WO2002079187A1 - Methoxy-1,3,5-triazine derivatives as antiviral agents - Google Patents

Methoxy-1,3,5-triazine derivatives as antiviral agents Download PDF

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Publication number
WO2002079187A1
WO2002079187A1 PCT/KR2002/000565 KR0200565W WO02079187A1 WO 2002079187 A1 WO2002079187 A1 WO 2002079187A1 KR 0200565 W KR0200565 W KR 0200565W WO 02079187 A1 WO02079187 A1 WO 02079187A1
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amino
methoxy
triazine
indazolyl
lff
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PCT/KR2002/000565
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French (fr)
Inventor
Yong-Ho Chung
Chi-Woo Lee
Wang-Yong Yang
Hak-Dong Lee
Whui-Jung Park
Yoon-Young Chang
Jin-Soo Lee
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Dong Wha Pharm. Ind. Co., Ltd
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Publication of WO2002079187A1 publication Critical patent/WO2002079187A1/en

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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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to methoxy-1 , 3, 5-triazine derivatives and their pharmaceutical composition. More specifically, the present invention relates to methoxy- 1, 3, 5-triazine derivatives and their pharmaceutically acceptable salts represented below in formula 1, which have excellent inhibitory effects on proliferation of hepatitis B virus (HBV) and hepatitis C virus (HCV) .
  • the present invention also includes the process for preparing compounds of formula 1 and their pharmaceutical composition as effective ingredients against viruses.
  • Ri is H or C ⁇ -C 3 alkyl group
  • R 2 is H; hydroxy; straight or branched C ⁇ -C alkyl group; straight or branched C ⁇ -C 3 alkoxy group; C ⁇ -C 3 hydroxyalkyl group; C 2 -C ⁇ dialkylamino group; C 3 -C ⁇ cycloalkyl group; lactam; saturated or unsaturated a 5 or 6 membered heterocyclic compounds containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with straight or branched C ⁇ C 3 alkyl group; bicyclo compounds containing 1 to 2 heteroatoms selected from N, 0 and S; or Ri and R 2 are joined to form a 5 or 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with hydroxy, straight or branched C1-C4 alkyl group, C ⁇ C 3 hydroxyalkyl group, carbamoyl, C ⁇ -C 3 alky
  • the compound of formula 1 is the stereoisomer of (R) or (S) and the present invention contains both their stereoisomers and racemic compounds.
  • Hepatitis B virus causes acute or chronic hepatitis, which may progress to liver cirrhosis and liver cancer. It is estimated that three hundred million people are infected with HBV in the world (Tiollais & Buendia, Sci . Am . , 264, 48, 1991). There have been many studies on the molecular biological characteristics of HBV and its relationship to liver diseases in order to find ways to prevent and treat hepatitis B. Various vaccines and diagnostic drugs have been developed and much effort is being focused on research to find effective anti-hepatitis B agent.
  • HBV genome consists of genes for polymerase (P) , surface protein (pre-Sl, pre-S2 and S), core protein (pre-C and C) , and X protein. Of these proteins expressed from HBV genes, polymerase, surface protein, and core protein are structural proteins and X protein has a regulatory function.
  • the gene for HBV polymerase occupies about 80% of the whole virus genome and produces a protein of 94kD size with 845 amino acids, which has several functions in the replication of virus genome.
  • This polypeptide includes sequences responsible for activities of protein primer, RNA dependent DNA polymerase, DNA dependent DNA polymerase, and RNase H. Kaplan and his coworkers first discovered reverse transcriptase activities of polymerase, which led to many studies on replicating mechanism of HBV.
  • DNAs are synthesized by the action of HBV polymerase, attached to short chain to form complete double helix for HBV genome.
  • Complete double helical DNA genome of HBV produces pre-genomic mRNA and mRNAs of core protein, surface protein, and regulatory protein by the action of RNA polymerase. Using these mRNAs, virus proteins are synthesized.
  • Polymerase has an important function in the production of virus genome, forming a structure called replicasome with core protein and pre-genomic mRNA. This process is called encapsidation.
  • Polymerase has repeated units of glutamic acid at the 3' -end with high affinity for nucleic acids, which is responsible for facile encapsidation.
  • (-) DNA strand is synthesized by reverse transcribing action of HBV polymerase and (+) DNA strand is made by the action of DNA dependent DNA polymerase and the (+) DNA strand produces pre-genomic mRNAs. The whole process is repeated until the pool of more than 200 to 300 genomes is maintained (Tiollais and Buendia, Scien tific American , 264: 48-54, 1991).
  • nucleoside compounds such as lamivudine and famvir have been reported to be useful inhibitors of HBV proliferation, although they have been originally developed as therapeutics for the treatment of acquired immune deficiency syndrome (AIDS; referred as "AIDS" hereinafter) and herpes zoster infection (Germ, J. L, Hepa tology, 14: 198-199, 1991; Lok, A. S. P., J. Viral Hepa ti tis, 1: 105-124, 1994; Dienstag, J. L. et al . , New England Journal of Medicine, 333: 1657-1661, 1995).
  • AIDS acquired immune deficiency syndrome
  • nucleoside compounds are considered a poor choice for treatment of hepatitis B because of their high cost and side effects such as toxicity, appearance of resistant virus and recurrence of the disease after stopping treatment.
  • Effort to find therapeutics for hepatitis B among non-nucleoside compounds has been continued and antiviral effects against HBV have been reported for quinolone compounds (EP 563732, EP 563734), iridoides compounds (KR 94-1886) , and terephthalic amide derivatives (KR 96-72384, KR 97-36589, KR 99-5100) .
  • effective drugs for hepatitis B have not been developed yet and therapeutic method mainly depends on symptomatic treatments.
  • HCV Hepatitis C virus
  • HCV genome is single stranded (+)-RNA of 9.5 kb in length and express polyprotein consisting of 3010 amino acids.
  • the HCV polyprotein is cleaved co- and posttranslationally by cellular and viral protease to yield 3 structural proteins and 6 nonstructural proteins.
  • 5'- and 3' -terminus of the HCV genome contain untranslated regions (UTR) , which have highly conserved nucleotide sequence of all most genotype. Recently, it is known that 5' -UTR is a 330 ⁇ 341 nucleotide sequence and 3'- UTR includes 98 nucleotides at the back of poly A, termed to X region which might be played a role of RNA replication and translation of virus.
  • Amino end part of HCV genome produces structural proteins (Core, El and E2) and the other part produces non-structural proteins.
  • the core is the main structural component of the viral capsid and the envelope protein consists of El and E2. These proteins are cleaved by signal peptidase in endoplasmic reticulum. Serin-type protease NS3 and cofactor NS4A cleaves nonstructural proteins.
  • NS5B protein is a RNA-dependant RNA polymerase. This protein plays an important role in the regulation of H
  • HCV infection presents a major public health problem worldwide because the community-acquired HCV infection hasn't regulated yet. From the viewpoint of retrospective studies, HCV infection distributes worldwide and 1.5 - 2% of the world's population is infected.
  • HCV infection is generally developed into chronic hepatitis and has a high probability of progression to liver cirrhosis and liver cancer. Because hepatitis C virus belongs to completely different family, it cannot be inhibited using HBV vaccine.
  • the treatment of ⁇ -interferon has been tried, but its antiviral effect depends on the genotypes of HCV and the shown effect is also weak. Since HCV was discovered in 1987, there has been attempted a lot of research, but remarkably effective drug hasn't yet developed.
  • ⁇ -Interferon is the unique choice for the treatment so far, but it has confirmed that the its medical care rate is less than 30%, HCV is recurred after cessation of its treatment and several interferon-resistant mutant virus generates. So far, there aren't specific antiviral agents with proliferation inhibitory activity against HCV.
  • the present invention provides methoxy-1, 3, 5-triazine derivatives represented by following formula 1 and their pharmaceutically acceptable salts:
  • Ri is H or C ⁇ -C 3 alkyl group
  • R 2 is H; hydroxy; straight or branched C 1 -C 4 alkyl group; straight or branched C ⁇ -C 3 alkoxy group; C ⁇ C 3 hydroxyalkyl group; C 2 -C 6 dialkylamino group; C 3 -C 6 cycloalkyl group; lactam; saturated or unsaturated a 5 or 6 membered heterocyclic compounds containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with straight or branched C ⁇ C 3 alkyl group;
  • R 3 is 5-indazolyl or 6-indazolyl group.
  • the compound of formula 1 is the stereoisomer of (R) or (S) and the present invention contains both their stereoisomers and racemic compounds.
  • R is hydrogen atom
  • R 2 is hydroxy, methyl, ethyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, pyrrolyl, indolyl, pyridinyl, pyrrolidinyl, imidazolyl, piperidinyl or isonicotinyl group, n is an integer between 0 and 3.
  • 5-indazoly and 6-indazolyl group represent below in formula 2 and formula 3.
  • More preferable compounds in accordance with the present invention are as follows; 1) 2- ( lff-5-indazolyl) amino-4-methoxy-6- (2-morpholino ethyl) amino-1 , 3, 5-triazine;
  • the compounds represented by formula 1 of the present invention may be utilized in the form of salts and the acid addition salts prepared by adding pharmaceutically acceptable free acids are useful.
  • Compounds of formula 1 may be changed to the corresponding acid addition salts according to the general practices in this field.
  • Both inorganic and organic acids may be used as free acids in this case.
  • inorganic acids hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid may be used.
  • citric acid citric acid, acetic acid, lactic acid, tarta ⁇ c acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid or aspartic acid
  • organic acids citric acid, acetic acid, lactic acid, tarta ⁇ c acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid or aspartic acid may be used.
  • the present invention also provides a process for preparing methoxy-1, 3, 5-triazine derivatives of formula 1, represented by scheme 1 as follows: scheme 1
  • the process for preparing in the present invention comprises the following steps of:
  • step 1 1) reacting 2 , 4-dichloro-6-methoxy-l, 3, 5-triazine (4_) with 5-aminoindazole or 6-aminoindazole (_5) in the presence of a base in order to prepare 2-chloro-6- methoxy-1, 3, 5-triazine derivatives substituted with aminoindazole (_6) (step 1); and
  • step 2 Chemical reagents used as starting and reaction materials in the scheme 1, namely, 2 , 4-dichloro-6- methoxytriazine (4_) , 5-aminoindazole, 6-aminoindazole (5_) and amine compounds ( 7_) , are commercially available and may be purchased or can be easily done by one with general knowledge in the technical field.
  • step 1 2-chloro-6-methoxy-l, 3, 5-triazine derivatives (_6) was prepared by reaction of the 2,4- dichloro-6-methoxy-l , 3, 5-triazine (4_) with 5-aminoindazole or 6-aminoindazole in the presence of the base at the proper conditions (temperature and solvent).
  • tertiary organic base having weak basicity such as triethylamine, N. N- diisopropylethylamine, ⁇ J-methylmorpholine, N- methylpiperidine, 4-dimethylaminopyridine, N, N- dimethylaniline, 2 , 6-lutidine, pyridine.
  • the reaction temperature is preferably 0 ⁇ 10 ° C .
  • a solvent a single or a mixture of solvents selected from chloroform, methylene chloride, acetonitrile, tetrahydrofuran, methanol, ethanol is preferable.
  • compounds of the formula 1 is prepared by reacting 2-chloro-6-methoxy-l , 3, 5-triazine obtained by step 1 with amine compound at the proper conditions (solvent , temperature) .
  • the amine compound (5_) in the step 2 is also used to introduce Ri, R 2 substituents into the desired compound of formula 1 and an appropriate amine compound should be selected depending on the substituent desired.
  • amine compounds (7_) a re methyamine, ethylamine, isopropylamine, cyclopropylamine, ethanolamine, propanolamine, morpholine and piperazine, etc. It is advisable to use the amine compound (7_) a bit excess to increase the yield.
  • the base using in step 2 is the same one of the step 1 and tertiary organic base is preferred.
  • reaction solvent is single or mixed solvent selected from the type of alcohol (as methanol, ethanol, isopropanol, etc) , acetonitrile, chloroform and methylene chloride, etc.
  • the reaction temperature may be changed by the class of the amine compound (7_) and is preferably 0 ⁇ 10 ° C .
  • the present invention provides the pharmaceutical compositions of therapeutics containing methoxy-1, 3, 5-triazine derivatives and their pharmaceutically acceptable salts of formula 1 as effective ingredients to prevent and treat hepatitis B.
  • the present invention also provides the pharmaceutical compositions of therapeutics containing methoxy-1 , 3, 5- triazine derivatives and their pharmaceutically acceptable salts of formula 1 as effective ingredients to prevent and treat hepatitis C.
  • Compounds of formula 1 may be taken orally as well as through other routes in clinical uses; for example, it may be administered intravenously, subcutaneously, intraperitoneally, locally and in the form of general drugs.
  • compounds of formula 1 may be mixed with pharmaceutically acceptable excipients and made into various pharmaceutically acceptable forms; for example, tablets, capsules, trochese, solutions, suspensions for oral administration; injection solutions, suspensions, and dried powder to be mixed with distilled water for the formulation of instant injection solution.
  • Effective dosage for compound of formula 1 is generally 10—500 mg/kg, preferably 50 ⁇ 300 mg/kg for adults, which may
  • ⁇ Preparation example 1> preparation of 2-chloro-4- (1H-5- indazolyl) amino-6-methoxy-1 , 3 , 5-triazine
  • Example 1> preparation of 2- (lH-5-indazolylamino) -4- methoxy-6- (2-morpholinoethyl) amino-1 , 3 , 5-triazine
  • Example 2 preparation of 2- (lH-6-indazolylamino) -4- methoxy-6- (2-morpholinoethyl) amino-1 , 3 , 5-triazine
  • the example 3-example 50 were prepared according to the synthetic method of example 1 and 2.
  • the table 1 showed melting point, yield, nomenclature, staring material (6) and amines (7) of compound 3-50.
  • the table 2 is showed ⁇ ' ⁇ -NMR result of compound 3-50.
  • Injection solution containing effective ingredient 50mg was made in following method.
  • the compound 5g of example 1, sodium chloride 0.6g and ascorbic acid O.lg were solved in distilled water to be 100ml volume totally. This solution sterilized for 30 minutes at 60 ° C.
  • Preparation 2 Preparation of tablet Tablet containing effective ingredient 60mg was made in following method.
  • the compound of example 1 was mixed with lactose 175.9g, starch 180g and colloidal silicic acid 32g. 10% gellatin solution was added to this mixture and the mixture was ground, filtered in 14 mesh and dried. Finally, starch 160g, talc 50g and stearic acid magnesium salts 5g were added to the mixture and tablet was formed.
  • the present inventors submitted application for a patent concerning HBV polymerase genetically expressed in and separated from E. col i , the process of their preparation, and the method to measure the enzyme activities (KR 94-3918, KR 96-33998).
  • HBV polymerase was used which had been expressed in E . coli as stated above.
  • the method used in the present invention to measure in vi tro reverse transcribing activities of HBV polymerase is as follows. Basic principles are the same as those for ELISA, nucleotides with biotin- or digoxigenin- group are included as substrates and anti-DIG antibodies attached to peroxidase enzyme recognize the polymerized substrates.
  • reaction buffer solution [Tris-Cl (pH 7.5) 0.1 M, NaCl 0.1 M, MgCl 2 0.01 M, KC1 0.2 M, EDTA 0.002 M, DTT 0.05 M] were added to a well coated with streptavidin. 10 ⁇ l of reaction mixture containing poly A/UTP,as a RNA template-primer, DIG- UTP, biotin-UTP and UTP were added and subsequently test compounds prepared were also added at the final concentration of 10, 1 and 0.1 ⁇ g/ml. The mixture was
  • HCV polymerase the action of HCV polymerase
  • streptavidin coated on the bottom of wells due to dioxigenin and biotin attached to nucleotides.
  • the compounds used in the experiments have higher than 100 for IC 50 and are considered to have little cytotoxicity.
  • novel methoxy-1, 3, 5-triazine derivatives represented by formula 1 of the present invention have the dramatic inhibitory effect on proliferation of HBV and HCV with little side effect, and may be useful as therapeutic agents for prevention and treatment of hepatitis B and C.
  • compounds of the present invention being non- nucleosidic, do not have problems such as toxicity and early development of resistant virus strains observed by nucleoside substances.
  • compounds of the present invention may be used together with nucleoside compounds since the former seem to act on allosteric binding pockets while the latter work in the domain of polymerase activities.

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Abstract

Methoxy-1,3,5-triazine derivatives and their pharmaceutically acceptable salts are described in which the derivatives have excellent inhibitory effects on proliferation of hepatitis B virus(HBV) and hepatitis C virus(HCV) so that they can be easily used as an effective ingredient against viruses. In addition, the process for preparing the derivatives is also described.

Description

METHOXY-l,3,5-TRIAZINE DERIVATIVES AS ANTIVIRAL AGENTS
TECHNICAL FIELD
The present invention relates to methoxy-1 , 3, 5-triazine derivatives and their pharmaceutical composition. More specifically, the present invention relates to methoxy- 1, 3, 5-triazine derivatives and their pharmaceutically acceptable salts represented below in formula 1, which have excellent inhibitory effects on proliferation of hepatitis B virus (HBV) and hepatitis C virus (HCV) . The present invention also includes the process for preparing compounds of formula 1 and their pharmaceutical composition as effective ingredients against viruses.
Figure imgf000002_0001
wherein,
Ri is H or Cι-C3 alkyl group,
R2 is H; hydroxy; straight or branched Cι-C alkyl group; straight or branched Cι-C3 alkoxy group; Cι-C3 hydroxyalkyl group; C2-Cδ dialkylamino group; C3-Cε cycloalkyl group; lactam; saturated or unsaturated a 5 or 6 membered heterocyclic compounds containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with straight or branched Cι~C3 alkyl group; bicyclo compounds containing 1 to 2 heteroatoms selected from N, 0 and S; or Ri and R2 are joined to form a 5 or 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with hydroxy, straight or branched C1-C4 alkyl group, Cι~C3 hydroxyalkyl group, carbamoyl, Cχ-C3 alkylcarbamoyl , Cι~C3 alkoxycarbonyl group, aryl group, or arylcarbonyl group, n is an integer of 0 to 4, R3 is 5-indazolyl or 6-indazolyl group.
In the case that R2 has the chiral carbon, the compound of formula 1 is the stereoisomer of (R) or (S) and the present invention contains both their stereoisomers and racemic compounds.
BACKGROUND OF THE INVENTION
Hepatitis B virus (HBV; referred as "HBV" hereinafter) causes acute or chronic hepatitis, which may progress to liver cirrhosis and liver cancer. It is estimated that three hundred million people are infected with HBV in the world (Tiollais & Buendia, Sci . Am . , 264, 48, 1991). There have been many studies on the molecular biological characteristics of HBV and its relationship to liver diseases in order to find ways to prevent and treat hepatitis B. Various vaccines and diagnostic drugs have been developed and much effort is being focused on research to find effective anti-hepatitis B agent.
HBV genome consists of genes for polymerase (P) , surface protein (pre-Sl, pre-S2 and S), core protein (pre-C and C) , and X protein. Of these proteins expressed from HBV genes, polymerase, surface protein, and core protein are structural proteins and X protein has a regulatory function.
The gene for HBV polymerase occupies about 80% of the whole virus genome and produces a protein of 94kD size with 845 amino acids, which has several functions in the replication of virus genome. This polypeptide includes sequences responsible for activities of protein primer, RNA dependent DNA polymerase, DNA dependent DNA polymerase, and RNase H. Kaplan and his coworkers first discovered reverse transcriptase activities of polymerase, which led to many studies on replicating mechanism of HBV.
HBV enters liver when antigenic protein on virion surface is recognized by hepatic cell-specific receptor. Inside the liver cell, DNAs are synthesized by the action of HBV polymerase, attached to short chain to form complete double helix for HBV genome. Complete double helical DNA genome of HBV produces pre-genomic mRNA and mRNAs of core protein, surface protein, and regulatory protein by the action of RNA polymerase. Using these mRNAs, virus proteins are synthesized. Polymerase has an important function in the production of virus genome, forming a structure called replicasome with core protein and pre-genomic mRNA. This process is called encapsidation. Polymerase has repeated units of glutamic acid at the 3' -end with high affinity for nucleic acids, which is responsible for facile encapsidation. When replicasome is formed, (-) DNA strand is synthesized by reverse transcribing action of HBV polymerase and (+) DNA strand is made by the action of DNA dependent DNA polymerase and the (+) DNA strand produces pre-genomic mRNAs. The whole process is repeated until the pool of more than 200 to 300 genomes is maintained (Tiollais and Buendia, Scien tific American , 264: 48-54, 1991).
Recently, nucleoside compounds such as lamivudine and famvir have been reported to be useful inhibitors of HBV proliferation, although they have been originally developed as therapeutics for the treatment of acquired immune deficiency syndrome (AIDS; referred as "AIDS" hereinafter) and herpes zoster infection (Germ, J. L, Hepa tology, 14: 198-199, 1991; Lok, A. S. P., J. Viral Hepa ti tis, 1: 105-124, 1994; Dienstag, J. L. et al . , New England Journal of Medicine, 333: 1657-1661, 1995). However, these nucleoside compounds are considered a poor choice for treatment of hepatitis B because of their high cost and side effects such as toxicity, appearance of resistant virus and recurrence of the disease after stopping treatment. Effort to find therapeutics for hepatitis B among non-nucleoside compounds has been continued and antiviral effects against HBV have been reported for quinolone compounds (EP 563732, EP 563734), iridoides compounds (KR 94-1886) , and terephthalic amide derivatives (KR 96-72384, KR 97-36589, KR 99-5100) . In spite of much effort, however, effective drugs for hepatitis B have not been developed yet and therapeutic method mainly depends on symptomatic treatments.
Hepatitis C virus (referred as "HCV" hereinafter) is a virus that belongs to the flaviviridae having a membrane. HCV genome is single stranded (+)-RNA of 9.5 kb in length and express polyprotein consisting of 3010 amino acids. The HCV polyprotein is cleaved co- and posttranslationally by cellular and viral protease to yield 3 structural proteins and 6 nonstructural proteins.
5'- and 3' -terminus of the HCV genome contain untranslated regions (UTR) , which have highly conserved nucleotide sequence of all most genotype. Recently, it is known that 5' -UTR is a 330~341 nucleotide sequence and 3'- UTR includes 98 nucleotides at the back of poly A, termed to X region which might be played a role of RNA replication and translation of virus. Amino end part of HCV genome produces structural proteins (Core, El and E2) and the other part produces non-structural proteins. The core is the main structural component of the viral capsid and the envelope protein consists of El and E2. These proteins are cleaved by signal peptidase in endoplasmic reticulum. Serin-type protease NS3 and cofactor NS4A cleaves nonstructural proteins. NS5B protein is a RNA-dependant RNA polymerase. This protein plays an important role in the regulation of HCV replication.
It is reported that an infection by HCV is generated from a blood transfusion and community-acquired infection. Approximately 70% of HCV infected individuals will develop chronic hepatitis, of which 20% will progress to severe chronic liver disease within 5 years. Such higher progression rate, rarely in RNA virus, shows that HCV is a major cause of generating liver cancer. Mechanism studies of the continuous infection of HCV have not been reported. HCV test is therefore carried out in all blood and the infection opportunity by the blood transfusion is remarkably decreased. But, HCV infection presents a major public health problem worldwide because the community-acquired HCV infection hasn't regulated yet. From the viewpoint of retrospective studies, HCV infection distributes worldwide and 1.5 - 2% of the world's population is infected. Compared to HBV, HCV infection is generally developed into chronic hepatitis and has a high probability of progression to liver cirrhosis and liver cancer. Because hepatitis C virus belongs to completely different family, it cannot be inhibited using HBV vaccine. The treatment of α-interferon has been tried, but its antiviral effect depends on the genotypes of HCV and the shown effect is also weak. Since HCV was discovered in 1987, there has been attempted a lot of research, but remarkably effective drug hasn't yet developed. α-Interferon is the unique choice for the treatment so far, but it has confirmed that the its medical care rate is less than 30%, HCV is recurred after cessation of its treatment and several interferon-resistant mutant virus generates. So far, there aren't specific antiviral agents with proliferation inhibitory activity against HCV.
Therefore, we, inventors of the present invention, tried to develop therapeutics to treat hepatitis B with little chance of toxicity, side effects, and development of resistant viral strains. We found the compounds with excellent antiviral effect against HBV; synthesized novel methoxy-1 , 3, 5-triazine derivatives represented in formula 1 and completed the invention by showing their dramatic inhibitory effect on proliferation of HCV as well as of HBV.
SUMMARY OF THE INVENTION It is an objective of this invention to provide methoxy-1, 3, 5-triazine derivatives, their pharmaceutically acceptable salts, and the process for preparing them.
It is a further objective of this invention to provide a pharmaceutical composition containing derivatives stated above with cost effectiveness and little chance of side effects, as a therapeutic agent as well as a preventive agent for hepatitis B and hepatitis C.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides methoxy-1, 3, 5-triazine derivatives represented by following formula 1 and their pharmaceutically acceptable salts:
Figure imgf000009_0001
wherein ,
Ri is H or Cι-C3 alkyl group,
R2 is H; hydroxy; straight or branched C1-C4 alkyl group; straight or branched Cι-C3 alkoxy group; Cι~C3 hydroxyalkyl group; C2-C6 dialkylamino group; C3-C6 cycloalkyl group; lactam; saturated or unsaturated a 5 or 6 membered heterocyclic compounds containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with straight or branched Cι~C3 alkyl group;
bicyclo compounds containing 1 to 2 heteroatoms selected from N, 0 and S; or Ri and R2 are joined to form a 5 or 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with hydroxy, straight or branched C1-C4 alkyl group, Cι~C3 hydroxyalkyl group, carbamoyl, Cι~C alkylcarbamoyl, Cι-C3 alkoxycarbonyl group, aryl group, or arylcarbonyl group, n is an integer of 0 to 4,
R3 is 5-indazolyl or 6-indazolyl group.
In the case that R2 has the chiral carbon, the compound of formula 1 is the stereoisomer of (R) or (S) and the present invention contains both their stereoisomers and racemic compounds.
More preferably, wherein,
R is hydrogen atom,
R2 is hydroxy, methyl, ethyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, pyrrolyl, indolyl, pyridinyl, pyrrolidinyl, imidazolyl, piperidinyl or isonicotinyl group, n is an integer between 0 and 3.
In the present invention, 5-indazoly and 6-indazolyl group represent below in formula 2 and formula 3.
Figure imgf000011_0001
More preferable compounds in accordance with the present invention are as follows; 1) 2- ( lff-5-indazolyl) amino-4-methoxy-6- (2-morpholino ethyl) amino-1 , 3, 5-triazine;
2) 2- (lff-6-indazolyl) amino-4-methoxy-β- (2-morpholino ethyl) amino-1, 3, 5-triazine;
3) 2- ( 1ff-5-indazolyl) amino-4 -methoxy-6-methylamino-l, 3,5- triazine;
4) 2- (Iff- 6-indazolyl) amino-4 -methoxy-6-methylamino-l, 3,5- triazine;
5) 2- ( lff-5-indazolyl) amino-4-isopropylamino-6-methoxy-l, 3, 5- triazine; 6) 2- (lff-6-indazolyl) amino-4-isopropylamino-6-methoxy-l, 3, 5- triazine;
7) 2-cyclopropylamino-4- (lff-5-indazolyl) amino-6-methoxy-
1,3, 5-triazine;
8) 2-cyclopropylamino-4- ( Iff-6-indazolyl) amino- 6-methoxy- 1 , 3 , 5-triazine;
9) 2- ( Iff-5-indazolyl) amino-4 -methoxy- 6- (2-methoxy ethyl) amino- 1, 3, 5-triazine;
10) 2- (Iff- 6-indazolyl) amino-4 -methoxy- 6- (2-methoxy ethyl) amino-1, 3, 5-triazine;
11 ) 2- (2-hydroxyethyl ) amino-4- (lff-5-indazolyl) amino-6- methoxy-1, 3, 5-triazine;
12 ) 2- (2-hydroxyethyl ) amino-4- ( Iff- 6-indazolyl) amino- 6- methoxy-1, 3, 5-triazine; 13) 2- (2-dimethylaminoethyl) amino-4- ( lff-5-indazolyl) amino-6- methoxy-1, 3, 5-triazine;
14 ) 2- ( Iff-5-indazolyl) amino-4-methoxy-6-morpholinoamino-
1,3, 5-triazine;
15 ) 2- ( Iff- 6-indazolyl) amino-4-methoxy-6-morpholinoamino- 1, 3, 5-triazine;
16) 2- ( Iff-5-indazolyl) amino-4 -methoxy- 6- ( 4-methyl ) piperazine amino-1 ,3, 5-triazine; 17 ) 2- ( Iff- 6-indazolyl) amino-4 -methoxy- 6- ( 4 -methyl ) piperazine amino-1 ,3, 5-triazine ; 18) 2- (lff-5-indazolyl) amino-4-methoxy-6- (2- (2-pyridyl) ethyl) amino-1 , 3, 5-triazine;
19) 2- (lff-6-indazolyl) amino-4-methoxy-6- (2- (2-pyridyl) ethyl) amino-1, 3, 5-triazine;
20) 2- (lff-5-indazolyl) amino-4-methoxy-6- (3- (2-oxo- pyrrolidino) propyl) amino-1, 3, 5-triazine; 21) 2- (lff-6-indazolyl) amino-4-methoxy-6- (3- (2-oxo- pyrrolidino) propyl) amino-1, 3, 5-triazine;
22) 2- (lff-5-indazolyl) amino-4- (2- ( lff-3-indolyl) ethyl) amino- 6-methoxy-l, 3, 5-triazine; 23) 2- (lff-6-indazolyl) amino-4- (2- (lff-3-indolyl) ethyl) amino- 6-methoxy-l, 3, 5-triazine;
24) 2- (3- (lff-1-imidazolyl) propyl) amino-4- ( lff-5-indazolyl ) amino-6-methoxy-l, 3, 5-triazine;
25) 2- (3- (lff-1-imidazolyl) propyl) amino-4- ( Iff-6-indazolyl) amino-6-methoxy-l, 3, 5-triazine;
26) 2- (lff-5-indazolyl) amino-4-methoxy-6-morpholino-l, 3, 5- triazine;
27 ) 2- (Iff-6-indazolyl) amino-4-methoxy-6-morpholino-1, 3,5- triazine; 28) 2- (lff-1-imidazolyl) -4- ( lff-6-indazolyl ) amino-6-methoxy- 1,3, 5-triazine;
29) 2- (lff-5-indazolyl) amino-4-methoxy-6-pyrrolidino-l, 3, 5- triazine;
30) 2- (lff-6-indazolyl) amino-4-methoxy-6-pyrrolidino-l, 3, 5- triazine;
31) 2- (lff-6-indazolyl) amino-4-methoxy-6- ( (2S) -methoxy carbonyl) pyrrolidino-1, 3, 5-triazine;
32) 2- (4-hydroxy) piperidino-4- ( lff-5-indazolyl) amino-6- methoxy-1, 3, 5-triazine; 33) 2- (4-hydroxy) piperidino-4- (lff-6-indazolyl) amino-6- methoxy-1, 3, 5-triazine; 34 ) 2- (4-amido) piperidino-4- (Iff-5-indazolyl) amino-6-methoxy- 1,3, 5-triazine;
35) 2- ( 4-amido) piperidino-4- (Iff-6-indazolyl) amino-6-methoxy- 1, 3, 5-triazine;
36) 2- (lff-5-indazolyl) amino-4-methoxy-6- (4-Λf-methylamido) piperidino-1, 3, 5-triazine;
37 ) 2- (4-ethoxycarbonyl) piperidino-4- ( lff-5-indazolyl) amino- 6-methoxy-l, 3, 5-triazine; 38) 2- ( lff-5-indazolyl) amino-4-methoxy-6- (4-methyl) piperazino -1,3, 5-triazine;
39) 2- ( Iff-6-indazolyl) amino-4-methoxy- 6- (4-methyl) piperazino -1,3, 5-triazine;
40) 2- (4- (2-hydroxyethyl) )piperazino-4- (lff-5-indazolyl) amino -6-methoxy-l, 3, 5-triazine;
41 ) 2- (4- (2-hydroxyethyl) ) piperazino-4- ( Iff- 6-indazolyl) amino -6-methoxy-l, 3, 5-triazine;
42 ) 2- ( 4-ethoxycarbonyl) piperazino-4- ( Iff-5-indazolyl) amino- 6-methoxyl-l, 3, 5-triazine; 43) 2- (lff-5-indazolyl) amino-4-methoxy-6- (4- (Λf-methylamido methyl) )piperazino-l, 3, 5-triazine; 44 ) 2- (Iff-6-indazolyl) amino-4 -methoxy- 6- (4- (Λ.-methylamido methyl) )pipe azino-l, 3, 5-triazine; 45) 2- (lff-5-indazolyl) amino-4-methoxy-6- ( 4-nicotinoyl) piperazino-1, 3, 5-triazine; 46 ) 2- ( lff- 6-mdazolyl ) amιno-4 -methoxy- 6- ( 4 -nιcotmoyl ) pιperazmo-1 , 3 , 5-tnazme ;
47 ) 2- ( 4 - ( 5-ethoxycarbonyl-2 -methylthιo-l , 3-pyrιmιdmyl ) ) pιperazmo-4 - ( lff-5-mdazolyl ) ammo- 6 -methoxy-1 , 3 , 5- triazme ;
48) 2- (4- (5-ethoxycarbonyl-2-methylthιo-l, 3-pyrιmιdmyl) ) pιperazmo-4- (lff-6-mdazolyl) ammo-6-methoxy-l, 3,5- tπazme;
49) 2- ( lff-5-mdazolyl) ammo-4-methoxy-6- (3-morpholmopropyl) ammo-1 , 3, 5-trιazme; and
50) 2- ( Iff-6-indazolyl) ammo-4 -methoxy-6- (3-morpholmopropyl) ammo-1, 3,5-trιazme.
The compounds represented by formula 1 of the present invention may be utilized in the form of salts and the acid addition salts prepared by adding pharmaceutically acceptable free acids are useful. Compounds of formula 1 may be changed to the corresponding acid addition salts according to the general practices in this field. Both inorganic and organic acids may be used as free acids in this case. Among inorganic acids, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid may be used. Among organic acids, citric acid, acetic acid, lactic acid, tartaπc acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid or aspartic acid may be used.
The present invention also provides a process for preparing methoxy-1, 3, 5-triazine derivatives of formula 1, represented by scheme 1 as follows: scheme 1
Figure imgf000016_0001
(wherein, Rl r R2, R3 and n are as defined in formula 1.)
The process for preparing in the present invention comprises the following steps of:
1) reacting 2 , 4-dichloro-6-methoxy-l, 3, 5-triazine (4_) with 5-aminoindazole or 6-aminoindazole (_5) in the presence of a base in order to prepare 2-chloro-6- methoxy-1, 3, 5-triazine derivatives substituted with aminoindazole (_6) (step 1); and
2) reacting thus obtained compound (_6) with amine compound ( ) in the presence of a base in order to prepare methoxy-1, 3, 5-triazine derivatives (1)
(step 2) . Chemical reagents used as starting and reaction materials in the scheme 1, namely, 2 , 4-dichloro-6- methoxytriazine (4_) , 5-aminoindazole, 6-aminoindazole (5_) and amine compounds ( 7_) , are commercially available and may be purchased or can be easily done by one with general knowledge in the technical field.
A detail description will be stepwise given of the method for preparing of methoxy-1 , 3, 5-triazine derivatives of the present invention.
In the step 1, 2-chloro-6-methoxy-l, 3, 5-triazine derivatives (_6) was prepared by reaction of the 2,4- dichloro-6-methoxy-l , 3, 5-triazine (4_) with 5-aminoindazole or 6-aminoindazole in the presence of the base at the proper conditions (temperature and solvent).
In the step 1, it is preferably used tertiary organic base having weak basicity such as triethylamine, N. N- diisopropylethylamine, ΛJ-methylmorpholine, N- methylpiperidine, 4-dimethylaminopyridine, N, N- dimethylaniline, 2 , 6-lutidine, pyridine.
The reaction temperature is preferably 0~10 °C .
For a solvent, a single or a mixture of solvents selected from chloroform, methylene chloride, acetonitrile, tetrahydrofuran, methanol, ethanol is preferable. In the step 2, compounds of the formula 1 is prepared by reacting 2-chloro-6-methoxy-l , 3, 5-triazine obtained by step 1 with amine compound at the proper conditions (solvent , temperature) . The amine compound (5_) in the step 2 is also used to introduce Ri, R2 substituents into the desired compound of formula 1 and an appropriate amine compound should be selected depending on the substituent desired. For example, These amine compounds (7_) are methyamine, ethylamine, isopropylamine, cyclopropylamine, ethanolamine, propanolamine, morpholine and piperazine, etc. It is advisable to use the amine compound (7_) a bit excess to increase the yield.
The base using in step 2 is the same one of the step 1 and tertiary organic base is preferred.
And, the reaction solvent is single or mixed solvent selected from the type of alcohol (as methanol, ethanol, isopropanol, etc) , acetonitrile, chloroform and methylene chloride, etc. The reaction temperature may be changed by the class of the amine compound (7_) and is preferably 0~10 °C .
Furthermore, the present invention provides the pharmaceutical compositions of therapeutics containing methoxy-1, 3, 5-triazine derivatives and their pharmaceutically acceptable salts of formula 1 as effective ingredients to prevent and treat hepatitis B.
The present invention also provides the pharmaceutical compositions of therapeutics containing methoxy-1 , 3, 5- triazine derivatives and their pharmaceutically acceptable salts of formula 1 as effective ingredients to prevent and treat hepatitis C.
Compounds of formula 1 may be taken orally as well as through other routes in clinical uses; for example, it may be administered intravenously, subcutaneously, intraperitoneally, locally and in the form of general drugs.
For clinical use of drugs with the pharmaceutical compositions of the present invention, compounds of formula 1 may be mixed with pharmaceutically acceptable excipients and made into various pharmaceutically acceptable forms; for example, tablets, capsules, trochese, solutions, suspensions for oral administration; injection solutions, suspensions, and dried powder to be mixed with distilled water for the formulation of instant injection solution.
Effective dosage for compound of formula 1 is generally 10—500 mg/kg, preferably 50~300 mg/kg for adults, which may
be divided into several doses, preferably into 1~6 doses per day if deemed appropriate by a doctor or a pharmacist. Hereinafter the present invention describes in more detail. However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modifications and improvements within the spirit and scope of the present invention.
EXAMPLE
<Preparation example 1>: preparation of 2-chloro-4- (1H-5- indazolyl) amino-6-methoxy-1 , 3 , 5-triazine To the methanol solution 70 ml of 5-aminoindazole 1.8g was added triethylamine 1.72ml , the solution was cooled down to 5°C and then 2 , 4-dichloro-6-methoxy-l , 3, 5-triazine 1.8g was slowly added. The solid was precipitated, stirred for 1 hour, filtered under the reduced pressure and washed with methanol 20ml. The desired compound (2.35g, 76%) was obtained by drying of the solid product at 40~50°C in vacuo .
m.p. : >280 °C XH-NMR (DMSO-d6), ppm : 3.93(3H, s), 7.46-7.56 (2H, m) , 7.55- 8.11(2H. m) , 10.54-10.67 (IH, m) , 13.05(1H, brs)
<Preparation example 2>: preparation of 2-chloro-4- (1H-6- indazolyl) amino-6-methoxy-1 , 3 , 5-triazine
To the solution of 5-aminoindazole 1.8g in methanol 70 ml was added triethylamine 1.72ml , the solution was cooled down to 5°C and then 2, 4-dichloro-6-methoxy-l, 3, 5-triazine 1.8g was slowly added. The solid was precipitated, stirred for 1 hour, filtered under the reduced pressure and washed with methanol 20ml. The desired compound (2.32g, 75%) was obtained by drying of the solid product at 40 — 50°C in vacuo .
m.p. : >280 °C
XH-NMR (DMSO-d6), ppm : 3.99(3H, s), 7.28(1H, d) , 7.68(1H, d) , 8.00(1H, s), 8.18(1H, s), 10.71-10.84 ( IH, m) , 13.00(1H, s)
<Example 1>: preparation of 2- (lH-5-indazolylamino) -4- methoxy-6- (2-morpholinoethyl) amino-1 , 3 , 5-triazine
To the solution of 2-chloro-4- (lff-5-indazolyl) amino-6- methoxy-1, 3, 5-triazine o.3g obtained by preparation example 1 in methanol 30 ml were added triethylamine 0.23 ml and 4- (2-aminoethyl) morpholine 0.17 ml. The solution was refluxed 5 hours and then the solution was evaporated in vacuo, The residue was diluted with H20 20 ml. The solution was extracted with dichloromethane 30 ml. The organic layer was separated, concentrated under reduced pressure and stirred 1 hour in methanol 5 ml. The solid was precipitated, filtered and washed methanol. The desired compound ( 0.31g, 78%) was obtained by drying of the solid product at 40~50°C in va cuo .
m.p. : 203-207 °C XH-NMR (DMSO-d6), ppm : 2.44 (6H, m) , 3.51 (2H, m) , 3.54 (4H, m) , 3.79(3H, m) , 7.43(1H, m) , 7.54(1H, m) , 7.95(1H, s) , 8.15(1H, s) , 9.49(1H, m) , 12.91 (IH, m)
<Example 2>: preparation of 2- (lH-6-indazolylamino) -4- methoxy-6- (2-morpholinoethyl) amino-1 , 3 , 5-triazine
To the solution of 2-chloro-4- ( lff-6-indazolyl) amino-6- methoxy-1, 3, 5-triazine o.3g obtained by preparation example 2 in methanol 30 ml were added triethylamine 0.23 ml and 4- (2-aminoethyl) morpholine 0.17 ml, the solution was refluxed 2 hours and then the solution was cooled down at room temperature and added water, stirring for 3 hours. The solid was precipitated, filtered and washed water. The desired compound ( 0.30g, 75%) was obtained by drying of the solid product at 40~ 50°C in vacuo.
m.p. : 246~247 °C
^-NMR (DMSO-d6), ppm : 2.40(6H, m) , 3.53(6H, m) , 3.83(3H, m) , 7.36(1H, m) , 7.61(1H, m) , 7.93(1H, s), 8.20(1H, m) , 9.67(1H, m) , 12.86(1H, m)
The example 3-example 50 were prepared according to the synthetic method of example 1 and 2. The table 1 showed melting point, yield, nomenclature, staring material (6) and amines (7) of compound 3-50. the table 2 is showed ■'Ή-NMR result of compound 3-50. <Table 1>
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
<Table 2>
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
3.46(2H, m) , 3.87-4.04 (9H, m) , 7.25(1H, m) , 7.48-7.6K2H, m) , 7.88-7.90 (2H, m) , 8.25(1H,
46 DMSO-d5 brs), 8.68(2H, s) , 9.79(1H, s), 12.82(1H, brs)
1.25(3H, s), 2.49(3H, s), 3.64 (4H, m) , 3.81- 3.87(7H, m) 4.27 (2H, q), 7.45(1H, d) ,
47 DMSO-d6 7.57(1H, d) 8.00(1H, s), 8.09(1H, s) , 8.47(1H, s), 9.59(1H, s), 12.93(1H, s)
1.28(3H, t) , 2.49(3H, s) , 3.63-3.68(4H, m) , 3.87(7H, m) 4.27 (2H, q), 7.26(1H, d) ,
48 DMSO-d6 7.59(1H, d) 7.91(1H, s), 8.22(1H, s), 8.47 (IH, s), 9.77(1H, s) , 12.85(1H, s)
1.67(2H, m) 2.32(6H, m) , 3.29(2H, m) , 3.52 (2H, m) 3.56(2H, m) , 3.79(3H, s),
49 DMSO-d6 7.41(1H, m) 7.54 (1H, m) , 7.86(1H, s), 9.44 (IH, m) , 12.89(1H, m)
1.69(2H, m) 2.32(6H, m) , 3.33(2H, m) , 3.58 (4H, m) 3.84 (3H, m) , 7.32(1H, m) ,
50 DMSO-d6 7.57 (IH, m) 7.91(1H, s), 8.24 (1H, m) , 9.64 (IH, m) , 12.86(1H, m)
<Preparation 1> Preparation of Injection solution
Injection solution containing effective ingredient 50mg was made in following method. The compound 5g of example 1, sodium chloride 0.6g and ascorbic acid O.lg were solved in distilled water to be 100ml volume totally. This solution sterilized for 30 minutes at 60°C.
Constituents of the injection solution stated above is as follows.
The compound of example 1 ■5g
Sodium chloride- •0.6g
Ascorbic acid- •O.lg
Water for injection ad. •100ml
<Preparation 2> Preparation of tablet Tablet containing effective ingredient 60mg was made in following method. The compound of example 1 was mixed with lactose 175.9g, starch 180g and colloidal silicic acid 32g. 10% gellatin solution was added to this mixture and the mixture was ground, filtered in 14 mesh and dried. Finally, starch 160g, talc 50g and stearic acid magnesium salts 5g were added to the mixture and tablet was formed.
Constituents of the tablet stated above is as follows.
The compound of example 1 lOOOg
Lactose 175.9g
Starch 18Og
Colloidal silicic acid 32g
10% gellatin solution
Starch 160g
Talc 50g
Stearic acid magnesium salts 5g
<Experiment 1> Inhibitory effect on the in vitro activities of HBV polymerase in reverse transcription The following in vi tro experiment was performed to determine the effect of the compounds of formula 1 on the activity of HBV polymerase during reverse transcription.
The present inventors submitted application for a patent concerning HBV polymerase genetically expressed in and separated from E. col i , the process of their preparation, and the method to measure the enzyme activities (KR 94-3918, KR 96-33998). In the present experiments HBV polymerase was used which had been expressed in E . coli as stated above. The method used in the present invention to measure in vi tro reverse transcribing activities of HBV polymerase is as follows. Basic principles are the same as those for ELISA, nucleotides with biotin- or digoxigenin- group are included as substrates and anti-DIG antibodies attached to peroxidase enzyme recognize the polymerized substrates.
To the wells coated with streptavidin, 20 μl of HBV
polymerase, 20 μl of reaction mixture (10 μM each of DIG-UTP
and Biotin-UTP, 46 mM Tris-HCl, 266 mM KC1, 27.5 mM MgCl2, 9.2 mM DTT substrate/primer hybrid), and 20 μl of test
compound (added to 1, 0.1, and 0.01
Figure imgf000031_0001
were added and
allowed to react at 22°C for 15 hrs. During this reaction, HBV polymerase catalyzes DNA synthesis, and digoxigenin and biotin attached to nucleotides form bonds to streptavidin coated on the bottom of wells. When the reaction was done, each well was washed with 250 μl, of cleaning buffer (pH 7.0) for 30 seconds, which was repeated five times to remove remaining impurities. 200 μl, of anti-DIG-POD antibody was
added to each well and allowed to react for 1 hr at 37 °C, and the wells were washed with cleaning buffer to remove impurities. 200 μl, of ABTS™, a substrate of peroxidase, was
then added to each well and allowed to react at room temperature for 30 min. Absorbency was measured at 405 nm using ELISA reader.
The inhibitory effects in HBV polymerase activities for reverse transcription were calculated using the group without test compound as a control and the results are shown in Table 3 as follows. <Table 3>
Inhibitory effect on the HBV polymerase activities in reverse transcription
Figure imgf000032_0001
Figure imgf000033_0001
<Experiment 2> Inhibitory effect on the in vitro HCV activity in RNA-dependant RNA-polymerase .
The following in vi tro experiment was performed to determine inhibitory effects of compounds of formula 1 on the activity in RNA-dependant RNA-polymerase.
To test in vitro for HCV activity in RNA-dependant RNA- polymerase, the following experiment was carried out. First, 10 μl of HCV NS5B (RNA-polymerase) and 25 μl of
reaction buffer solution [Tris-Cl (pH 7.5) 0.1 M, NaCl 0.1 M, MgCl2 0.01 M, KC1 0.2 M, EDTA 0.002 M, DTT 0.05 M] were added to a well coated with streptavidin. 10 μl of reaction mixture containing poly A/UTP,as a RNA template-primer, DIG- UTP, biotin-UTP and UTP were added and subsequently test compounds prepared were also added at the final concentration of 10, 1 and 0.1 μg/ml. The mixture was
allowed to react 22 °C for 1 hr . The inhibitory activity was measured in comparison with negative control without the test compounds. At this time, RNA was formed from RNA by the action of HCV polymerase, forming bonds with streptavidin coated on the bottom of wells due to dioxigenin and biotin attached to nucleotides. When the reaction was completed, each well was washed with 200 μl, of washing buffer
(pH 7.0) for 30 sec. three times to remove remaining impurities. 200 μl of anti-DIG-POD antibody was added to each
well and allowed to react for 1 hr at 37°C, and the wells were washed with cleaning buffer to remove impurities. 200 μl of ABTS™, a substrate for peroxidase (POD) , was added to each well, allowed to react at room temperature for 30 min., and absorbency at 405 nm was measured for each solution using ELISA reader.
The percentage of inhibitory effect in the activity of HCV RNA polymerase, was calculated using the negative control without the test compounds and the results are represented in Table 4 as follows. <Table 4> Inhibitory effect on the HCV proliferation
Figure imgf000035_0001
Figure imgf000036_0001
<Experiment 4> Cytotoxicity test
To determine if compounds of formula 1 exhibit cytotoxicity, in vi tro tests were carried out using HepG2 cells with MTT analysis method as generally known and the results are showed in Table 5 as follows.
<Table 5> Cytotoxicities on the HepG2 cell
Figure imgf000037_0002
As a result, the compounds used in the experiments have higher than 100
Figure imgf000037_0001
for IC50 and are considered to have little cytotoxicity.
As described above, novel methoxy-1, 3, 5-triazine derivatives represented by formula 1 of the present invention have the dramatic inhibitory effect on proliferation of HBV and HCV with little side effect, and may be useful as therapeutic agents for prevention and treatment of hepatitis B and C. Moreover, it is expected that compounds of the present invention, being non- nucleosidic, do not have problems such as toxicity and early development of resistant virus strains observed by nucleoside substances. Furthermore, compounds of the present invention may be used together with nucleoside compounds since the former seem to act on allosteric binding pockets while the latter work in the domain of polymerase activities.

Claims

WHAT IS CLAIMED IS;
1. A compound of formula 1 or its pharmaceutically acceptable salt:
Figure imgf000038_0001
wherein,
Ri is H or Cι-C3 alkyl group,
R2 is H; hydroxy; straight or branched Cχ-C4 alkyl group; straight or branched C1-C3 alkoxy group; Cι-C3 hydroxyalkyl group; C2-C6 dialkylamino group; C3-C6 cycloalkyl group; lactam; saturated or unsaturated a 5 or 6 membered heterocyclic compounds containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with straight or branched Cι~C3 alkyl group; bicyclo compounds containing 1 to 2 heteroatoms selected from N, 0 and S; or Ri and R2 are joined to form a 5 or 6 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, 0 and S, which is unsubstituted or substituted with hydroxy, straight or branched C1-C4 alkyl group, Cι~C3 hydroxyalkyl group, carbamoyl, C1-C3 alkylcarbamoyl, C1-C3 alkoxycarbonyl group, aryl group, or arylcarbonyl group; n is an integer of 0 to 4; R3 is 5-indazolyl or 6-indazolyl group; in the case that R2 has the chiral carbon, the compound of formula 1 is the stereoisomer of (R) or (S) and the present invention contains both their stereoisomers and racemic compounds .
2. The compound of claim 1, wherein Ri is hydrogen atom; R2 is hydroxy, methyl, ethyl, isopropyl, cyclopropyl, morpholinyl, piperazinyl, pyrrolyl, indolyl, pyridinyl, pyrrolidinyl, imidazolyl, piperidinyl or isonicotinyl group; and n is an integer of 0 to 3.
3. The compound of claim 1, which is selected from the group consisting of: 1) 2- ( lff-5-indazolyl) amino-4-methoxy-6- (2-morpholino ethyl) amino-1, 3, 5-triazine;
2 ) 2- ( IH-6-indazolyl) amino-4 -methoxy- 6- (2-morpholino ethyl) amino-1, 3, 5-triazine ;
3) 2- ( 17.-5-indazolyl) amino-4 -methoxy- 6-methylamino-l, 3,5- triazine;
4 ) 2- (Iff-6-indazolyl) amino-4 -methoxy-6-methylamino-1, 3,5- triazine; 5) 2- (Iff-5-indazolyl) amino-4 -isopropylamino- 6-methoxy-l, 3,5- triazine; 6) 2- (lff-6-indazolyl) amino-4-isopropylamino-6-methoxy-l, 3, 5- triazine;
7 ) 2-cyclopropylamino-4- (Iff-5-indazolyl) amino-6-methoxy-
1,3, 5-triazine ;
8 ) 2 -cyclopropylamino-4- (Iff- 6-indazolyl) amino-6-methoxy- 1,3, 5-triazine;
9) 2- ( Iff-5-indazolyl) amino-4 -methoxy- 6- (2 -methoxy ethyl) amino-1, 3, 5-triazine;
10) 2- ( lff-6-indazolyl) amino-4-methoxy-6- (2-methoxy ethyl) amino-1, 3, 5-triazine; 11) 2- (2-hydroxyethyl) amino-4- ( lff-5-indazolyl) amino-6- methoxy-1, 3, 5-triazine; 12 ) 2- (2-hydroxyethyl) amino-4- ( Iff- 6-indazolyl ) amino- 6- methoxy-1, 3, 5-triazine; 13) 2- (2-dimethylaminoethyl) amino-4- ( lff-5-indazolyl) amino-6- methoxy-1 , 3, 5-triazine;
14 ) 2- ( Iff-5-indazolyl) amino-4-methoxy-6-morpholinoamino-
1,3, 5-triazine; 15) 2- ( lff-6-indazolyl) amino-4-methoxy-6-morpholinoamino- 1,3, 5-triazine; 16) 2- (lff-5-indazolyl) amino-4-methoxy-6- (4-methyl) piperazino amino-1, 3, 5-triazine; 17 ) 2- ( Iff- 6-indazolyl) amino-4-methoxy- 6- ( 4-methyl ) piperazino amino-1, 3, 5-triazine; 18) 2- (lff-5-indazolyl) amino-4-methoxy-6- (2- (2-pyridyl) ethyl) amino-1 , 3, 5-triazine; 19) 2- (lff-6-indazolyl) amino-4-methoxy-6- (2- (2-pyridyl) ethyl) amino-1, 3, 5-triazine;
20) 2- (lff-5-indazolyl) amino-4-methoxy-6- (3- (2-oxo- pyrrolidino) propyl) amino-1, 3, 5-triazine; 21) 2- (lff-6-indazolyl) amino-4-methoxy-6- (3- (2-oxo- pyrrolidino) propyl) amino-1, 3, 5-triazine ;
22) 2- (lff-5-indazolyl) amino-4- (2- ( lH-3-indolyl) ethyl) amino- 6-methoxy-l, 3, 5-triazine;
23) 2- (lff-6-indazolyl) amino-4- (2- ( lff-3-indolyl) ethyl) amino- 6-methoxy-l, 3, 5-triazine;
24) 2- (3- (lff-1-imidazolyl) propyl) amino-4- ( lff-5-indazolyl) amino-6-methoxy-l, 3, 5-triazine;
25) 2- (3- (lff-1-imidazolyl) propyl) amino-4- ( lff-6-indazolyl) amino-6-methoxy-l, 3, 5-triazine; 26) 2- (lff-5-indazolyl) amino-4-methoxy-6-morpholino-l, 3, 5- triazine;
27 ) 2- ( Iff-6-indazolyl) amino-4-methoxy-6-morpholino-l, 3,5- triazine;
28 ) 2- (lff-1-imidazolyl) -4- ( Iff-6-indazolyl) amino-6-methoxy- 1, 3, 5-triazine;
29) 2- (lff-5-indazolyl) amino-4-methoxy-6-pyrrolidino-l, 3, 5- triazine;
30) 2- (Iff-6-indazolyl) amino-4-methoxy-6-pyrrolidino-l, 3,5- triazine; 31) 2- (lff-6-indazolyl) amino-4-methoxy-6- ( (2S) -methoxy carbonyl) pyrrolidino-1, 3, 5-triazine; 32 ) 2- ( 4-hydroxy) piperidino-4- (Iff-5-indazolyl) amino-6- methoxy-1, 3, 5-triazine; 33) 2- ( 4-hydroxy) piperidino-4- ( If-6-indazolyl) amino-6- methoxy-1 , 3, 5-triazine;
34 ) 2- ( 4-amido) piperidino-4- ( Iff-5-indazolyl) amino-6-methoxy-
1,3, 5-triazine; 35) 2- ( 4-amido) piperidino-4- ( Iff- 6-indazolyl) amino-6-methoxy-
1,3, 5-triazine; 36) 2- (lff-5-indazolyl) amino-4-methoxy-6- (4-Λf-methylamido) piperidino-1, 3, 5-triazine;
37 ) 2- ( 4-ethoxycarbonyl) piperidino-4- ( lff-5-indazolyl) amino-
6-methoxy-l , 3, 5-triazine;
38 ) 2- (lff-5-indazolyl) amino-4-methoxy-6- (4-methyl) piperazino -1 , 3, 5-triazine;
39) 2- ( Iff-6-indazolyl) amino-4 -methoxy-6- ( 4-methyl) piperazino -1,3, 5-triazine;
40) 2- ( 4- (2-hydroxyethyl) ) piperazino-4- ( Iff-5-indazolyl) amino -6-methoxy-l ,3, 5-triazine; 41) 2- (4- (2-hydroxyethyl) ) piperazino-4- (lff-6-indazolyl) amino -6-methoxy-l, 3, 5-triazine;
42) 2- (4-ethoxycarbonyl) piperazino-4- ( lff-5-indazolyl) amino- 6-methoxyl-l, 3, 5-triazine;
43) 2 - (Iff-5-indazolyl) amino-4 -methoxy-6- (4- ( N-methylamido methyl) ) piperazino-1, 3, 5-triazine ; 44) 2- (Iff- 6-indazolyl) amino-4 -methoxy-6- (4- ( N-methylamido methyl) ) piperazino-1, 3, 5-triazine;
45) 2- (lff-5-indazolyl) amino-4-methoxy-6- ( 4-nicotinoyl) piperazino-1, 3, 5-triazine; 46) 2- ( lff-6-indazolyl) amino-4-methoxy-6- (4-nicotinoyl) piperazino-1, 3, 5-triazine; 47) 2- (4- (5-ethoxycarbonyl-2-methylthio-l, 3-pyrimidinyl) ) piperazino-4- (Iff-5-indazolyl) amino-6-methoxy-l, 3,5- triazine; 48) 2- ( 4- (5-ethoxycarbonyl-2-methylthio-l, 3-pyrimidinyl) ) piperazino-4- (lff-6-indazolyl) amino-6-methoxy-l, 3, 5- triazine; 49) 2- ( Iff-5-indazolyl) amino-4-methoxy-6- (3-morpholinopropyl) amino-1, 3, 5-triazine; and 50) 2- ( lff-6-indazolyl ) amino-4-methoxy-6- (3-morpholinopropyl) amino-1, 3, 5-triazine.
4. A process for preparing the compound of claim 1, which comprises : 1) reacting 2, 4-dichloro-6-methoxy-l, 3, 5-triazine (_4) with 5-aminoindazole or 6-aminoindazole (_5) in the presence of a base in order to prepare 2-chloro-6- methoxy-1 , 3, 5-triazine derivative substituted with aminoindazole { 6 ) ; and 2) reacting thus obtained compound ( 6 ) with amine compound (7_) in the presence of a base in order to prepare the compound of claim 1 : Scheme 1
Figure imgf000044_0001
(wherein, Ri, R2, R3 and n are as defined in formula 1.)
5. A pharmaceutical composition for treating or preventing hepatitis B, which comprises the compound of claim 1 or its pharmaceutically acceptable salt as an effective ingredient.
6. A pharmaceutical composition for treating or preventing hepatitis C, which comprises the compound of claim 1 or its pharmaceutically acceptable salt as an effective ingredient.
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WO2011067195A1 (en) 2009-12-02 2011-06-09 F. Hoffmann-La Roche Ag Biomarkers for predicting sustained response to hcv treatment
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WO2012154353A1 (en) * 2011-04-14 2012-11-15 Bristol-Myers Squibb Company Macrocyclic triazine compounds for the treatment of hepatitis c
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US9868743B2 (en) 2013-02-07 2018-01-16 Bristol-Myers Squibb Company Macrocyclic molecules as HCV entry inhibitors
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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100490893B1 (en) * 2002-10-11 2005-05-23 (주) 비엔씨바이오팜 2-methoxy-1,3,5-triazine derivatives, method for preparing thereof and antiviral pharmaceutical composition comprising the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962453A (en) * 1995-08-08 1999-10-05 Nippon Shinyaku Co. Ltd. Triazine derivative and medicine
WO2001047897A1 (en) * 1999-12-28 2001-07-05 Pharmacopeia, Inc. Cytokine, especially tnf-alpha, inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0563732A (en) * 1991-09-05 1993-03-12 Nec Corp Facsimile store and forward exchange
DE4210942A1 (en) * 1992-04-02 1993-10-07 Bayer Ag 7-Oxo-7H-pyrido [1,2,3-d, e] [1,4] benzoxacin-6-carboxylic acids and esters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5962453A (en) * 1995-08-08 1999-10-05 Nippon Shinyaku Co. Ltd. Triazine derivative and medicine
WO2001047897A1 (en) * 1999-12-28 2001-07-05 Pharmacopeia, Inc. Cytokine, especially tnf-alpha, inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CRESSERI ANGEL ET AL.: "Aspects of the metabolism of triazine derivatives active in experimentally induced virus infections", BR. J. PHARMACOL. CHEMOTHER., vol. 27, no. 3, 1966, pages 486 - 490 *
LUDOVICI D.W. ET AL.: "Evoluation of anti-HIV drug candidates Part 2: Diaryltriazine (DATA) analogues", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 17, 3 September 2001 (2001-09-03), pages 2229 - 2234, XP009167508, DOI: doi:10.1016/S0960-894X(01)00411-5 *

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