S.C.R.L. Utilisation d'un inhibiteur de transcriptase inverse non-nucleosidique en association avec des inhibiteurs de nucleosides pour le traitement d'infections a vih
WO1997006804A1 (fr) * 1995-08-19 1997-02-27 Glaxo Group Limited Analogues de nucleosides 1,3-oxathiolane utilises dans le traitement de l'hepatite c
WO2000003998A1 (fr) * 1998-07-17 2000-01-27 Novirio Pharmaceuticals Limited 6-benzyl-4-oxopyrimidines substitues, procede pour leur preparation et compositions pharmaceutiques les contenant
WO2000013708A1 (fr) * 1998-09-04 2000-03-16 Viropharma Incorporated Methodes de traitement ou de prevention des infections virales et des maladies associees

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANTONELLO MAI ET AL: "5-ALKYL-2-ALKYLTHIO-6-(2,6-DIHALOPHENYLME THYL)-3,4-DIHYDROPYRIMIDIN-4 (3H)-ONES" JOURNAL OF MEDICINAL CHEMISTRY,AMERICAN CHEMICAL SOCIETY. WASHINGTON,US, vol. 42, 25 February 1999 (1999-02-25), pages 619-627, XP002123507 ISSN: 0022-2623 *
DALE A. STRINGFELLOW ET AL: "5-HALO-6- PHENYL PYRIMIDINES: A NEW SERIES OF INTERFERON- INDUCING AGENTS" INTERFERON: PROP. CLIN. USES, 1980, pages 315-326, XP000979815 *
LI, L. H. ET AL: "Effect of mouse hepatitis virus infection on combination therapy of P388 leukemia with cyclophosphamide and pyrimidinones" LAB. ANIM. SCI. (1987), 37(1), 41-4 , XP002159448 *
MAI A ET AL: "SYNTHESIS AND ANTI-HIV-1 ACTIVITY OF THIO ANALOGUES OF DIHYDROALKOXYBENZYLOXOPYRIMIDINES" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 38, no. 17, 1995, pages 3258-3263, XP000578131 ISSN: 0022-2623 *
RENIS, H. E. ET AL: "Protection of mice from herpes simplex virus infection by 5-halo-6-aryl-isocytosines" CURR. CHEMOTHER. INFECT. DIS., PROC. INT. CONGR. CHEMOTHER., 11TH (1980), MEETING DATE 1979, VOLUME 2, 1411-13. EDITOR(S): NELSON, JOHN D.;GRASSI, CARLO. PUBLISHER: AM. SOC. MICROBIOL., WASHINGTON, D. C. , XP000981311 *
WEED S D ET AL: "ANTI VIRAL PROPERTIES OF 6 ARYL PYRIMIDINES" CURR. CHEMOTHER. INFECT. DIS., 1980, pages P1408-1409, XP000981310 *

Cited By (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7223769B2 (en) 2002-03-12 2007-05-29 Sumitomo Chemical Company, Limited Pyrimidine compounds and their use as pesticides
US7973028B2 (en) 2003-05-12 2011-07-05 Sumitomo Chemical Company, Limited Pyrimidine compound and pests controlling composition containing the same
US7928110B2 (en) 2003-05-12 2011-04-19 Sumitomo Chemical Company, Limited Pyrimidine compound and pests controlling composition containing the same
US8129526B2 (en) 2003-05-12 2012-03-06 Sumitomo Chemical Company, Limited Pyrimidine compound and pests controlling composition containing the same
US7732448B2 (en) 2003-05-12 2010-06-08 Sumitomo Chemical Company, Limited Pyrimidine compounds and pests controlling composition containing the same
US7968537B2 (en) 2003-05-12 2011-06-28 Sumitomo Chemical Company, Limited Pyrimidine compound and pests controlling composition containing the same
WO2005019225A1 (fr) * 2003-08-21 2005-03-03 Kyorin Pharmaceutical Co., Ltd. Procede de production d'un compose presentant un antagonisme par rapport au recepteur nk1 et production d'un intermediaire de celui-ci
EP2206715A1 (fr) 2004-02-24 2010-07-14 Japan Tobacco, Inc. Composé héterotétracycliques fusionnés et leur utilisation en tant qu'inhibiteurs de la polymérase du HCV
US7977331B1 (en) 2004-02-24 2011-07-12 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor
US7659263B2 (en) 2004-11-12 2010-02-09 Japan Tobacco Inc. Thienopyrrole compound and use thereof as HCV polymerase inhibitor
WO2007047146A2 (fr) * 2005-10-11 2007-04-26 Intermune, Inc. Inhibiteurs de réplication virale
WO2007047146A3 (fr) * 2005-10-11 2007-11-01 Intermune Inc Inhibiteurs de réplication virale
WO2007119889A1 (fr) 2006-04-18 2007-10-25 Japan Tobacco Inc. Nouveau compose de piperazine et son utilisation en tant qu'inhibiteur de la polymerase du vhc
WO2008061740A1 (fr) * 2006-11-23 2008-05-29 Novartis Ag Pyrimidines et leur utilisation comme antagonistes du récepteur cxcr2
US8440681B2 (en) 2007-08-28 2013-05-14 Irm Llc 2-biphenylamino-4-aminopyrimidine derivatives as kinase inhibitors
US8765939B2 (en) 2007-11-22 2014-07-01 Astrazeneca Ab Pyrimidline derivatives having immune modulating properties that act via TLR7 for the treatment of viral or allergic diseases and cancers
US8268990B2 (en) 2007-11-22 2012-09-18 Astrazeneca Ab Compounds
US8445505B2 (en) 2008-06-25 2013-05-21 Irm Llc Pyrimidine derivatives as kinase inhibitors
US8859574B2 (en) 2008-06-25 2014-10-14 Irm Llc Compounds and compositions as kinase inhibitors
US8519129B2 (en) 2008-06-25 2013-08-27 Irm Llc Pyrimidine derivatives as kinase inhibitors
JP2015129153A (ja) * 2008-08-20 2015-07-16 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 置換ピリジン誘導体および置換ピリミジン誘導体ならびにそれらのウイルス感染の治療における使用
WO2010022121A1 (fr) * 2008-08-20 2010-02-25 Schering Corporation Dérivés de pyridine et pyrimidine substituées et leur utilisation dans le traitement d'infections virales
US8541434B2 (en) 2008-08-20 2013-09-24 Merck Sharp & Dohme Corp. Ethynyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8697694B2 (en) 2008-08-20 2014-04-15 Merck Sharp & Dohme Corp. Substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8715638B2 (en) 2008-08-20 2014-05-06 Merck Sharp & Dohme Corp. Ethenyl-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
JP2012500278A (ja) * 2008-08-20 2012-01-05 シェーリング コーポレイション 置換ピリジン誘導体および置換ピリミジン誘導体ならびにそれらのウイルス感染の治療における使用
US8470834B2 (en) 2008-08-20 2013-06-25 Merck Sharp & Dohme Corp. AZO-substituted pyridine and pyrimidine derivatives and their use in treating viral infections
US8476288B2 (en) 2009-05-21 2013-07-02 Astrazeneca Ab Salts 756
US9533978B2 (en) 2009-05-21 2017-01-03 Sumitomo Dainippon Pharma Co., Ltd Pyrimidine derivatives and their use in the treatment of cancer and further diseases
JP2013508299A (ja) * 2009-10-16 2013-03-07 リブ−エックス ファーマシューティカルズ，インコーポレイテッド 抗微生物性化合物および抗微生物性化合物の製造方法および使用方法
US10391094B2 (en) 2010-11-07 2019-08-27 Impact Biomedicines, Inc. Compositions and methods for treating myelofibrosis
US9045472B2 (en) 2010-12-16 2015-06-02 Astrazeneca Ab Imidazoquinoline compounds
WO2012113920A1 (fr) 2011-02-24 2012-08-30 Katholieke Universiteit Leuven Dérivés d'arylsulfone agissant contre les virus de béta-herpès humains
US9376398B2 (en) 2012-05-18 2016-06-28 Sumitomo Dainippon Pharma Co., Ltd Carboxylic acid compounds
US11299465B2 (en) 2012-05-18 2022-04-12 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US10150743B2 (en) 2012-05-18 2018-12-11 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
US10562861B2 (en) 2012-05-18 2020-02-18 Sumitomo Dainippon Pharma Co., Ltd. Carboxylic acid compounds
CN106496190A (zh) * 2016-10-18 2017-03-15 北京瑞济善健康科技有限公司 新型ns5b抑制剂及其用途
CN107951887A (zh) * 2016-10-18 2018-04-24 李文超 一种抗病毒药物
CN107954983A (zh) * 2016-10-18 2018-04-24 陈利华 嘧啶酮类化合物及其用途

Also Published As

Publication number Publication date
WO2001007027A3 (fr) 2001-08-09
AU6111000A (en) 2001-02-13

Similar Documents

Publication Publication Date Title
WO2001007027A2 (fr) Inhibiteurs d'helicase virale
US6316492B1 (en) Methods for treating or preventing viral infections and associated diseases
AU751201B2 (en) Methods for treating or preventing viral infections and associated diseases
JP4558314B2 (ja) ウイルスポリメラーゼインヒビター
EP1414441B1 (fr) Inhibiteurs de polymerase virale
Borowski et al. Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy
CN101277950B (zh) 丝氨酸蛋白酶抑制剂
Pfefferkorn et al. Inhibitors of HCV NS5B polymerase. Part 1: Evaluation of the southern region of (2Z)-2-(benzoylamino)-3-(5-phenyl-2-furyl) acrylic acid
US20120114604A1 (en) Combinations for HCV Treatment
WO2000024725A1 (fr) Composes pentacycliques utiles en tant qu'inhibiteurs de l'helicase de ns3 du virus de l'hepatite c
US8187874B2 (en) Drug discovery method
KR20010099623A (ko) 바이러스 감염 및 관련 질병을 치료 또는 예방하는화합물, 조성물 및 방법
WO2011031934A1 (fr) Inhibiteurs du virus de l'hépatite c
Das et al. Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors
WO2024037520A1 (fr) Composé amide et son procédé de préparation, composition pharmaceutique et utilisation associée
US20230120707A1 (en) Compounds and Method of Treating COVID-19
KR20080031281A (ko) 락탐을 함유하는 ｈｃｖ 억제제
Watkins Evolution of HCV NS5B non-nucleoside inhibitors
JP4663733B2 (ja) 抗ウイルス物質としての置換５−オキソピラゾールおよび置換［１，２，４］トリアゾール
Manfredini et al. Hindered nucleoside analogs as antiflaviviridae agents
EP3050871B1 (fr) Nouveau dérivé de bis-amide et son utilisation
CN101541748A (zh) 治疗丙型肝炎的方法
Shi et al. Dengue drug discovery
Yu et al. Discovery and development of hepatitis C virus inhibitors targeting the NS5A protein
Belema et al. Discovery and clinical validation of HCV inhibitors targeting the NS5A protein

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP