US20090156595A1 - Pteridines useful as HCV inhibitors and methods for the preparation thereof - Google Patents

Pteridines useful as HCV inhibitors and methods for the preparation thereof Download PDF

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US20090156595A1
US20090156595A1 US11/914,018 US91401806A US2009156595A1 US 20090156595 A1 US20090156595 A1 US 20090156595A1 US 91401806 A US91401806 A US 91401806A US 2009156595 A1 US2009156595 A1 US 2009156595A1
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alkyl
hydrogen
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Pierre Jean-Marie Bernard Raboisson
Dominique Louis Nestor Ghislain Surleraux
Tse-I Lin
Oliver Lenz
Kenneth Alan Simmen
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Janssen R&D Ireland ULC
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Tibotec Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/10—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with an aromatic or hetero-aromatic ring directly attached in position 2
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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 the use of pteridines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections.
  • the present invention relates to compounds per se and their use as medicines.
  • the present invention also concerns processes for the preparation of such compounds, pharmaceutical compositions comprising them, and combinations of said compounds with other anti-HCV agents.
  • HCV hepatitis C virus
  • HCV is a positive-sense, single-stranded RNA virus, with a genome of around 9,600 bases.
  • the genome comprises both 5′ and 3′ untranslated regions which adopt RNA secondary structures, and a central open reading frame that encodes a single polyprotein of around 3,010-3,030 amino acids.
  • the polyprotein encodes ten gene products which are generated from the precursor polyprotein by an orchestrated series of co- and posttranslational endoproteolytic cleavages mediated by both host and viral proteases.
  • the viral structural proteins include the core nucleocapsid protein, and two envelope glycoproteins E1 and E2.
  • the non-structural (NS) proteins encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by non-structural protein 5b (NS5B).
  • NS5B non-structural protein 5b
  • the viral helicase and protease functions both encoded in the bifunctional NS3 protein, have been shown to be essential for replication of HCV RNA in chimpanzee models of infection (Kolykhalov, A. A., Mihalik, K., Feinstone, S. M., and Rice, C. M. J. Virol. 74, 2046-2051, 2000).
  • HCV also encodes a metalloproteinase in the NS2 region.
  • HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection.
  • HCV type 1 is the predominant genotype in the US and Europe. For instance, HCV type 1 accounts for 70 to 75 percent of all HCV infections in the United States.
  • the extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. An estimated 170 million persons worldwide are infected with hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma)
  • HCC hepatocellular carcinoma
  • Liver cirrhosis due to HCV infection is responsible for about 10,000 deaths per year in the U.S.A. alone, and is the leading cause for liver transplantations.
  • Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use.
  • the introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence.
  • the existing infections will continue to present a serious medical and economic burden for decades (Kim, W.R. Hepatology, 36, 5 Suppl. S30-S34, 2002).
  • HCV therapies are based on (pegylated) interferon-alpha (IFN- ⁇ ) in combination with ribavirin.
  • This combination therapy yields a sustained virologic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3.
  • combination therapy has significant side effects and is poorly tolerated in many patients. For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients.
  • Major side effects of combination therapy include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. The development of more effective, convenient and tolerated treatments is a major public health objective.
  • US20040038856 discloses methods of treating fibroproliferative disorders associated with TGF- ⁇ signaling, by administering non-peptide small molecule inhibitors of TGF- ⁇ specifically binding to the type I TGF- ⁇ receptor (TGF ⁇ -R1).
  • the inhibitors are preferably quinazoline derivatives.
  • WO04/048930 further describes methods for counteracting a loss in ⁇ -adrenergic sensitivity in the ⁇ -adrenergic signal transduction pathway by administering an effective amount of a compound capable of inhibiting TGF- ⁇ signaling through a TGF- ⁇ receptor.
  • WO04/065392 relates to condensed pyridines and pyrimidines and their use as ALK-5 receptor ligands.
  • the invention discloses therapeutically active substituted quinoline and quinazoline compounds, the use thereof in therapy, particularly in the treatment or prophylaxis of disorders characterised by overexpression of transforming growth factor ⁇ (TGF- ⁇ ), and pharmaceutical compositions for use in such therapy.
  • TGF- ⁇ transforming growth factor ⁇
  • HCV RNA can be detected in blood in 1-3 weeks. Within an average of 50 days virtually all patients develop liver cell injury. The majority of patients are asymptomatic and anicteric. Only 25-35 percent develop malaise, weakness, or anorexia, and some become icteric. Antibodies to HCV (anti-HCV) almost invariably become detectable during the course of illness. Anti-HCV can be detected in 50-70 percent of patients at the onset of symptoms and in approximately 90 percent of patients 3 months after onset of infection. HCV infection is self-limited in only 15 percent of cases. Recovery is characterized by disappearance of HCV RNA from blood and return of liver enzymes to normal.
  • Chronic hepatitis C is typically an insidious process, progressing, if at all, at a slow rate without symptoms or physical signs in the majority of patients during the first two decades after infection. Symptoms first appear in many patients with chronic hepatitis C at the time of development of advanced liver disease.
  • inflammatory cells infiltrate the portal tracts and may also collect in small clusters in the parenchyma.
  • the latter instance is usually accompanied by focal liver cell necrosis.
  • the margin of the parenchyma and portal tracts may become inflamed, with liver cell necrosis at this site (interface hepatitis). If and when the disease progresses, the inflammation and liver cell death may lead to fibrosis. Mild fibrosis is confined to the portal tracts and immediately adjacent parenchyma. More severe fibrosis leads to bridging between portal tracts and between portal tracts and hepatic veins.
  • Such fibrosis can progress to cirrhosis, defined as a state of diffuse fibrosis in which fibrous septae separate clusters of liver cells into nodules. The extent of fibrosis determines the stage of disease and can be reliably assessed. Severe fibrosis and necroinflammatory changes predict progression to cirrhosis. Once cirrhosis is established, complications can ensue that are secondary to liver failure and/or to portal hypertension, such as jaundice, ascites, variceal hemorrhage, and encephalopathy. The development of any of these complications marks the transition from a compensated to a decompensated cirrhosis.
  • Chronic hepatitis C infection leads to cirrhosis in at least 20 percent of patients within 2 decades of the onset of infection. Cirrhosis and end-stage liver disease may occasionally develop rapidly, especially among patients with concomitant alcohol use. Chronic infection by HCV is associated with an increased risk of liver cancer.
  • the prevailing concept is that hepatocellular carcinoma (HCC) occurs against a background of inflammation and regeneration associated with chronic hepatitis over the course of approximately 3 or more decades. Most cases of HCV-related HCC occur in the presence of cirrhosis.
  • Liver fibrosis is one of the processes that occurs when the liver is damaged. Such damage may be the result of viral activity (e.g., chronic hepatitis types B or C) or other liver infections (e.g., parasites, bacteria); chemicals (e.g., pharmaceuticals, recreational drugs, excessive alcohol, exposure to pollutants); immune processes (e.g., autoimmune hepatitis); metabolic disorders (e.g., lipid, glycogen, or metal storage disorders); or cancer growth (primary or secondary liver cancer). Fibrosis is both a sign of liver damage and a potential contributor to liver failure via progressive cirrhosis of the liver.
  • viral activity e.g., chronic hepatitis types B or C
  • other liver infections e.g., parasites, bacteria
  • chemicals e.g., pharmaceuticals, recreational drugs, excessive alcohol, exposure to pollutants
  • immune processes e.g., autoimmune hepatitis
  • metabolic disorders e.g., lipid, glycogen, or metal storage disorders
  • liver fibrosis may be caused by different ethiological agents, including the Hepatitis C virus. Most importantly, liver fibrosis is a specific condition in the disease progression of patients infected with HCV.
  • HCV replication refers to the process of reproducing or making copies of HCV RNA.
  • HCV replication both refers to the replication of the HCV virus as a whole or the replication of the HCV RNA genome.
  • HCV hepatocellular carcinoma
  • the compounds of the invention are valuable in that they may diminish the HCV viral load of a patient to undetected levels.
  • the present invention thus relates to the use of a compound of the formula (I) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV.
  • Said compound is a pteridine of the formula (I):
  • the present invention further relates to the use of a compound of the formula (II) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV.
  • Said compound is a pteridine of the formula (II):
  • the present invention further relates to the use of a compound of the formula (III) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV.
  • Said compound is a pteridine of the formula (III):
  • R 1 , L, R 2 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , Het 1 , and Het 2 have the meaning as indicated above;
  • the present invention further relates to the use of a compound of the formula (IV) for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV.
  • Said compound is a pteridine of the formula (IV):
  • One embodiment relates to the use of the compounds of formulae (II), (IV), or (V) as specified above, wherein n is 1.
  • the invention relates to a method of inhibiting HCV replication in a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formulae (I), (II), (III), (IV), or (V) as specified above or as further specified hereinafter.
  • the method of inhibiting HCV replication in a mammal infected with HCV comprises the administration of an HCV inhibitory effective amount of a compound of formulae (II), (IV), or (V) wherein n is 1.
  • the invention relates to a method of treating a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formulae (I), (II), (III), (IV), or (V) as specified above or as further specified hereinafter.
  • the method of treating a mammal infected with HCV comprises the administration of an HCV inhibitory effective amount of a compound of formulae (II), (IV), or (V) wherein n is 1.
  • the present invention relates to the use of a compound of the formula (VI) for the manufacture of a medicament for inhibiting HCV replication in a mammal infected with HCV.
  • Said compound is a pteridine of the formula (VI):
  • R 1 , R 8 , R 9 , R 11 , R 12 , R 6 are as defined above.
  • the invention relates to a method of inhibiting HCV replication in a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formula (VI) as specified above or as further specified hereinafter.
  • the invention relates to a method of treating a mammal infected with HCV, said method comprising the administration of an HCV inhibitory effective amount of a compound of formula (VI) as specified above or as further specified hereinafter.
  • Still further embodiments of the invention relate to the use of the compounds of the formulae (V) or (VI) for the manufacture of a medicament for inhibiting HCV replication in a mammal infected with HCV.
  • Said compounds are pteridines of the formulae (V) or (VI) wherein, where applicable n is 1, and
  • R 1 is hydrogen or amino
  • R 8 is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl
  • R 9 represents hydrogen, C 1-4 alkyl, —COR 6 , —COOR 7 , or —CONR 4a R 4b
  • R 11 represents hydrogen, fluoro, or pyrrolidin-1-yl
  • R 12 represents halo, C 1-4 alkyl, or polyhaloC 1-4 alkyl
  • R 6 is hydrogen, or C 1-4 alkyl
  • R 7 is hydrogen, or C 1-4 alkyl
  • R 4a and R 4b independently, are hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl.
  • FIG. 1 For purposes of this specification, FIG. 1 , R 8 , R 9 , R 11 , R 12 are as defined in the previous paragraph.
  • Still further embodiments of the invention relate to the use of the compounds of the formulae (V) or (VI) for the manufacture of a medicament for inhibiting HCV replication in a mammal infected with HCV.
  • Said compounds are pteridines of the formulae (V) or (VI) wherein, where applicable n is 1, and
  • R 1 is hydrogen;
  • R 8 is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl;
  • R 9 represents hydrogen, C 1-4 alkyl, or —COOR 7 ;
  • R 11 represents fluoro, or pyrrolidin-1-yl;
  • R 12 represents halo, or C 1-4 alkyl; and
  • R 7 is hydrogen, or C 1-4 alkyl.
  • further embodiments of the invention relate to a method of inhibiting HCV replication in a mammal infected with HCV, and to a method of treating a mammal infected with HCV, said methods comprising the administration of an HCV inhibitory effective amount of a compound of formulae (V) or (VI) wherein, where applicable n is 1, and R 1 , R 8 , R 9 , R 11 , R 12 are as defined in the previous paragraph.
  • the present invention relates to a pteridine of the formula (VII):
  • R 1 is hydrogen or amino
  • R 8 is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl
  • R 9 represents hydrogen, C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b
  • R 6 is independently hydrogen, or C 1-4 alkyl
  • each R 7 is independently hydrogen, or C 1-4 alkyl
  • each R 4a and R 4b is independently hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl; with the proviso that when R 8 is hydrogen, R 9 is not hydrogen.
  • the present invention relates to a pteridine of the formula (VII), a salt, stereoisomeric form, and racemic mixture thereof, wherein
  • R 8 is C 1-6 alkyl, phenylC 1-4 alkyl; R 1 , R 4a , R 4b , R 6 , R 7 , and R 9 are as recited in the previous paragraph.
  • the present invention relates to a pteridine of the formula (VII), a salt, stereoisomeric form, and racemic mixture thereof, wherein
  • R 9 represents C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b ;
  • R 1 , R 4a , R 4b , R 6 , R 7 , and R 8 are as recited in the second previous paragraph.
  • the present invention relates to a pteridine of the formula (VIII):
  • R 1 is independently hydrogen or amino
  • R 8 is hydrogen, C 1-6 alkyl, phenylC 1-4 alkyl
  • R 9 represents hydrogen, C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b
  • R 6 is independently hydrogen, or C 1-4 alkyl
  • each R 7 is independently hydrogen, or C 1-4 alkyl
  • each R 4a and R 4b is independently hydrogen, C 1-4 alkyl, 2-oxo-pyrrolidin-1-yl-C 1-4 alkyl; with the proviso that when R 8 is hydrogen, R 9 is not hydrogen.
  • the present invention relates to a pteridine of the formula (VIII), a salt, stereoisomeric form, and racemic mixture thereof, wherein
  • R 9 represents C 1-4 alkyl, —COR 6 , COOR 7 , or —CONR 4a R 4b ;
  • R 1 , R 4a , R 4b , R 6 , R 7 , and R 8 are as recited in the previous paragraph.
  • the present invention relates to a pteridine of the formula (VIII), a salt, stereoisomeric form, and racemic mixture thereof, wherein
  • R 8 is C 1-6 alkyl, phenylC 1-4 alkyl; R 1 , R 4a , R 4b , R 6 , R 7 , and R 9 are as recited in the second previous paragraph.
  • the present invention relates to a pteridine of the formula (VII) or (VIII) as set forth above, wherein
  • R 1 is hydrogen; R 8 is hydrogen; R 9 represents C 1-4 alkyl.
  • the present invention relates to a pteridine of the formula (VII) or (VIII) as set forth above, wherein
  • R 1 is hydrogen; R 8 is C 1-6 alkyl; R 9 represents hydrogen.
  • a method of treating clinical conditions relating to HCV infection in a mammal comprising the administration of an HCV inhibitory effective amount of a compound of formula (V) wherein R 1 , R 8 , R 9 , R 11 , R 12 are as defined hereinafter.
  • the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) show activity against the HCV virus and are therefore useful as a medicament, and in the manufacture of a medicament for preventing, treating or combating infection, clinical conditions, or a disease associated with HCV infection.
  • the compounds of formulae (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) show activity against the HCV virus and are therefore useful as a medicament, and in the manufacture of a medicament for preventing, treating or combating clinical conditions associated with HCV infection other than liver fibrosis.
  • C 1-2 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 2 carbon atoms, such as, for example, methyl, ethyl, and the like.
  • C 1-4 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, the groups defined for C 1-2 alkyl and propyl, butyl, 2-methyl-propyl and the like.
  • C 1-6 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, the groups defined for C 1-4 alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like.
  • C 1-10 alkyl as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as, for example, the groups defined for C 1-6 alkyl and heptyl, octyl, nonyl, decyl and the like.
  • C 2-4 alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 4 carbon atoms, such as, for example, ethenyl, prop-1-enyl, but-1-enyl, but-2-enyl, and the like. Preferred are C 2-4 alkenyls having one double bond.
  • C 2-6 alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, the groups defined for C 2-4 alkenyl and pent-1-enyl, pent-2-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, 1-methyl-pent-2-enyl and the like. Preferred are C 2-6 alkenyls having one double bond.
  • C 2-10 alkenyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 10 carbon atoms, such as, for example, the groups defined for C 2-6 alkenyl and hept-1-enyl, hept-2-enyl, 2-methyl-hept-1-enyl, oct-3-enyl, non-4-enyl, 1-methyl-non-2-enyl and the like.
  • C 2-4 alkynyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 4 carbon atoms, such as, for example, ethynyl, prop-1-ynyl, but-1-ynyl, but-2-ynyl, and the like. Preferred are C 2-4 alkynyls having one triple bond.
  • C 2-6 alkynyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, the groups defined for C 2-4 alkynyl and pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, 1-methyl-pent-2-ynyl, pent-2-en-4-ynyl and the like.
  • C 2-10 alkynyl as a group or part of a group defines straight and branched chained hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 10 carbon atoms, such as, for example, the groups defined for C 2-6 alkynyl and hept-1-ynyl, hept-2-ynyl, 2-methyl-hept-1-ynyl, oct-3-ynyl, non-4-ynyl, 1-methyl-non-2-ynyl and the like.
  • C 1-6 alkanediyl as a group or part of a group defines bivalent straight and branched chained hydrocarbons having from 1 to 6 carbon atoms such as, for example, methanediyl, 1,2-ethanediyl, or 1,1-ethanediyl, 1,3-propanediyl, 1,3-butanediyl, 1,4-butanediyl, 1,3-pentanediyl, 1,5-pentanediyl, 1,4-hexanediyl, 1,6-hexanediyl, and the like.
  • C 3-7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • aryl as a group or part of a group is meant to include phenyl or naphtyl. In a preferred embodiment, the term “aryl” as a group or part of a group is phenyl.
  • halo is generic to fluoro, chloro, bromo or iodo.
  • polyhaloC 1-4 alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C 1-4 alkyl, for example, 1,1,1-trifluoroethyl, 1,1-difluoro-ethyl, the polyhalomethyl groups mentioned hereinafter, and the like.
  • a preferred subgroup of polyhaloC 1-4 alkyl is polyhalomethyl, wherein the latter as a group or part of a group is defined as mono- or polyhalo-substituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl.
  • more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC 1-4 alkyl, they may be the same or different.
  • protecting group refers to an amino-protecting group such as such as C 1-10 alkoxy-carbonyl, arylC 1-10 alkoxy-carbonyl, like benzoyl, anisoyl-, isobutyroyl-, acetyl-, or tert-butylbenzoyl (Breipohl et al. (1997) Tetrahedron 53, 14671-14686).
  • the protecting group may be as well an acid-labile protecting group such as dimethoxytrityl.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl
  • pentyl includes 1-pentyl, 2-pentyl and 3-pentyl.
  • N-oxide forms of the present compounds are meant to comprise any one of the compounds of the present invention wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • the salts of the compounds of the present invention are those wherein the counter-ion is pharmaceutically or physiologically acceptable.
  • salts having a pharmaceutically unacceptable counter-ion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of the present invention. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, hemisulphuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, aspartic, dodecyl-sulphuric, heptanoic, hexanoic, benzoic, nicotinic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and
  • the compounds of the present invention containing an acidic proton may also be converted into their non-toxic metal or amine addition base salt form by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the compound may also be supplied as a salt with a pharmaceutically acceptable cation.
  • base addition salt forms can be converted by treatment with an appropriate acid into the free acid form.
  • salts also comprises the hydrates and the solvent addition forms that the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the compounds the present invention include all stereoisomeric forms thereof, both as isolated stereoisomers and mixtures of these stereoisomeric forms.
  • stereochemically isomeric forms of compounds of the present invention defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess.
  • chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound.
  • All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyl-tartaric acid, ditoluoyltartaric acid and camphosulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of the compounds of the present invention can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the present compounds may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
  • an 1,2,4-oxadiazole may be substituted with a hydroxy or a mercapto group in the 5-position, thus being in equilibrium with its respective tautomeric form as depicted below.
  • prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of the present invention.
  • the reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8 th ed, McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs”, p 13-15) describing prodrugs generally is hereby incorporated.
  • Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • a substituent containing sulfhydryl could be coupled to a carrier which renders the compound biologically inactive until removed by endogenous enzymes or, for example, by enzymes targeted to a particular receptor or location in the subject.
  • Prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • the present invention is also intended to include all isotopes of atoms occurring on the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include C-13 and C-14.
  • the term “compounds of formula (I)”, “compounds of formula (II)”, “compounds of formula (III)”, “compounds of formula (IV)”, “compounds of formula (V)”, “compounds of formula (VI)”, “compounds of formula (VII)”, “compounds of formula (VIII)”, “compounds of formulas (V) to (VIII)”, or “the compounds of present invention” or similar term is meant to include the compounds of general formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, as well as their quaternized nitrogen analogues.
  • An interesting subgroup of the compounds of formula (V) or any subgroup thereof are the N-oxides, salts and all the stereoisomeric forms of the compounds of formula (V).
  • Embodiments of the present invention are those compounds of the present invention or any of the subgroups thereof wherein the 4-pyridyl forms a N-oxide, for example the N-oxide of compound nr. 24.
  • Further embodiments of the present invention are those compounds of the present invention or any of the subgroups of compounds of the present invention wherein the compound occurs as an acid-addition salt, wherein the salt preferably is selected from hydrochloride, hydrobromide, trifluoroacetate, fumarate, chloroacetate, methanesulfonate, oxalate, acetate and citrate.
  • the salt preferably is selected from hydrochloride, hydrobromide, trifluoroacetate, fumarate, chloroacetate, methanesulfonate, oxalate, acetate and citrate.
  • R 1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-6 alkyl, C 1-4 alkoxyC 1-4 alkyl, di-C 1-4 alkylaminoC 1-4 alkyl, piperidin-1-yl-C 1-4 alkyl, arylC 1-6 alkyl, wherein the aryl group may be further substituted with C 1-4 alkyl, or C 1-4 alkoxy.
  • R 1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-4 alkyl, C 1-4 alkoxyC 1-4 alkyl, di-C 1-4 alkylaminoC 1-4 alkyl, piperidin-1-yl-C 1-4 alkyl, arylC 1-6 alkyl, wherein the aryl group may be further substituted with C 1-4 alkoxy.
  • R 1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from C 1-2 alkyl, C 1-2 alkoxyC 1-2 alkyl, di-C 1-2 alkylaminoC 1-2 alkyl, piperidin-1-yl-C 1-2 alkyl, arylC 1-2 alkyl, wherein the aryl group may be further substituted with C 1-2 alkoxy.
  • R 1 is independently hydrogen, amino, mono- or disubstituted amino, wherein the substituent(s) of the amino may be selected from methyl, methoxyethyl, dimethylaminoethyl, piperidin-1-ylethyl, benzyl, wherein the phenyl group may be further substituted with methoxy.
  • R 1 is independently hydrogen, amino, or monosubstituted amino, wherein the substituent of the amino may be selected from methoxyethyl, dimethylaminoethyl, piperidin-1-ylethyl, and benzyl, wherein the phenyl group is further substituted with methoxy.
  • R 8 is hydrogen, C 1-10 alkyl, aminoC 1-10 alkyl, arylC 1-10 alkyl, Het 1 C 1-6 alkyl, or a protecting group, wherein the aryl is optionally substituted with 1 to 3 substituents selected from C 1-4 alkyl, C 1-4 alkyl-carbonyl, halo, —OR 6 , —NR 4a R 4b , —SR 5 , and polyhaloC 1-4 alkyl.
  • R 8 is hydrogen, C 1-6 alkyl, aminoC 1-6 alkyl, arylC 1-6 alkyl, Het 1 C 1-6 alkyl, or C 1-6 alkoxy-carbonyl.
  • R 8 is hydrogen, C 1-6 alkyl, aminoC 1-4 alkyl, phenylC 1-4 alkyl, pyrrolidin-1-ylC 1-4 alkyl, or C 1-6 alkoxy-carbonyl.
  • each R 9 represents, independently, hydrogen, C 1-4 alkyl, polyhaloC 1-4 alkyl, halo, —COR 6 , —COOR 7 , —CON 4a R 4b , —OR 7 , —NR 4a R 4b , —NR 4a COR 6 , —NR 4a SO 2 R 5 , —SR 5 , or morpholin-4-yl, and wherein the C 1-4 alkyl may be further substituted with —COOR 7 .
  • each R 9 represents, independently, hydrogen, C 1-4 alkyl, —COR 6 , —COOR 7 , or —CON 4a R 4b , and wherein the C 1-4 alkyl may be further substituted with —COOR 7 .
  • each R 9 represents, independently, hydrogen, C 1-4 alkyl, —COR 6 , —COOR 7 , or —CONR 4a R 4b .
  • Compounds of particular interest are those compounds of formula (V) listed in Table 1 below, in particular compounds number 1, number 7, number 21, number 23, number 24, and number 25, and its N-oxides, salts and stereoisomers.
  • a number of synthetic routes may be employed to produce the compounds of the invention. In general, they may be synthesized using reactions known in the art. Any art-known method for synthesis may be employed. However, the following synthetic routes are convenient for preparation of the invention compounds.
  • the compounds of the formula (V) may be synthesized following a procedure adapted from Wamhoff, H.; Kroth, E. Synthesis, 1994, 405-410 as described in Scheme 1.
  • a methyl 3-amino-2-pyrazinecarboxylate (1a) is reacted with acylchloride in the presence of a suitable solvent such as chloroform or pyridine to afford 3-acylamino-pyrazin-2-carboxylates (1b).
  • Said 3-acylaminopyrazin-2-carboxylates (1b) are converted with for example ammonium hydroxide into 3-acylaminopyrazin-2-amides (1d).
  • 3-acylaminopyrazine-2-carboxamides (1d) may already be obtained by acylation of 3-amino-2-pyrazinecarboxamide (1c).
  • the 3-acylaminopyrazin-2-amides (1d) are then cyclized by the addition of a base to form pteridin-4-ol derivatives of formula (1e).
  • the alcohol may then be replaced by a halogen with the help of a halogenating agent such as thionyl chloride in a suitable solvent like chloroform, dichloroethane or tetrahydrofuran (THF) in presence of a catalytic amount of dimethylformamide (DMF).
  • a halogenating agent such as thionyl chloride in a suitable solvent like chloroform, dichloroethane or tetrahydrofuran (THF) in presence of a catalytic amount of dimethylformamide (DMF).
  • the pteridin-4-ol may be converted in a one-pot procedure into the pteridines of formula (V) by reacting compounds of formula (1e) with an amine or alcohol of the formula HLR 2 together with a suitable base, such as TEA or DIPEA in the presence of benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoro-phosphate (PyBOP).
  • a suitable base such as TEA or DIPEA
  • benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoro-phosphate PyBOP
  • HLR 2 H is hydrogen
  • L and R 2 have the meanings indicated above in the definition of the substituents of compound of formula (V).
  • the compounds of the formula (V) can be prepared from the corresponding pteridinones as starting materials followed by their conversion to the iminochlorides and the subsequent displacement of the chlorine atom with an appropriate amine such as a 4-aminopyridine as shown below in Scheme 2.
  • the manner of administration and formulation of the compounds useful in the invention and their related compounds will depend on the nature of the condition, the severity of the condition, the particular subject to be treated, and the judgment of the practitioner; formulation will depend on mode of administration.
  • the compounds of the invention are small molecules, they are conveniently administered by oral administration by compounding them with suitable pharmaceutical excipients so as to provide tablets, capsules, syrups, and the like.
  • suitable formulations for oral administration may also include minor components such as buffers, flavoring agents and the like.
  • the amount of active ingredient in the formulations will be in the range of 5%-95% of the total formulation, but wide variation is permitted depending on the carrier.
  • Suitable carriers include sucrose, pectin, magnesium stearate, lactose, peanut oil, olive oil, water, and the like.
  • the compounds useful in the invention may also be administered through suppositories or other transmucosal vehicles.
  • formulations will include excipients that facilitate the passage of the compound through the mucosa such as pharmaceutically acceptable detergents.
  • the compounds may also be administered topically, or in formulation intended to penetrate the skin.
  • These include lotions, creams, ointments and the like which can be formulated by known methods.
  • the compounds may also be administered by injection, including intravenous, intramuscular, subcutaneous or intraperitoneal injection.
  • Typical formulations for such use are liquid formulations in isotonic vehicles such as Hank's solution or Ringer's solution.
  • Alternative formulations include nasal sprays, liposomal formulations, slow-release formulations, and the like, as are known in the art.
  • Any suitable formulation may be used.
  • a compendium of art-known formulations is found in Remington's Pharmaceutical Sciences , latest edition, Mack Publishing Company, Easton, Pa. Reference to this manual is routine in the art.
  • the dosages of the compounds of the invention will depend on a number of factors which will vary from patient to patient. However, it is believed that generally, the daily oral dosage will utilize 0.001-100 mg/kg total body weight, preferably from 0.01-50 mg/kg and more preferably about 0.01 mg/kg-10 mg/kg. The dose regimen will vary, however, depending on the conditions being treated and the judgment of the practitioner.
  • the compounds of the invention can be administered as individual active ingredients, or as mixtures of several embodiments of this formula.
  • the compounds of the invention may be used as single therapeutic agents or in combination with other therapeutic agents.
  • the compounds of the present invention are useful in the treatment of individuals infected by HCV and for the prophylaxis of these individuals.
  • the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with flaviviruses.
  • Conditions which may be prevented or treated with the compounds of the present invention especially conditions associated with HCV and other pathogenic flaviviruses, such as Yellow fever, Dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, West Nile virus and Kunjin virus.
  • the conditions associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviruses the conditions include yellow fever, dengue fever, hemorraghic fever and encephalitis.
  • the compounds of the present invention or any subgroup thereof may therefore be used as medicines against the above-mentioned conditions.
  • Said use as a medicine or method of treatment comprises the systemic administration to HCV-infected subjects of an amount effective to combat the conditions associated with HCV and other pathogenic flaviviruses. Consequently, the compounds of the present invention can be used in the manufacture of a medicament useful for treating conditions associated with HCV and other pathogenic flaviviruses.
  • the invention relates to the use of a compound of formula (V) or any subgroup thereof as defined herein in the manufacture of a medicament for treating or combating infection or disease associated with HCV infection in a mammal.
  • the invention also relates to a method of treating a flaviviral infection, or a disease associated with flavivirus infection comprising administering to a mammal in need thereof an effective amount of a compound of formula (V) or a subgroup thereof as defined herein.
  • the present invention relates to the use of formula (V) or any subgroup thereof as defined herein for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with flaviviruses, in particular HCV.
  • the present invention relates to the use of formula (V) or any subgroup thereof as defined herein for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with flaviviruses, wherein said HCV is inhibited in its replication.
  • the combination of previously known anti-HCV compound such as, for instance, interferon- ⁇ (IFN- ⁇ ), pegylated interferon- ⁇ and/or ribavirin, and a compound of the present invention can be used as a medicine in a combination therapy.
  • the term “combination therapy” relates to a product containing mandatory (a) a compound of the present invention, and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections, in particular, in the treatment of infections with HCV type 1.
  • the compounds of this invention may be co-administered in combination with for instance, interferon- ⁇ (IFN- ⁇ ), pegylated interferon- ⁇ and/or ribavirin, as well as therapeutics based on antibodies targeted against HCV epitopes, small interfering RNA (Si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease, NS3 helicase and NS5B polymerase.
  • IFN- ⁇ interferon- ⁇
  • Si RNA small interfering RNA
  • ribozymes DNAzymes
  • DNAzymes DNAzymes
  • antisense RNA small molecule antagonists of for instance NS3 protease
  • NS3 helicase and NS5B polymerase small RNA
  • the present invention relates to the use of a compound of formula (V) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (V) and (pegylated) IFN- ⁇ and/or ribavirin.
  • Appropriate cell types can be equipped by stable transfection with a luciferase reporter gene whose expression is dependent on a constitutively active gene promoter, and such cells can be used as a counter-screen to eliminate non-selective inhibitors. All patents, patent applications and articles referred to before or below are incorporated herein by reference.
  • Triethylamine (1.04 mL, 7.17 mmol) was added to a solution of 2-(5-bromo-2-fluoro-phenyl)pteridin-4-one 104 (800 mg, 2.49 mmol), 4-aminopyridine (469 mg, 4.98 mmol) and PyBOP (2.59 g, 4.98 mmol) in CH 2 Cl 2 .
  • the reaction mixture was partitioned between CH 2 Cl 2 /Petroleum ether (2:1, 300 mL) and ice-cold 1N HCl (300 mL). The pH of the water phase was adjust to 12 with conc. NaOH and extracted with AcOEt, dried (Na 2 SO 4 ) and evaporated.
  • Triethylamine (140 ⁇ L, 1.00 mmol) was slowly added to a solution of 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid 16 (150 mg, 0.340 mmol), PyBOP (0.350 mg, 0.68 mmol), and 1-(3-aminopropyl)pyrrolidinone (97 mg, 0.68 mmol) in CH 2 Cl 2 (10 mL).
  • the title product was synthesized by reaction of the 2-(5-bromo-2-pyrrolidin-1-yl-phenyl)pteridin-4-one 110 and 4-amino-3-methylpyridine following the procedure described for 4-(4-pyridylamino)-2-(5-bromo-2-fluorophenyl)pteridine 1 (LCMS analysis).
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(methylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(3,3-dimethylbutylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(benzylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-3-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 1-(2-pyridyl)piperazine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(4-morpholino)aniline following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-amino-2-methylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-[2-(pyrrolidin-1-yl)ethylamino]pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)-pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-bromo-2-fluorophenyl)-pteridin-4-one 104 with 4-(phenethylamino)pyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the title product was synthesized by reaction of the 2-(5-chloro-2-fluorophenyl)-pteridin-4-one with 4-amino-3-ethylpyridine following the procedure described for 4-[(butyl)(4-pyridyl)amino]-2-(5-bromo-2-fluorophenyl)pteridine 3.
  • the compounds of the present invention are examined for activity in the inhibition of HCV RNA replication in a cellular assay.
  • the assay demonstrates that the present compounds exhibit activity against HCV replicons functional in a cell culture.
  • the cellular assay is based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method is as follows.
  • the assay utilizes the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc).
  • Huh-Luc This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild type NS3-NS5B regions of HCV type 1b translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase).
  • IRS Internal Ribosome Entry Site
  • EMCV encephalomyocarditis virus
  • FfL-luciferase reporter portion
  • neo R neomycine phosphotransferase
  • the replicon cells are plated in 384 well plates in the presence of the test and control compounds which are added in various concentrations. Following an incubation of three days, HCV replication is measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLuxTM ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound on luciferase activity is monitored on the Huh-Luc cells, enabling a dose-response curve for each test compound. EC50 values are then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.
  • Compound nr. 21 was dissolved in a 10% hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) solution at a final concentration of 1 mg base-eq./ml, .pH 4.36.
  • Tissue samples were homogenized in demineralized water.
  • Plasma and tissue samples were analysed for compound nr. 21, using a qualified research LC-MS/MS method.
  • the studied tissues together with plasma had quite similar concentration time profiles, indicating distribution equilibrium between plasma and tested tissues.
  • the mean maximum tissue concentrations (C max ) were achieved at the same time as in plasma at 0.5 h post dose, indicating a rapid equilibrium.
  • the highest concentration was observed in the liver (4057 ng/g) followed by heart (678 ng/g) with a tissue to plasma ratios of 24 and 3.8 respectively (Table 4 and FIG. 1 ).
  • the mean half-life (t 1/2(2-8h) ) estimated for the liver was 3.5 h and 3.4 h for the heart which was comparable with that of plasma (2.9 h). Tissue levels declined in a similar pattern to plasma and at 8 h post dose only low levels of the compound were still detectable, indicating no major evidence for retention.

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070155716A1 (en) * 2004-09-30 2007-07-05 Simmen Kenneth A Hcv inhibiting bi-cyclic pyrimidines
US20080182863A1 (en) * 2005-03-25 2008-07-31 Kenneth Alan Simmen Fused Bicyclic Inhibitors of Hcv
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
US9290502B2 (en) 2005-05-12 2016-03-22 Janssen Sciences Ireland Uc Pteridines useful as HCV inhibitors and methods for the preparation thereof
US9393256B2 (en) 2011-09-16 2016-07-19 Gilead Pharmasset Llc Methods for treating HCV
US10039779B2 (en) 2013-01-31 2018-08-07 Gilead Pharmasset Llc Combination formulation of two antiviral compounds

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007076034A2 (en) 2005-12-21 2007-07-05 Abbott Laboratories Anti-viral compounds
ATE475660T1 (de) 2005-12-21 2010-08-15 Abbott Lab Antivirale verbindungen
EP1971611B1 (en) 2005-12-21 2012-10-10 Abbott Laboratories Anti-viral compounds
US20090318456A1 (en) * 2006-07-06 2009-12-24 Gilead Sciences, Inc. Substituted pteridines for the treatment and prevention of viral infections
US10144736B2 (en) 2006-07-20 2018-12-04 Gilead Sciences, Inc. Substituted pteridines useful for the treatment and prevention of viral infections
EP2094276A4 (en) 2006-12-20 2011-01-05 Abbott Lab ANTIVIRAL COMPOUNDS
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US8173621B2 (en) 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
PA8855801A1 (es) 2008-12-23 2010-07-27 Sintesis de nucleosidos de purina
NZ593648A (en) 2008-12-23 2013-09-27 Gilead Pharmasset Llc Nucleoside phosphoramidates
WO2010075517A2 (en) 2008-12-23 2010-07-01 Pharmasset, Inc. Nucleoside analogs
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
TWI576352B (zh) 2009-05-20 2017-04-01 基利法瑪席特有限責任公司 核苷磷醯胺
BR112012021135A2 (pt) * 2010-02-24 2016-06-21 Syngenta Participations Ag microbicidas
SI2609923T1 (sl) 2010-03-31 2017-10-30 Gilead Pharmasset Llc Postopek za kristalizacijo (s)-izopropil 2-(((s)-(perfluorofenoksi) (fenoksi)fosforil)amino)propanoata
ES2551944T3 (es) 2010-03-31 2015-11-24 Gilead Pharmasset Llc (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihidropirimidin-1-(2H)-il)-4-fluoro-3-hidroxi-4-metiltetrahidrofuran-2-il)metoxi)(fenoxi)fosforil)amino)propanoato de isopropilo cristalino
ES2900570T3 (es) 2013-08-27 2022-03-17 Gilead Pharmasset Llc Formulación de combinación de dos compuestos antivirales
PL3321265T3 (pl) 2015-03-04 2020-11-16 Gilead Sciences, Inc. Związki 4,6-diamino-pirydo[3,2-d]pirymidynowe i ich wykorzystanie jako modulatorów receptorów toll-podobnych
WO2018045150A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators
SI3507276T1 (sl) 2016-09-02 2022-01-31 Gilead Sciences, Inc. Spojine modulatorja toličnih receptorjev
CN107501173B (zh) * 2017-08-17 2020-07-24 武汉桀升生物科技有限公司 一种在温和条件下合成4-烷胺基吡啶的方法
TW202212339A (zh) 2019-04-17 2022-04-01 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202210480A (zh) 2019-04-17 2022-03-16 美商基利科學股份有限公司 類鐸受體調節劑之固體形式
TW202115056A (zh) 2019-06-28 2021-04-16 美商基利科學股份有限公司 類鐸受體調節劑化合物的製備方法

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3873545A (en) * 1971-10-05 1975-03-25 S M B Anciens Etablissements J Pyrido(2, 3d) pyrimidines
US5852028A (en) * 1995-12-18 1998-12-22 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
US5935966A (en) * 1995-09-01 1999-08-10 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
US6184226B1 (en) * 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US20040032430A1 (en) * 2002-06-04 2004-02-19 Kai Yung System and method for generating user interfaces for different instrument types
US20040038856A1 (en) * 2002-05-17 2004-02-26 Sarvajit Chakravarty Treatment of fibroproliferative disorders using TGF-beta inhibitors
US20040132159A1 (en) * 1999-05-13 2004-07-08 Ziyang Zhong Novel beta-secretase and modulation of beta-secretase activity
US20050004143A1 (en) * 2003-03-28 2005-01-06 Sundeep Dugar Bi-cyclic pyrimidine inhibitors of TGFbeta
US20070155716A1 (en) * 2004-09-30 2007-07-05 Simmen Kenneth A Hcv inhibiting bi-cyclic pyrimidines
US20090131460A1 (en) * 2005-05-12 2009-05-21 Tibotec Pharmaceuticals Ltd. Pyrido[2,3-d]pyrimidines useful as hcv inhibitors, and methods for the preparation thereof
US8030318B2 (en) * 2005-03-25 2011-10-04 Tibotec Pharmaceuticals Ltd. Fused bicyclic inhibitors of HCV

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL112249A (en) 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
GB2295387A (en) 1994-11-23 1996-05-29 Glaxo Inc Quinazoline antagonists of alpha 1c adrenergic receptors
JP2002533464A (ja) 1998-12-28 2002-10-08 カー・イュー・ルーベン・リサーチ・アンド・ディベロップメント プテリジン誘導体の免疫抑制作用
EP1242385B1 (en) 1999-12-28 2009-11-25 Pharmacopeia, Inc. Cytokine, especially tnf-alpha, inhibitors
DE60128709T2 (de) 2000-09-15 2007-12-27 Vertex Pharmaceuticals Inc., Cambridge Triazol-verbindungen als protein-kinase-inhibitoren
PT1370553E (pt) 2001-03-23 2006-09-29 Bayer Corp Inibidores de rhoquinase
GB0127430D0 (en) 2001-11-15 2002-01-09 Smithkline Beecham Corp Compounds
GB0127433D0 (en) 2001-11-15 2002-01-09 Smithkline Beecham Corp Compounds
DE60320933D1 (de) 2002-01-10 2008-06-26 Bayer Healthcare Ag Rho-kinase inhibitoren
JP2003321472A (ja) 2002-02-26 2003-11-11 Takeda Chem Ind Ltd Ｇｒｋ阻害剤
WO2003078426A1 (en) 2002-03-15 2003-09-25 Vertex Pharmaceuticals, Inc. Azolylaminoazine as inhibitors of protein kinases
ATE365733T1 (de) 2002-03-15 2007-07-15 Vertex Pharma Zusammensetzungen brauchbar als protein-kinase- inhibitoren
DE60332604D1 (de) 2002-03-15 2010-07-01 Vertex Pharma Azolylaminoazine als proteinkinasehemmer
AU2003220299A1 (en) 2002-03-15 2003-09-29 Vertex Pharmaceuticals, Inc. Azinylaminoazoles as inhibitors of protein kinases
KR100516434B1 (ko) 2002-04-04 2005-09-22 (주) 비엔씨바이오팜 6-(4-치환된-아닐리노)피리미딘 유도체, 그 제조방법 및 이를 포함하는 항바이러스용 약학적 조성물
US7202249B2 (en) 2002-08-27 2007-04-10 Bristol-Myers Squibb Company Antagonists of chemokine receptors
WO2004024159A1 (en) 2002-09-10 2004-03-25 Scios Inc. INHIBITORS OF TFGβ
US20040127575A1 (en) 2002-11-22 2004-07-01 Feng Ying Method for counteracting a pathologic change in the beta-adrenergic pathway
US20040138188A1 (en) 2002-11-22 2004-07-15 Higgins Linda S. Use of TGF-beta inhibitors to counteract pathologic changes in the level or function of steroid/thyroid receptors
WO2004065392A1 (en) * 2003-01-24 2004-08-05 Smithkline Beecham Corporation Condensed pyridines and pyrimidines and their use as alk-5 receptor ligands
US7148226B2 (en) 2003-02-21 2006-12-12 Agouron Pharmaceuticals, Inc. Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
US7232824B2 (en) * 2003-09-30 2007-06-19 Scios, Inc. Quinazoline derivatives as medicaments
MY148676A (en) 2004-06-04 2013-05-31 Bioniche Life Sciences Inc Use of imatinib to treat liver disorders and viral infections
US20060281763A1 (en) 2005-03-25 2006-12-14 Axon Jonathan R Carboxamide inhibitors of TGFbeta
CN101189234B (zh) 2005-03-25 2011-08-17 泰博特克药品有限公司 Hcv的杂二环抑制剂
AR056347A1 (es) 2005-05-12 2007-10-03 Tibotec Pharm Ltd Uso de compuestos de pteridina para fabricar medicamentos y composiciones farmaceuticas

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3873545A (en) * 1971-10-05 1975-03-25 S M B Anciens Etablissements J Pyrido(2, 3d) pyrimidines
US5935966A (en) * 1995-09-01 1999-08-10 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
US5852028A (en) * 1995-12-18 1998-12-22 Signal Pharmaceuticals, Inc. Pyrimidine carboxylates and related compounds and methods for treating inflammatory conditions
US6184226B1 (en) * 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
US6277989B1 (en) * 1998-08-28 2001-08-21 Scios, Inc. Quinazoline derivatives as medicaments
US6476031B1 (en) * 1998-08-28 2002-11-05 Scios, Inc. Quinazoline derivatives as medicaments
US20040132159A1 (en) * 1999-05-13 2004-07-08 Ziyang Zhong Novel beta-secretase and modulation of beta-secretase activity
US20040038856A1 (en) * 2002-05-17 2004-02-26 Sarvajit Chakravarty Treatment of fibroproliferative disorders using TGF-beta inhibitors
US20040032430A1 (en) * 2002-06-04 2004-02-19 Kai Yung System and method for generating user interfaces for different instrument types
US20050004143A1 (en) * 2003-03-28 2005-01-06 Sundeep Dugar Bi-cyclic pyrimidine inhibitors of TGFbeta
US20070155716A1 (en) * 2004-09-30 2007-07-05 Simmen Kenneth A Hcv inhibiting bi-cyclic pyrimidines
US8030318B2 (en) * 2005-03-25 2011-10-04 Tibotec Pharmaceuticals Ltd. Fused bicyclic inhibitors of HCV
US20090131460A1 (en) * 2005-05-12 2009-05-21 Tibotec Pharmaceuticals Ltd. Pyrido[2,3-d]pyrimidines useful as hcv inhibitors, and methods for the preparation thereof

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7977342B2 (en) 2004-09-30 2011-07-12 Tibotec-Virco Virology Bvba HCV inhibiting bi-cyclic pyrimidines
US20070155716A1 (en) * 2004-09-30 2007-07-05 Simmen Kenneth A Hcv inhibiting bi-cyclic pyrimidines
US20080182863A1 (en) * 2005-03-25 2008-07-31 Kenneth Alan Simmen Fused Bicyclic Inhibitors of Hcv
US8030318B2 (en) 2005-03-25 2011-10-04 Tibotec Pharmaceuticals Ltd. Fused bicyclic inhibitors of HCV
US9290502B2 (en) 2005-05-12 2016-03-22 Janssen Sciences Ireland Uc Pteridines useful as HCV inhibitors and methods for the preparation thereof
US9951075B2 (en) 2005-05-12 2018-04-24 Janssen Sciences Ireland Uc Pteridines useful as HCV inhibitors and methods for the preparation thereof
US9708328B2 (en) 2005-05-12 2017-07-18 Janssen Sciences Ireland Uc Pteridines useful as HCV inhibitors and methods for the preparation thereof
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
EP3042910A2 (en) 2010-11-30 2016-07-13 Gilead Pharmasset LLC 2'-spiro-nucleosides for use in the therapy of hepatitis c
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
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
US9393256B2 (en) 2011-09-16 2016-07-19 Gilead Pharmasset Llc Methods for treating HCV
US10456414B2 (en) 2011-09-16 2019-10-29 Gilead Pharmasset Llc Methods for treating HCV
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
US10039779B2 (en) 2013-01-31 2018-08-07 Gilead Pharmasset Llc Combination formulation of two antiviral compounds

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US20160158238A1 (en) 2016-06-09
AR056347A1 (es) 2007-10-03
IL186750A (en) 2014-08-31
AU2006245675A1 (en) 2006-11-16
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US20170275288A1 (en) 2017-09-28
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CA2608326A1 (en) 2006-11-16
WO2006120251A1 (en) 2006-11-16
US20160159803A1 (en) 2016-06-09
JP2008540493A (ja) 2008-11-20
EP1881834A1 (en) 2008-01-30
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KR20080005978A (ko) 2008-01-15
IL186750A0 (en) 2008-02-09
ATE554772T1 (de) 2012-05-15
US9290502B2 (en) 2016-03-22
CA2608326C (en) 2015-11-10
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US9708328B2 (en) 2017-07-18
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