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WO2010083645A1 - Pyrimido[5,4-e][1,2,4]triazines et leurs utilisations - Google Patents

Pyrimido[5,4-e][1,2,4]triazines et leurs utilisations Download PDF

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Publication number
WO2010083645A1
WO2010083645A1 PCT/CN2009/070252 CN2009070252W WO2010083645A1 WO 2010083645 A1 WO2010083645 A1 WO 2010083645A1 CN 2009070252 W CN2009070252 W CN 2009070252W WO 2010083645 A1 WO2010083645 A1 WO 2010083645A1
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WO
WIPO (PCT)
Prior art keywords
pyrimido
triazin
phenyl
fluoro
amine
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2009/070252
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English (en)
Inventor
Ben Li
Li Chen
Renhai Chen
Peibin Zhai
Dean Cameron Baylis
Jonathan Coates
John Deadman
Eric Jones
David Rhodes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tali Digital Ltd
SHANGHAI TARGETDRUG CO Ltd
Original Assignee
Avexa Ltd
SHANGHAI TARGETDRUG CO Ltd
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Filing date
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Priority to PCT/CN2009/070252 priority Critical patent/WO2010083645A1/fr
Publication of WO2010083645A1 publication Critical patent/WO2010083645A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to novel pyrimido[5,4-e][l,2,4]triazine compounds and analogues thereof for the treatment of viral infections, particularly HCV infections.
  • the hepatitis C virus is an RNA virus that belongs to the family flaviviridae. HCV replicates in the cytoplasm of hepatocytes, but is not directly cytopathic. In -70% of cases, HCV causes a persistent infection that appears to rely on rapid production of virus and continuous cell-to-cell spread, along with a lack of vigorous T-cell immune response to HCV antigens.
  • the HCV turnover rate can be quite high with replication ranging between 10 10 to 10 12 virions per day, and a predicted viral half-life of 2 to 3 hours.
  • HCV Hepatitis C virus
  • HCV replication can be described as follows.
  • the virus attaches to a susceptible host cell via a specific receptor and the entire HCV genome is posited into the host cell cytoplasm and then translated into a single polyprotein which is then cleaved into the mature proteins.
  • Complementary (-)strand RNA is synthesized by the non- structural protein components of the proteo lyrically processed polyprotein and is used as a template for genomic progeny RNA synthesis. Assembly of the progeny HCV is thought to occur during budding, characteristically into cytoplasmic vacuoles rather than at the cell surface. Release occurs often without the imminent destruction of the infected cell.
  • NS5B gene-product which is an RNA-dependent RNA polymerase (RdRp) that catalyzes the replication of HCV.
  • RdRp RNA-dependent RNA polymerase
  • the enzyme is a prime target in the search for inhibitors of HCV replication and a variety of in vitro assays for HCV NS5B polymerase activity have been developed.
  • Specific inhibitors of the HCV polymerase identified from screening campaigns using the NS5B polymerase can be broadly classified as either non-nucleoside compounds that may affect an initiation step or nucleoside analogs that may inhibit polymerase elongation.
  • soluble forms of the NS5B protein have been crystallized to reveal an X-ray derived structure similar to other polymerases, but with an encircled active site.
  • Recent X-ray derived structures of compounds bound to NS5B reveal a variety of potentially distinct inhibitor pockets, many of which localize to the thumb domain.
  • HCV RNA polymerase also known as the NS5B gene-product or HCV NS5B polymerase
  • genotypes There are six known genotypes (numbered 1 through 6) and more than 50 subtypes (e.g., Ia, Ib, 2a). Frequent HCV mutations and numerous subtypes have made the search for specifically targeted antiviral agents with a high genetic barrier to selection of resistance challenging.
  • Genotype 1 is the most common in the United States (about 75 percent of cases). Genotypes 2 and 3 are present in only 10 to 20 percent of patients. Patients with genotypes 2 and 3 have a high response rate to treatment (approximately 75% success) whereas genotype 1 shows a lower rate of response to combination therapy (45 %) and requires a longer course of treatment.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • Ri is selected from the group consisting of H, C 1-10 alkyl, aryl and heteroaryl;
  • each R 2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 3 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 4 and R 5 is independently selected from the group consisting of H, C 1-10 alkyl, Ci.iocycloalkyl, C 1-3 alkylaryl, and aryl; or
  • each R 7 is independently selected from the group consisting of H, Ci_i O alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 8 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 9 and Ri 0 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, and aryl; or
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.
  • a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof wherein:
  • Ri is selected from the group consisting of H, C 1-10 alkyl, aryl and heteroaryl;
  • each R 2 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 3 is independently selected from the group consisting of H, Ci_ioalkyl, Ci_iocycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 4 and R 5 is independently selected from the group consisting of H, C 1-10 alkyl, Ci.iocycloalkyl, C 1-3 alkylaryl, and aryl; or
  • each R 7 is independently selected from the group consisting of H, Ci_i O alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, aryl;
  • each R 8 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, halo, aryl;
  • each R 9 and Ri 0 is independently selected from the group consisting of H, C 1-10 alkyl, Ci_i 0 cycloalkyl, Ci_ 3 alkylaryl, and aryl; or
  • Ri is selected from the group consisting of aryl and heteroaryl.
  • Ri is optionally substituted phenyl.
  • the phenyl is substituted with one or more substituents independently selected from halo (more preferably fluoro), methoxy, and NHC(O)CH 3 .
  • Ri is 4-fluorophenyl.
  • Ri is 3,4-dimethoxyphenyl.
  • A is OR 2 wherein R 2 is methyl.
  • A is NR 4 R 5 .
  • R 4 is H and R 5 is Ci_i O alkyl.
  • R 4 is H and R5 is optionally substituted benzyl.
  • the one or more optional substituents are independently selected from the group consisting of halo (more preferably fluoro), SO 2 NH 2 , S O 2 NH(Ci. C 3 alky 1), and S O 2 N(Ci. C 3 alky I) 2
  • the heterocycle is selected from the group consisting of morpholine, piperidine,, and piperazine.
  • the compound of formula I is a compound of formula II or III, wherein Ri, A, R9, Rio and Ri 2 are as defined above.
  • halo or halogen refers to fluorine (fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo).
  • alkyl either used alone or in compound terms such as NH(alkyl) or N(alkyl) 2 , refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, or 1 to 10 carbon atoms as appropriate.
  • suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 2-, 3- or 4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-methylpentyl.
  • cycloalkyl refers to cyclic hydrocarbon groups. Suitable cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • aryl refers to a C 6 -CiO aromatic hydrocarbon group, for example phenyl or naphthyl.
  • alkylaryl includes, for example, benzyl.
  • heterocycle when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3 _ 6 ,wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue.
  • Suitable heteroatoms include, O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • Suitable examples of heterocyclic groups may include pyrrolidinyl, piperidyl, piperazinyl, morpholino, quinolinyl, isoquinolinyl, thiomorpholino, dioxanyl,
  • heteroaryl includes a 5- or 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S.
  • Suitable examples of heteroaryl groups include furanyl, thiophenyl, tetrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazolyl, oxadiazolyl etc.
  • the heteroaromatic ring may be fused to a 5- or 6-membered aromatic or heteroaromatic ring to form a bicyclic aromatic ring system eg benzofuran.
  • each alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl group may be optionally substituted with one or more of Ci-C 3 alkyl, C 3 -C 6 cycloalkyl, C 6 aryl, heterocyclyl, heteroaryl, d-C 3 alkylOH, alkylaryl, OH, OCi-C 3 alkyl, halo, CN, NO 2 , CO 2 H, CO 2 Ci_C 3 alkyl, CONH 2 , CONH(C i_C 3 alkyl), CON(C i_C 3 alkyl) 2 , NHCO(C i_C 3 alkyl), trifluoromethyl, NH 2 , NH(Ci_C 3 alkyl), N(Ci_C 3 alkyl) 2 , SO 2 NH 2 , S O 2 NH(Ci.
  • an optionally substituted aryl group may be 4-methylphenyl or 4-hydroxyphenyl group, and an optionally substituted alkyl group may be 2-hydroxyethyl, trifluoromethyl, or difluoromethyl.
  • Each optional alkyl, cycloalkyl, alkylaryl, aryl, heterocyclyl, or heteroaryl substituent may also be optionally substituted.
  • optional substituents also include suitable nitrogen protecting groups (see “Protective Groups in Organic Synthesis” Theodora Greene and Peter Wuts, third edition, Wiley Interscience, 1999).
  • salts of the compound of formula I are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • pharmaceutically acceptable derivative may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula I or an antibacterially active metabolite or residue thereof.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
  • pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, n
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
  • Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates like dimethyl and diethyl sulfate; and others.
  • This invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I.
  • This invention also encompasses methods of treating or preventing a viral infection in a subject by administering prodrugs of compounds of the formula I.
  • Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, hydroxy and carboxylic acid groups of compounds of formula I.
  • the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
  • Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain.
  • Prodrugs also include phosphate derivatives of compounds of formula I (such as acids, salts of acids, or esters) joined through a phosphorus-oxygen bond to a free hydroxyl of compounds of formula I.
  • the compounds of formula I may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form.
  • the invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof.
  • Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution.
  • the compound is selcted from one of the following compounds:
  • the compound is selected from the compounds set out below:
  • the present invention provides a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof.
  • a compound according to the first aspect or a pharmaceutically acceptable derivative, salt or prodrug thereof, or a composition according to the fourth aspect in the preparation of a medicament for the treatment or prophylaxis of a viral infection in a subject.
  • the term "effective amount” means the amount of the subject composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • treatment does not necessarily mean that the viral infection is completely cured.
  • treatment encompasses any reduction in the viral load and/or inhibition of replication in the subject being treated.
  • the compounds of the present invention may be administered by any suitable means, for example, parenterally, such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • parenterally such as by subcutaneous, intravenous, intramuscular, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions).
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the subject is a human being, whether male or female.
  • the viral infection of the second and third aspects is a HCV infection.
  • the present invention provides pharmaceutical composition
  • a pharmaceutically acceptable carrier, diluent or excipient comprising a compound according to the first aspect and a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions of the present invention may contain other therapeutic agents as described below, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
  • compositions include those for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compounds of the invention may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids as solutions, suspensions, emulsions, elixirs or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • 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-butane diol.
  • the 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 diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions and methods of the present invention may further comprise other therapeutically active compounds which are usually applied in the treatment of the above mentioned pathological conditions.
  • Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles.
  • the combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
  • an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0..5 to 5 or 5 to 50 mg/kg per day.
  • compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • N'-(2-chloro-5-nitropyrimidin-4-yl)benzohydrazide (0.2Og, 0.68 mmol) was added in small portions to the mixture of sodium methoxide (0.11 g, 2.04 mmol) and methanol (5 mL). After the reaction mixture was refluxed for 2 h the mixture was filtered, concentrated and subjected to flash chromatography to afford a brown solid (0.12 g, 61%).
  • Step D 7-Methoxy-3-phenyl-l ,2-dihydropyrimido[5,4-e] [ 1 ,2,4]triazine
  • N'-(2-chloro-5-nitropyrimidin-4-yl)-4- fluorobenzohydrazide prepared as step B in Example 1.1, 1.0 g, 3.21 mmol
  • benzyl amine (0.68 mL, 6.24 mmol
  • Et 3 N (1.80 mL, 12.84 mmol) in ethanol (30 mL)
  • the mixture was filtered and washed to give the title product as a pale yellow solid (1.20 g, 98%).
  • Step B Benzyl-[3-(4-fluoro-phenyl)-l,2-dihydro-pyrimido[5,4-e][l,2,4]triazin-7-yl]- amine
  • Example 3.3 The more polar product isloated from Example 3.2 is decribed in Example 3.3
  • Example 3.2 the more polar productt is the title compound as a pale yellow solid (0.050 g, 31%).
  • Step A N'-(5-Amino-2-chloropyrimidin-4-yl)-4-fluorobenzohydrazide
  • Step B 3-(4-Fluorophenyl)-7-methoxy-l,2-dihydropyrimido[5,4-e][l,2,4]triazine
  • Step C Ethyl- [3-(4-fluoro-phenyl)-7-methoxy-pyrimido[5,4-e][ 1,2,4] triazin-5-yl]- amine
  • N'-(2-chloro-5-nitropyrimidin-4-yl)-4- fluorobenzohydrazide prepared as step B in Example 1.1, 0.200 g, 0.643 mmol
  • methanol 15 mL
  • Pd(OH) 2 /C 0.040 g, 20%
  • the mixture was filtered, washed and concentrated to give crude amine as a brown oil (0.160 g, 100%).
  • Step B 3 -(4 -fluorophenyl) -1,2 -dihydropyrimido[ 5,4-e] ' [ 1 , 2, 4]triazine
  • Step C N-(4-fluorobenzyl)-3-(4-fluorophenyl)pyrimido[ 5,4-e] [1, 2,4] 'triazin-5-amine
  • a standard RdRP assay was performed with HCV NS5B in 20 uL reactions containing 20 mM Tris-Cl pH 7.0, 5 mM MgCl 2 , 5 mM MnCl 2 , 5mM DTT, 5U RNAsin, 100 ug/mL BSA, 400-500 ng of NS5B protein, 0.2 ug poly(C) template and 10 mM GTP plus ImCi [(X- 33 P]-GTP, at 25°C for 2 h. The reaction was terminated upon addition of 2 uL 0.45 M EDTA.

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Abstract

La présente invention porte sur un composé de la formule (I) ou sur un dérivé, un sel ou un promédicament de qualité pharmaceutique de celui-ci : formule (I). La présente invention porte en outre sur des compositions pharmaceutiques comportant un composé de la formule (I) et sur des procédés de traitement ou de prévention d'infections virales, en particulier d'infections au VHC, par l'administration d'un composé de la formule (I).
PCT/CN2009/070252 2009-01-21 2009-01-21 Pyrimido[5,4-e][1,2,4]triazines et leurs utilisations Ceased WO2010083645A1 (fr)

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Cited By (1)

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US3813393A (en) * 1971-07-13 1974-05-28 Hoffmann La Roche Pyrimidotriazines
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Publication number Priority date Publication date Assignee Title
CN102060782A (zh) * 2010-11-18 2011-05-18 孙智华 制备氯代嘧啶或其类似物的方法

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