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WO1999036410A1 - Composes de triazine antiviraux - Google Patents

Composes de triazine antiviraux Download PDF

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Publication number
WO1999036410A1
WO1999036410A1 PCT/US1999/000945 US9900945W WO9936410A1 WO 1999036410 A1 WO1999036410 A1 WO 1999036410A1 US 9900945 W US9900945 W US 9900945W WO 9936410 A1 WO9936410 A1 WO 9936410A1
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WO
WIPO (PCT)
Prior art keywords
cycloalkyl
fused
aryl
cycloalkenyl
compound
Prior art date
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PCT/US1999/000945
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English (en)
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WO1999036410A9 (fr
Inventor
Jaime E. Arenas
Sharon T. Cload
Elizabeth S. Fleming
Yi Bin Xiang
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Scriptgen Pharmaceuticals, Inc.
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Publication date
Application filed by Scriptgen Pharmaceuticals, Inc. filed Critical Scriptgen Pharmaceuticals, Inc.
Priority to JP2000540126A priority Critical patent/JP2002509140A/ja
Priority to CA002318362A priority patent/CA2318362A1/fr
Priority to EP99902309A priority patent/EP1053230A1/fr
Publication of WO1999036410A1 publication Critical patent/WO1999036410A1/fr
Publication of WO1999036410A9 publication Critical patent/WO1999036410A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/66—Derivatives of melamine in which a hetero atom is directly attached to a nitrogen atom of melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C07D251/70—Other substituted melamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • 1,3,5-triazine derivatives their use as inhibitors of the replication of the Hepatitis B virus (HBV), and their use in the treatment of viral hepatitis caused by HBN.
  • HBV Hepatitis B virus
  • antibiotics such as erythromycin and aminoglycosides.
  • the first suggestion that some antibiotic translation inhibitors interact specifically with RNA came from the genetic mapping of resistance to kanamycin and gentamicin to the methylation of 16S RNA (Thompson et al., Mol. Gen. Genet. 201:168, 1985). Erythromycin binds to bacterial RNA .and releases peptidyl-tRNA and mRNA (Menninger et al., Mol. Gen. Genet. 243:225, 1994).
  • 2-DOS-containing aminoglycosides bind specifically to the structures of HIV RNA known as the RRE, block binding of the HIV Rev protein to this RNA, and thereby inhibit HIV replication in tissue culture cells (Zapp et al., Cell 74:969, 1993).
  • aminoglycosides have long been developed as translation inhibitors, they were only recently shown to bind to rRNA in the absence of proteins (Purohit and Stern, Nature 370:659, 1994).
  • Hygromycin B inhibits coronaviral RNA synthesis and is thought to do so by binding to the viral RNA and blocking specifically the translation of viral RNA (Macintyre et al., Antimicrob. Agents Chemother. 35:2630, 1991). Therefore, compounds that bind to functionally important regions of nucleic acids of viruses and microorganisms may be useful as inhibitors of replication or other functions, i.e. , as antiviral agents and antibiotics.
  • the present invention pertains specifically to a novel class of drugs comprising RNA ligands that alter the function(s) of their target RNAs.
  • This class of compounds comprises substituted 1,3,5-triazine derivatives that specifically recognize an essential and multifunctional RNA structure of the HBV pregenomic
  • RNA known as the encapsidation signal ( ⁇ RNA). It has been unexpectedly found that this class of compounds can function as inhibitors of HBV replication.
  • ⁇ RNA shown in Figure 2A, consists of a short sequence that folds into a stem-loop structure interrupted by a 6 nucleotide bulge.
  • ⁇ RNA which is contained within the open reading frame encoding the HBV precore protein, is also required for various steps of the HBV viral replication cycle, including encapsidation of the pregenome into viral particles and initiation of minus strand DNA synthesis.
  • ⁇ RNA may also play a role in folding and activation of the HBV-encoded polymerase.
  • U.S. Patent No. 5,225,405 to Paramelle et al. refers to 4,6-bt.s- allylamino-l,3,5-triazin-2-yl derivatives which reverse acquired resistance to anti- cancer and anti-malarial agents.
  • Paramelle et al. state that the disclosed triazine derivatives, when administered at the same time with a cytotoxic agent, reduce or completely suppress multidrug resistance.
  • the triazine compounds presumably act by inhibiting the action of an inducible membrane protein that normally functions to increase the efflux of the cytotoxic agent, thereby reducing its intracellular concentration.
  • Paramelle et al. are silent as to the use of the triazine derivatives as antiviral agents.
  • U.S. Patent No. 4,508,898 to Ogilvie relates to nucleoside analogs that have a 1,3,5-triazine moiety, wherein the analog compounds exhibited antiviral activity.
  • the compounds of Ogilvie do not comprise 2,4,6-triamino- 1,3,5-triazine derivatives, but rather, are N-substituted purine and pyrimidine compounds.
  • European Patent Application No. 172 608 to Kim et al. relates to 1,3,5-triazine derivatives that exhibit anti-ulcer, anti-inflammatory and anti- depressant activities.
  • Kim et al. fail to suggest that the disclosed triazine derivatives can be used as antiviral agents.
  • 4,254,122 to Brown relates to 6- acylaminotetrahydro-l,3,5-triazine-2,4-dione derivatives that exhibit analgesic activities.
  • the disclosed uses of the compound include their use as antiinflammatory agents and as inhibitors of prostaglandin synthetase.
  • European Patent Application No. 795 549 to Gluzman et al. refers to bis-aryloxy(amino)-triazinyl-oxy(amino)aryl derivatives as antiviral agents.
  • the compounds of Gluzman et al. are dimers, linked by bicyclic or heterocyclic substituted moieties, and Gluzman et al. fails to suggest the use of the monomers as therapeutic compounds and/or compositions.
  • Gluzman et al. fails to suggest the use of the monomers as therapeutic compounds and/or compositions.
  • the present invention provides methods for inhibiting viral and/or microbial replication, preventing or treating viral and/or microbial infection, and pharmaceutical formulations for use in such methods comprising a compound of the formulae IA
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, non- aromatic heterocyclic, fused or poly cyclic ring, and aryloxy; wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, nitro, trihalomethyl, aryl, aryloxy, alkoxy, amino, carbonyl, carboxyl, ester, amide, primary, secondary or tertiary amines, cyano, cycloalkyl, alkenyl, cycloalkenyl or alkenyl; and wherein said aryl, aryloxy, heteroaryl, non-aromatic heterocyclic, or fused or poly cyclic ring is optionally substitute
  • antiviral and antibiotic formulations comprising one or more compounds represented by the formulae set forth above and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or diluent, and methods of administering such formulations to a patient in need of antiviral and/or antibacterial therapy. It is also an object of the present invention to provide a method of detecting a target nucleic acid by contacting the target nucleic acid with at least one compound of the formulae set forth above and pharmaceutically acceptable salts thereof, .and monitoring an interaction between the target nucleic acid and the at least one compound of the formulae set forth above.
  • Figures 1A-1K are graphic illustrations of preferred 1,3,5-triazine compounds of the present invention.
  • Figure 2A is a schematic illustration of the HBV pregenomic sequence that corresponds to the encapsidation signal ( ⁇ RNA).
  • Figure 2B is a schematic illustration of the target RNAs used in the method of the present invention.
  • Figure 3 is a graphical illustration of the reduction in virus production when compound 5 and the antiviral drug 2'-deoxy-3'-thiacytidine were tested at various concentrations alone and in combinations in an antiviral assay using 2.2.15 cells producing HBV.
  • Figures 4A, 4B, and 4C are graphical illustrations of the percentage viral reduction when compounds 5 and antiviral drug 2'-deoxy-3'-thiacytidine were tested in combination, with molar ratios of 1:15, 1:5, and 1:1.5, respectively.
  • Figures 5 A and 5B are photographic and schematic representations, respectively, of the results of the reaction of rRNA, ⁇ RNA, RNase, and compound 5 at concentrations ranging from 0 and 200 ⁇ M.
  • FIGS. 6 A and 6B are graphical and schematic illustrations, respectively, of the change in the melting temperature (tm) of ⁇ RNA in the presence and absence of compound 6. Detailed Description of the Invention
  • the term "ligand" refers to an agent that binds a target RNA.
  • the agent may bind the target RNA when the target RNA is in a native or alternative conformation, or when it is partially or totally unfolded or denatured.
  • a ligand can be an agent that binds anywhere on the target RNA. Therefore, the ligands of the present invention encompass agents that in and of themselves may have no apparent biological function beyond their ability to bind to the target RNA.
  • test ligand refers to an agent, comprising a compound, molecule, or complex, which is being tested for its ability to bind to a target RNA.
  • target RNA refers to a RNA sequence for which identification of a ligand or binding partner is desired.
  • Target RNAs include without limitation sequences known or believed to be involved in the etiology of a given disease, condition or pathophysiological state, or in the regulation of physiological function.
  • Target RNAs may be derived from any living organism, such as a vertebrate, particularly a mammal and even more particularly a human, or from a virus, bacterium, fungus, protozoan, parasite or bacteriophage.
  • Target RNAs may comprise wild type sequences, or, alternatively, mutant or variant sequences, including those with altered stability, activity, or other variant properties, or hybrid sequences to which heterologous sequences have been added.
  • target RNA as used herein includes RNA that has been chemically modified, such as, for example, by conjugation of biotin, peptides, modified bases, fluorescent molecules, and the like.
  • Target RNA sequences for use in the present invention are typically between about 5 and about 500 nt, preferably between about 30 and about 100 nt, and most preferably about 50 nt.
  • Target RNAs may be isolated from native sources, or, more preferably, are synthesized in vitro using conventional polymerase-directed cell-free systems such as those employing T7 RNA polymerase.
  • the target RNA is HBV ⁇ RNA.
  • Figure 2A shows the actual portion of the HBV pregenomic sequence that corresponds to the encapsidation signal ( ⁇ RNA).
  • Figure 2B shows the ⁇ RNA sequence used as target RNA in the method of the present invention, and the RRE RNA target used for specificity tests.
  • the target RNA was prepared by in vitro transcription of a linearized plasmid containing the cloned target sequence, with bacteriophage SP6 RNA polymerase in the presence of ⁇ P 32 -UTP to obtain radiolabeled target RNA using methods known to those of ordinary skill in the art.
  • treatment with regard to a viral or microbial infection includes preventing, retarding, and/or reducing a disease, pathological condition or one or more symptoms thereof, in vertebrates, e.g. , birds, and mammals, particularly humans.
  • the altering or inhibiting any of the following processes can be considered very useful for the treatment of infection mediated by HBV. They are:
  • treatment constitutes any improvement in one or more clinical or histological symptoms or diagnostic markers observed by the attending physician or determined by quantitative or semiquantitative techniques.
  • appropriate techniques include analysis of blood and urine.
  • inhibiting replication refers to any detectable reduction in replication or growth of virus, bacteria or fungi, e.g. between about
  • antifungal refer to any compound that inhibits growth of or destroys microorganisms, bacteria, or fungi.
  • aryl means an aromatic carbocyclic ring system having a single radical containing about 6 to about 10 carbon atoms.
  • An aryl group may be a fused or polycyclic ring system.
  • Exemplary aryl groups include phenyl or napthyl.
  • aryloxy means an O-aryl group.
  • An aryloxy group is optionally substituted on the aryl moiety of the aryloxy.
  • Suitable substituents include halogen, hydroxy, alkyl, nitro, trihalomethyl, aryl, aryloxy, alkoxy, amino, carbonyl, carboxyl, ester, amide, primary, secondary or tertiary amines, cyano, cycloalkyl, alkenyl, cycloalkenyl and alkynyl.
  • alkyl means a straight or branched saturated hydrocarbon group. Preferred alkyl groups include those having from 1-
  • cycloalkyl means a non-aromatic monocyclic or fused or polycyclic ring system of about 3 to about 10 ring carbon atoms.
  • one or more of the ring carbon atoms of the cycloalkyl may be replaced by a heteroatom, such as nitrogen, oxygen or sulfur.
  • exemplary cycloalkyl groups include cyclohexyl.
  • cycloalkenyl means a non-aromatic monocyclic or fused or polycyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 ring carbon atoms.
  • one or more of the ring carbon atoms of the cycloalkyl may be replaced by a heteroatom, such as nitrogen, oxygen or sulfur.
  • carbonyl or “carbonyl moiety” refers to any chemical moiety comprising a carbonyl functional group, e.g. , a ketone, aldehyde, carboxylic acid, acid halide, amide, peptide, anhydride and ester.
  • a carbonyl functional group e.g. , a ketone, aldehyde, carboxylic acid, acid halide, amide, peptide, anhydride and ester.
  • heteroatom includes nitrogen, oxygen and sulfur, as well as any atom other than a carbon.
  • ring system refers to an aromatic or non- aromatic carbocyclic compound, in which one or more of the ring carbon atoms may be replaced by a heteroatom, such as nitrogen, oxygen or sulfur.
  • the ring system may be optionally substituted by one or more halogens, C 1 to C 12 alkyl, aryl, vinyl, alkyl(aryl), vinyl(aryl) and nitro groups.
  • fused ring system refers to ring systems wherein at least two adjacent carbon centers join one or more cyclic structures.
  • a fused ring system as used herein may be aromatic or non-aromatic, or may be composed of separate aromatic and non-aromatic moieties.
  • Exemplary carbocyclic fused ring systems are represented by the formulas:
  • Exemplary fused ring systems in which one or more of the ring carbon atoms is replaced by a heteroatom include the following:
  • polycyclic ring system refers to ring systems having two or more cyclic compounds bonded in tandem.
  • a polycyclic ring system as used herein may be aromatic or non-aromatic, or may be composed of separate aromatic and non-aromatic moieties.
  • An exemplary carbocyclic polycyclic ring system is represented by the formula
  • An exemplary polycyclic ring system in which one or more of the ring carbon atoms is replaced by a heteroatom include the following:
  • fused or polycyclic ring systems may optionally be substituted by one or more halogens, C, to C 12 alkyl, aryl, vinyl, alkyl(aryl), vinyl(aryl) and nitro groups.
  • heteroaryl means an about 5 to 10- membered aromatic monocyclic or fused or polycyclic ring system having a single radical in which one or more of the carbon atoms in the ring system is other than carbon, for example, nitrogen, oxygen or sulfur.
  • An exemplary heteroaryl group is pyridine.
  • An exemplary fused or polycyclic heteroaryl group is indole.
  • heterocyclyl or “heterocyclic” means an aromatic or non-aromatic about 5 to about 10-membered monocyclic or fused or polycyclic ring system in which one or more of the carbon atoms in the ring system is other than carbon, for example, nitrogen, oxygen or sulfur.
  • a heterocyclyl group may be a fused or polycyclic ring system.
  • Exemplary heterocyclyl groups include piperidine, morpholino, and azepanyl.
  • the term "primary, secondary, or tertiary amine” refers to amine compounds having one, two, or three functional groups, respectively. Suitable functional groups include halogens, amines, to C 12 alkyl groups, aryl, vinyl, alkyl(aryl), vinyl(aryl) and nitro groups.
  • amide refers to groups having the amide functional group -C(0)NH-, wherein alkyl, alkenyl or alkynyl groups may be bonded to the C or N atom of the amide group.
  • high affinity refers to a compound that binds tightly to its target.
  • Preferred compounds of the present invention will exhibit an IC 50 at or below 50 ⁇ M, preferably at or below 10 ⁇ M, and more preferably at or below 1 ⁇ M.
  • the term "specificity" refers to a compound having either high or low affinity for its target.
  • a highly specific compound will be unaffected by competitor RNA and will not have an effect on a heterologous assay using a different target, independent of the compound's affinity.
  • compounds of the present invention will exhibit no activity or at least a 5-fold higher IC 50 value in a heterologous assay than in a specific assay.
  • the present invention provides methods for inhibiting the replication of viruses and microorganisms and for preventing or treating viral or microbial infection, which comprise administering 1,3,5-triazine compounds and pharmaceutically acceptable salts thereof.
  • the compounds bind Hepatitis B virus (HBV) ⁇ RNA with high affinity and specificity, and thereby alter its function.
  • the formulations of the invention comprise triazine derivatives represented by the formulae IA
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, non- aromatic heterocyclic, fused or polycyclic ring and aryloxy; wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, nitro, trihalomethyl, aryl, aryloxy, alkoxy, amino, carbonyl, carboxyl, ester, amide, primary, secondary or tertiary amines, cyano, cycloalkyl, alkenyl, cycloalkenyl or alkynyl; and wherein said aryl, aryloxy, heteroaryl, non-aromatic heterocyclic or fused or polycyclic ring is optionally substituted by one
  • the invention is directed to compounds of formula IB wherein one or R 1 and R 2 is an optionally substituted aryl. In another embodiment, the invention is directed to compounds of formula IB wherein one of R 7 or R 8 is an optionally substituted aryl
  • Non-limiting examples of the compounds of the invention include:
  • cyanuric chloride (IX) is first reacted with two equivalents of a reagent chosen from a group consisting of a primary amine and a secondary amine, to afford a singly substituted triazine of the formula (X).
  • the 2,4-diamino-6-chloro-l,3,5 triazine of the formula (XI) can then be reacted with two equivalents of a reagent chosen from a group consisting of a primary amine, secondary amine, and hydrazine.
  • a reagent chosen from a group consisting of a primary amine, secondary amine, and hydrazine.
  • the reaction affords a trisubstituted triazine of the formula (XII).
  • Compound (XII) can then be further reacted with a reagent chosen from a group consisting of aldehydes and ketones to afford 2,4,6- substituted-l,3,5-triazines of the formula (XIV).
  • Example 1 2-fluorobenzaldehyde N-[4-(benzylamino)-6-(tert-butylamino)-l ,3,5- triazin-2-yl]hydrazone (compound 93).
  • the product was used in the next step without purification.
  • Example 2 2-hydroxybenzaldehyde N-[4-(benzylamino)-6-(diethylamino)-l ,3,5- triazin-2-yl]hydrazone (compound 155).
  • the product was used in the next step without purification.
  • the target RNA is radiolabelled and the
  • ohgonucleotide is labeled with biotin; in this case, the extent of hybridization is
  • Ligands that exhibit inhibitory activity in a primary in vitro assay are
  • RNA competitor such as, e.g. , ribosomal RNA
  • RNA is the HIV derived RRE RNA and the biotinylated ohgonucleotide is
  • ligand for ⁇ RNA is expressed as the ratio between the IC 50 value obtained with the
  • present invention preferably exhibit IC 50 values for their interaction with ⁇ RNA at
  • 2.2.15 cells contain copies of the complete HBV genome integrated into the cell's genome, and 2.2.15 cells are not susceptible
  • HBV HBV virus
  • Cytotoxicity is measured by the neutral red uptake method
  • nucleic acids may be RNA or DNA, may form part of the
  • genome of the virus or microorganism or an intermediate thereof may represent expressed mRNA species or any other functional nucleic acid unique to the
  • RNA structure was assessed by incubating an end-labeled RNA with the amount of RNase needed to yield a ladder representing single cut events at each possible cleavage site in the RNA structure (based upon a gel electrophoresis analysis). The presence of a
  • the melting temperature of the RNA was determined by monitoring the
  • hepatitis B virus replication and/or prevent or treat infection caused by: hepatitis B virus, hepatitis
  • C virus herpes simplex virus, types 1 and 2, varicella-zoster, cytomegalo virus,
  • Epstein-Barr virus polyomavirus, papillomavirus, parvovirus, vaccinia virus,
  • viruses belonging to the viral families include, without limitation, viruses belonging to the viral families adenoviridae, hepadnaviridae, herpesviridae, papovaviridae, parvoviridae, poxviridae, arenaviridae, bunyaviridae, flaviviridae, orthomyxoviridae,
  • DNA and RNA viruses include, but are not limited to: upper and
  • adenoviruses treatment of immunocompromised individuals, wherein a compromised immune system is associated with cytomegalovirus; infectious
  • polyomavirus polyomavirus
  • smallpox as well as complications arising from smallpox
  • encephalitis each of which being associated with variola, molluscum and
  • parainfluenza associated with paramyxoviruses
  • enteric associated with paramyxoviruses
  • neuromuscular associated with paramyxoviruses
  • RNA binding molecules e.g. , neomycin, erythromycin
  • the compounds and compositions of the present invention can be any aminoglycosides and aminoglycosides, the compounds and compositions of the present invention can be any aminoglycosides and aminoglycosides, the compounds and compositions of the present invention.
  • Antibiotics are used in the treatment of infectious diseases in plants, animals and man, and may kill and/or inhibit the growth of
  • the compounds and compositions of the present invention may be used as bacteriocidal, bacteriostatic and broad-spectrum antibiotic
  • compositions of the present invention can be administered in any order.
  • compositions of the present invention can be administered alone, or can be co-
  • antiviral agents such as, e.g. , Acyclovir, ⁇ -interferon, ribavirin, and various others
  • protease inhibitors e.g. , ritonavir, indinavir, saquinavir, and/or additional non- triazine based antibiotics, such as, e.g. , erythromycin, gentamycin, nanamycin, and
  • formulations of the present invention can be
  • liquid preparations for mucosal administration e.g. , oral, nasal,
  • intramuscular, intravenous administrations, and the like such as sterile solutions
  • suspensions or emulsions e.g, for administration by injection, can be formulated
  • the toxicity such as by determining the lethal dose (LD) and LD 50 in a suitable
  • the formulations can be administered in a pharmaceutically effective amount, an antiviral effective amount and/or in an antimicrobial effective amount,
  • compositions of the present invention can be solutions,
  • compositions may contain a suitable carrier, diluent, or excipient, such as sterile
  • compositions can be water, physiological saline, glucose, or the like. Moreover, the compositions can be water, physiological saline, glucose, or the like. Moreover, the compositions can be
  • auxiliary substances such as wetting or
  • emulsifying agents pH buffering agents, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the
  • Suitable dosages for compositions of the present invention can be
  • compositions and/or antibiotic agent in a composition can be 0.1 to 250 mg/kg/day, preferably below 100 mg/kg/day, and most preferably below 50 mg/kg/day.
  • the compounds of the present invention can be any organic compound that can be used in a further embodiment.
  • the compounds of the present invention can be any organic compound that can be used in a further embodiment.
  • invention can be used in a method of detecting and/or purification of nucleic acids
  • the compounds of the invention can be covalently attached to a chromatographic support and a nucleic acid
  • target nucleic acid as the other components of the solution elute from the column in
  • the compounds of the present invention could be used as inhibitors of specific steps of the viral replication cycle in order to study the
  • the compound could be used for detection of specific RNA species in samples by using a triazine derivative
  • RNA target by electron-microscopy or light microscopy using tissue culture preparations was assessed for RNA target by electron-microscopy or light microscopy using tissue culture preparations.
  • Compounds of the invention were obtained from commercial sources.
  • Compound 32 is available from MicroSource Discovery Systems, Inc., Gaylordsville, Connecticut; compounds 64, 136, and 148 are available from
  • the high throughput assays were performed in 96-well plates
  • the reaction was incubated at 25 °C for 60 minutes, and
  • SAAP streptavidin alkaline phosphatase conjugate
  • wash buffer 50 mM Tris-HCl, pH 7.5, 200 mM KCl
  • columns 1 and 7 and Rx is the hybrids retained in the presence of a test drug, x.
  • Biotinylated oligonucleotides 262.104 A (5'-biotin-TTA GGC AC A
  • SP6 promoter was used as a template for the synthesis of radiolabeled ⁇ RNA using
  • radiolabeled RRE RNA are shown in Table 1 for the following ligands.
  • the antiviral activity of the compounds of the present invention is the antiviral activity of the compounds of the present invention.
  • HBV hybridization probe A 3.2kb full genome length HBV fragment was
  • plasmid clone e.g. , pAM6
  • HBV gel standard l.O ⁇ l HBV standards (100 ng/ml) plus 5 ⁇ l tracking dye
  • HBV standards were made by performing separate
  • pAM6 produces HBV DNA fragments of 3.2, 1.85, and 1.35kb, as well as a plasmid fragment of 4.3kb. This mixture served as a positive and a negative
  • HBV media standards Culture medium (RP2) was collected from confluent
  • HBV DNA Approximately a 2-fold loss of HBV DNA (as compared to the
  • the final product was diluted to a standard concentration of lOng HBV
  • the adjusted standard pool was again rechecked by blot hybridization.
  • the adjusted standard pool was stored at - 70 °C in 5ml aliquots in screw-capped tubes and stable for at least 5 years.
  • 2.2.15 cells was RPMI 1640.
  • Fetal Bovine Serum (FBS) was added at either 2% or
  • Flasks and plates were routinely seeded at a density of 3-5 x IO 4
  • T-75 flask, grown in medium with 4% FBS was subcultured in up to 6, 96-well or
  • This assay format is well suited to the screening of test compounds for potential antiviral activity.
  • the assay provides a threshold assessment of
  • antiviral activity by measuring (i) the levels of HBV virion release from the cells and (ii) cytotoxicity. Two rows of cells were used for each compound, and 4 rows for the assay controls (two for untreated, and two for positive antiviral control,
  • the medium was aspirated off of the toxicity plates and discarded.
  • Toxicity plates were then incubated with neutral red dye (MTT can also be used if
  • Tubes were aliquoted to make up 465 ⁇ l of the highest test concentration. The other tubes were left empty. The tubes were covered with the rack lids, and stored at -20 °C or at an appropriate temperature. Tubes
  • the compound dilution series was prepared for antiviral treatment as
  • the first tube was mixed by pipeting up and down with a
  • pipetman (a multichannel pipetman permits the simultaneous processing of multiple compounds). 70 ⁇ l of test compound-
  • test compound-containing medium 280 ⁇ l
  • test compounds were analyzed in a 3.3-fold
  • the untreated cells received lOO ⁇ l RP2 per
  • test compounds (a total of 300 ⁇ l medium per well). 5. A single plate was used for the toxicity treatments for each test
  • the untreated cells received lOO ⁇ l RP2 per well. Treatment was
  • the assay was terminated and samples harvested for quantitative analysis of HBV virion DNA, by removing the culture medium 24 hours following the 9th day of treatment and storing the culture medium in 96-well U-bottom culture plates. These samples were
  • This assay format serves to further define the action of potential
  • antiviral agents by permitting an assessment of the levels of intracellular HBV DNA
  • the medium is collected at the end of the treatment period for analysis of
  • HBV virion DNA For analysis of intracellular HBV DNA, the monolayers are
  • Tubes for the last day of treatment for toxicity testing contain the same amount of compound as used the
  • RP2 (without drugs) are added to each well. Culture medium is continually changed and test compounds are added each day for a
  • Table 2 shows the antiviral activity of a group of ⁇ RNA ligands.
  • the cytotoxic potential of the compounds can also be
  • the compounds show a potent antiviral activity.
  • the compounds show a potent antiviral activity.
  • results demonstrating inactivity may be due to a number of factors, such as cell
  • compound 5 alone exhibits an EC ⁇ at 1300 nM.
  • the front row column of each plot shows the expected % viral reduction if the
  • viral reduction is the expected additive effect of 20 nM 3TC and 300 nM compound
  • reaction mixture contained 50 mM

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  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques renfermant des dérivés de 1,3,5-triazine. Les composés et formulations de la présente invention déploient toute une gamme d'activités, y compris des activités antivirales et antibiotiques, et les formulations peuvent être utilisées, seules ou combinées, dans le traitement de patients nécessitant une thérapie antivirale et/ou antibiotique. Les dérivés de triazine de la présente invention se lient aux acides nucléiques qu'ils inhibent et, de ce fait, possèdent de nombreuses applications dans le traitement d'états associés aux virus à ADN et à ARN.
PCT/US1999/000945 1998-01-13 1999-01-13 Composes de triazine antiviraux WO1999036410A1 (fr)

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JP2000540126A JP2002509140A (ja) 1998-01-13 1999-01-13 トリアジン抗ウイルス化合物
CA002318362A CA2318362A1 (fr) 1998-01-13 1999-01-13 Composes de triazine antiviraux
EP99902309A EP1053230A1 (fr) 1998-01-13 1999-01-13 Composes de triazine antiviraux

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JP2003519130A (ja) * 1999-12-28 2003-06-17 ファーマコペイア， インコーポレイテッド Ｎ−ヘテロ環ＴＮＦ−α発現阻害剤
US6680315B2 (en) 2000-06-15 2004-01-20 Synta Pharmaceuticals Corp. Triazine compounds
GB2397301A (en) * 2003-01-14 2004-07-21 Novo Pharmaceuticals Ltd De Substituted 1,3,5-triazine derivatives
WO2005058875A1 (fr) * 2003-12-19 2005-06-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes de piperazine triazine, leur obtention, et preparations pharmaceutiques les contenant
US7015227B2 (en) 2002-06-21 2006-03-21 Cgi Pharmaceuticals, Inc. Certain amino-substituted monocycles as kinase modulators
JP2006511476A (ja) * 2002-09-23 2006-04-06 レディ ユーエス セラピューティクス インコーポレイテッド 新規トリアジン化合物の組成物および方法
US7112587B2 (en) 2001-09-21 2006-09-26 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7132423B2 (en) 2001-09-21 2006-11-07 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7163943B2 (en) 2001-09-21 2007-01-16 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7169785B2 (en) 2001-09-21 2007-01-30 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
WO2007071199A1 (fr) * 2005-12-22 2007-06-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes de 2,4-disubstituee amido-6-substituee-[1,3,5]triazine ou de 1,3-pyrimidine, leurs procedes d'elaboration, et preparations pharmaceutiques les contenant et leurs utilisations
US7335770B2 (en) 2004-03-24 2008-02-26 Reddy U5 Therapeutics, Inc. Triazine compounds and their analogs, compositions, and methods
WO2008016547A3 (fr) * 2006-07-31 2008-04-10 Praecis Pharm Inc Inhibiteurs de kinases aurora provenant d'une bibliothèque de petites molécules codées
US7375222B2 (en) 2002-02-05 2008-05-20 Astellas Pharma Inc. 2,4,6-Triamino-1,3,5-triazine derivative
WO2008147540A1 (fr) * 2007-05-23 2008-12-04 New York University School Of Medicine Composés de s-triazine, compositions pharmaceutiques en contenant et leurs procédés d'utilisation
WO2009048750A3 (fr) * 2007-10-09 2009-05-28 Dow Agrosciences Llc (1,3,5)-triazinylphénylhydrazones insecticides
US7935698B2 (en) 2003-11-10 2011-05-03 Synta Pharmaceuticals Corporation Heteroaryl-hydrazone compounds
WO2012012528A1 (fr) 2010-07-20 2012-01-26 Vestaron Corporation Triazines et pyrimidines insecticides
US8119798B2 (en) 2006-08-01 2012-02-21 Glaxosmithkline Llc P38 kinase inhibitors
WO2012115575A1 (fr) * 2011-02-21 2012-08-30 Biomatcell Ab Dérivés pour induire une différenciation ostéogénique
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CN112843067A (zh) * 2019-11-26 2021-05-28 兰州大学 人源lrrk2蛋白小分子抑制剂及其应用
CN113893254A (zh) * 2021-09-07 2022-01-07 南开大学 一种去乙酰化酶sirt1变构激动剂及其应用
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JP6707763B2 (ja) * 2015-07-10 2020-06-10 国立大学法人 鹿児島大学 抗ｂ型肝炎ウイルス薬
WO2023054292A1 (fr) * 2021-09-28 2023-04-06 塩野義製薬株式会社 Composition pharmaceutique contenant un dérivé de triazine
MX2024003600A (es) * 2021-09-28 2024-04-09 Shionogi & Co Composicion farmaceutica que contiene un derivado de triazina.
KR20230119022A (ko) * 2021-11-24 2023-08-14 시오노기 앤드 컴파니, 리미티드 트라이아진 유도체를 함유하는 경구 투여하는 제제
JP7273455B1 (ja) * 2022-01-19 2023-05-15 塩野義製薬株式会社 新型コロナウイルス感染症治療用医薬

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JP2003519130A (ja) * 1999-12-28 2003-06-17 ファーマコペイア， インコーポレイテッド Ｎ−ヘテロ環ＴＮＦ−α発現阻害剤
US7045517B2 (en) 2000-06-15 2006-05-16 Synta Pharmaceuticals Corp. Triazine compounds
US6680315B2 (en) 2000-06-15 2004-01-20 Synta Pharmaceuticals Corp. Triazine compounds
US7335656B2 (en) 2001-09-21 2008-02-26 Reddy Us Therapeutics, Inc. Medical devices employing triazine compounds and compositions thereof
US7332488B2 (en) 2001-09-21 2008-02-19 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7332490B2 (en) 2001-09-21 2008-02-19 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7268134B2 (en) 2001-09-21 2007-09-11 Reddy Us Therapeutics, Inc. Medical devices employing triazine compounds and compositions thereof
US7265114B2 (en) 2001-09-21 2007-09-04 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7112587B2 (en) 2001-09-21 2006-09-26 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7132423B2 (en) 2001-09-21 2006-11-07 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7163943B2 (en) 2001-09-21 2007-01-16 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7169785B2 (en) 2001-09-21 2007-01-30 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7169784B2 (en) 2001-09-21 2007-01-30 Reddy Us Therapeutics, Inc. Medical devices employing triazine compounds and compositions thereof
US7173032B2 (en) 2001-09-21 2007-02-06 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
US7238692B2 (en) 2001-09-21 2007-07-03 Reddy Us Therapeutics, Inc. Medical devices employing triazine compounds and compositions thereof
US7375222B2 (en) 2002-02-05 2008-05-20 Astellas Pharma Inc. 2,4,6-Triamino-1,3,5-triazine derivative
US7015227B2 (en) 2002-06-21 2006-03-21 Cgi Pharmaceuticals, Inc. Certain amino-substituted monocycles as kinase modulators
JP2006188533A (ja) * 2002-09-23 2006-07-20 Reddy Us Therapeutics Inc 新規トリアジン化合物の組成物および方法
JP2006511476A (ja) * 2002-09-23 2006-04-06 レディ ユーエス セラピューティクス インコーポレイテッド 新規トリアジン化合物の組成物および方法
US7332489B2 (en) 2002-09-23 2008-02-19 Reddy Us Therapeutics, Inc. Methods and compositions of novel triazine compounds
GB2397301A (en) * 2003-01-14 2004-07-21 Novo Pharmaceuticals Ltd De Substituted 1,3,5-triazine derivatives
US7935698B2 (en) 2003-11-10 2011-05-03 Synta Pharmaceuticals Corporation Heteroaryl-hydrazone compounds
WO2005058875A1 (fr) * 2003-12-19 2005-06-30 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes de piperazine triazine, leur obtention, et preparations pharmaceutiques les contenant
US7335770B2 (en) 2004-03-24 2008-02-26 Reddy U5 Therapeutics, Inc. Triazine compounds and their analogs, compositions, and methods
WO2007071199A1 (fr) * 2005-12-22 2007-06-28 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Composes de 2,4-disubstituee amido-6-substituee-[1,3,5]triazine ou de 1,3-pyrimidine, leurs procedes d'elaboration, et preparations pharmaceutiques les contenant et leurs utilisations
CN101245051B (zh) * 2005-12-22 2011-04-20 中国科学院上海药物研究所 2，4-二取代氨基-6-取代-[1，3，5]三嗪类化合物、其制备方法、药物组合物及用途
JP2009545592A (ja) * 2006-07-31 2009-12-24 プリーシス・ファーマシューティカルズ・インコーポレイテッド コード化小分子ライブラリーからのオーロラキナーゼ阻害剤
WO2008016547A3 (fr) * 2006-07-31 2008-04-10 Praecis Pharm Inc Inhibiteurs de kinases aurora provenant d'une bibliothèque de petites molécules codées
US8138338B2 (en) 2006-07-31 2012-03-20 Glaxosmithkline Llc Aurora kinase inhibitors from an encoded small molecule library
US8119798B2 (en) 2006-08-01 2012-02-21 Glaxosmithkline Llc P38 kinase inhibitors
WO2008147540A1 (fr) * 2007-05-23 2008-12-04 New York University School Of Medicine Composés de s-triazine, compositions pharmaceutiques en contenant et leurs procédés d'utilisation
US8163748B2 (en) 2007-05-23 2012-04-24 New York University s-Triazine compounds, pharmaceutical compositions and method of using the same
EP2481730A1 (fr) 2007-10-09 2012-08-01 Dow AgroSciences LLC (1,3,5)-triazinyl phényl hydrazones insecticides
WO2009048750A3 (fr) * 2007-10-09 2009-05-28 Dow Agrosciences Llc (1,3,5)-triazinylphénylhydrazones insecticides
EP2481731A1 (fr) 2007-10-09 2012-08-01 Dow AgroSciences LLC (1,3,5)-triazinyl phényl hydrazones insecticides
WO2012012528A1 (fr) 2010-07-20 2012-01-26 Vestaron Corporation Triazines et pyrimidines insecticides
US8389718B2 (en) 2010-07-20 2013-03-05 Vestaron Corporation Insecticidal triazines and pyrimidines
CN103052628A (zh) * 2010-07-20 2013-04-17 韦斯塔隆公司 三嗪类和嘧啶类杀虫剂
US8785630B2 (en) 2010-07-20 2014-07-22 Vestaron Corporation Insecticidal triazines and pyrimidines
CN103052628B (zh) * 2010-07-20 2016-05-18 韦斯塔隆公司 三嗪类和嘧啶类杀虫剂
WO2012115575A1 (fr) * 2011-02-21 2012-08-30 Biomatcell Ab Dérivés pour induire une différenciation ostéogénique
CN110787166A (zh) * 2019-11-06 2020-02-14 中国医科大学 一种小分子化合物C28H26Cl2N8在大肠杆菌性脑膜炎中的应用
CN110787166B (zh) * 2019-11-06 2022-06-03 中国医科大学 一种小分子化合物C28H26Cl2N8在大肠杆菌性脑膜炎中的应用
CN112843067A (zh) * 2019-11-26 2021-05-28 兰州大学 人源lrrk2蛋白小分子抑制剂及其应用
CN112843067B (zh) * 2019-11-26 2023-01-06 兰州大学 人源lrrk2蛋白小分子抑制剂及其应用
CN113893254A (zh) * 2021-09-07 2022-01-07 南开大学 一种去乙酰化酶sirt1变构激动剂及其应用
CN116782904A (zh) * 2021-09-28 2023-09-19 盐野义制药株式会社 含有三嗪衍生物的医药组合物

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