WO2003002518A1 - Novel 2,4-difluorobenzamide derivatives as antiviral agents - Google Patents

Novel 2,4-difluorobenzamide derivatives as antiviral agents Download PDF

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Publication number
WO2003002518A1
WO2003002518A1 PCT/KR2002/001239 KR0201239W WO03002518A1 WO 2003002518 A1 WO2003002518 A1 WO 2003002518A1 KR 0201239 W KR0201239 W KR 0201239W WO 03002518 A1 WO03002518 A1 WO 03002518A1
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indazolyl
difluoro
group
benzamide
branched
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PCT/KR2002/001239
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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 Hwa Pharm. Ind. Co., Ltd.
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Publication of WO2003002518A1 publication Critical patent/WO2003002518A1/en

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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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

Definitions

  • the present invention relates to novel 2,4-difluorobenzamide derivatives and their pharmaceutical compositions. More specifically, the present invention relates
  • the present invention also relates to a process for preparing compounds of formula 1, non- nucleoside, and their pharmaceutical compositions as an effective ingredient
  • Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a C2-C6 alkylamino group, a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from the group consisting of N, O and S;
  • R 2 is H, a straight or branched C1-C3 alkyl group; or Ri and R 2 may comprise a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group; R3 is a 5- indazolyl or 6-indazolyl group; and n is an integer between 0 and 4.
  • HBV Hepatitis B virus
  • HBV genome consists of four different genes that respectively code for polymerase (P), surface protein (S), core protein (C), and X protein.
  • polymerase polymerase
  • S surface protein
  • C core protein
  • X protein X protein serves 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 the virus genome.
  • This polypeptide includes sequences responsible for activities of a 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 subsequent extensive researches on the study of replication mechanism of HBV.
  • DNAs are synthesized by the action of HBV polymerase, attached to a 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 and viral proteins are synthesized from these mRNAs.
  • 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 transcription 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, Scientific American, 264: 48-54, 1991).
  • HBV and HIV are different viruses, their replication mechanisms during the proliferation have some common steps, namely, the reverse transcription of virus RNA to form DNA and the removal of RNA strand from subsequently formed RNA-DNA hybrid.
  • nucleoside compounds such as lamivudine and famvir have been reported as useful inhibitors of HBV proliferation, although they have been originally developed as therapeutics for the treatment of acquired immune deficiency syndrome (AIDS; referred to as "AIDS” hereinafter) and herpes zoster infection (Gerin, J. L, Hepatology, 14: 198-199, 1991; Lok, A. S. P., J. Viral Hepatitis, 1: 105-124, 1994; Dienstag, J. L. et al, Ne ⁇ England Journal of Medicine, 333: 1657-1661, 1995).
  • AIDS acquired immune deficiency syndrome
  • herpes zoster infection Gerin, J. L, Hepatology, 14: 198-199, 1991; Lok, A. S. P., J. Viral Hepatitis, 1: 105-124, 1994; Dienstag, J. L. et al, Ne ⁇ England Journal of Medicine, 333: 1657-1661, 1995.
  • 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 218052), and terephthalic amide derivatives (KR 98-53296A, KR 98-86363A, KR 99-87861 A).
  • effective drugs for hepatitis B have not been developed yet and therapeutic method mainly depends on symptomatic treatments.
  • Hepatitis C virus (referred to as "HCV” hereinafter) is a virus having a membrane, which belongs to the flaviviridae.
  • HCV genome is single stranded (+)-RNA of 9.5 kb in length and expresses polyprotein consisting of 3010 amino acids.
  • the HCV polyprotein is cleaved posttranslationally by cellular and viral protease to yield 3 structural proteins and 6 nonstructural proteins.
  • Both 5'- and 3' -terminus of the HCV genome contain an untranslated region(UTR), which has highly conserved nucleotide sequence of most genotypes. Recently, it was known that 5'-UTR is a 330 ⁇ 341 nucleotide sequence and 3'-UTR includes 98 nucleotides at the end of poly A, which is expected to play a role of RNA replication and translation of virus.
  • Amino terminus 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.
  • HCV infection presents a major public health problem worldwide because the community-acquired HCV infection has not been under control.
  • HCV infection is distributed 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 a completely different family from that of HBV, it cannot be inhibited by means of HBV vaccine. The treatment of -interferon has been tried, but its antiviral effect depends on the genotype of HCV and it was not shown very effective. Since HCV was discovered in 1987, there has been attempted a lot of researches, but remarkably effective drug has not yet been developed.
  • Interferon is the unique choice for the treatment so far, but it has confirmed that 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 are no effective antiviral agents with proliferation inhibitory activity against HCV.
  • the present invention relates to novel 2,4-difluorobenzamide derivatives represented by the following formula 1 and their pharmaceutically acceptable salts,
  • Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a C 2 -C 6 alkylamino group, a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from a group consisting of N, O and S;
  • R 2 is H, a straight or branched C1-C3 alkyl group; or Ri and R 2 may consist of saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from a group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group; R3 is a 5-indazolyl or 6-indazolyl group, and n is an integer between 0 and 4. More preferable compounds in accordance with the present invention are as follows;
  • the compounds represented by the 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.
  • 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, tartaric 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
  • the present invention also provides a process for preparing 2,4- difluorobenzamide derivatives of formula 1, represented by the scheme 1 as follows,
  • Ri, R 2 , R3 and n are as defined in formula 1.
  • 2,4,5-trifluorobenzamide derivatives (4) were prepared by reaction of 2,4,5-trifluorobenzoyl chloride (2) with 5-aminoindazole or 6-aminoindazole (3) in the presence of the base.
  • tertiary organic base having weak basicity such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N- methylpiperidine, 4-dimethylaminopyridine, N,N-dimethylaniline, 2,6-lutidine, pyridine.
  • the preferred temperature is 0 ⁇ 5 ° C and the preferred reaction time is 1-2 hrs.
  • a solvent a single solvent selected from chloroform, methylene chloride, acetonitrile, tetrahydrofuran, methanol, ethanol is preferable.
  • 2,4-difluorobenzamide derivatives (1) were prepared by reacting 2,4,5-trifluorobenzamide derivatives (4) obtained by step 1 with amine compound (5) 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 (5) are ethanolamine, propanolamine, morpholine, piper azine, dimethylethylene diamine, hydroxypiperidine, etc.
  • the base used in step 2 is the same as in the step 1 and tertiary organic base including l,8-diazabicyclo-[5.4.0]-undec-7-ene(DBU) is preferred. It is advisable to use the amine compound (5) a bit excess to increase the yield.
  • the reaction solvent is single or mixed solvent selected from the group consisting of 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 (5) and is preferably 40 ⁇ 100 ° C .
  • novel 2,4-difluorobenzamide derivatives represented by formula 1 of the present invention have the excellent inhibitory effect on proliferation of HBV and HCV may be useful as therapeutic agents for prevention and treatment of hepatitis B and C.
  • the present invention provides the pharmaceutical compositions of therapeutics containing 2,4-difluorobenzamide derivatives and their pharmaceutically acceptable salts of formula 1 as effective ingredients to prevent and treat HBV and HCV.
  • compounds of formula 1 may be mixed with a pharmaceutically acceptable carrier and made into various pharmaceutically acceptable forms; for example, tablets, troches, lozenge, suspensions, powder or granule, emulsion, hard or soft capsules, syrup or elixirs, etc.
  • composition of the present invention can be administered parenterally, by subcutaneous injection, intravenous injection, intramuscular injection and intrathoracic injection.
  • parenteral formulation the composition of formula 1 is mixed with water by adding a stabilizer or buffer to make a solution or a suspension, then prepare this in an ampul or a vial.
  • Effective dosage for the compound of formula 1 is generally 10 ⁇ 500mg/kg for adults, which may be divided into several doses, preferably into 1 ⁇ 6 doses per day, if deemed necessary consulted with a doctor or a pharmacist.
  • the examples 3—36 were prepared according to the synthetic method of examples 1 and 2.
  • the table 1 showed yield, nomenclature, melting point, aminoindazole(3) used as starting material and amines(5) of compound 1-36.
  • the table 2 is showed ⁇ -NMR results of compound 1-36.
  • composition of the present invention, 2,4-difluorobenzamide derivatives and their pharmaceutically acceptable salts represented by formula 1 may be administered orally or parenterally.
  • An injection for parenteral administration and tablet for oral administration were prepared according to Preparation as follows.
  • Injection solution containing 50mg of an effective ingredient was made in following method. 5g of the compound of example 1, 0.6g of sodium chloride and O.lg of ascorbic acid were solved in distilled water to make the final volume of 100 ml. This solution was sterilized for 30 minutes at 20 ° C .
  • ⁇ Preparation 2> Preparation of tablets Tablets containing effective ingredient 60mg were made as follows. lOOOg of the compound of example 1 was mixed with 175.9g of lactose, 180g of starch and 32g of colloidal silicic acid. 10% gelatin solution was added to this mixture and the mixture was ground, filtered by using a 14 mesh and dried. Finally, 160g of starch, 50g of talc and 5g of stearic acid magnesium salt were added to the mixture and tablet was formed.
  • the present inventors filed an application for a patent concerning HBV polymerase genetically expressed in and separated from E.coli, the process of its preparation, and the method to measure the enzyme activities (KR 178,070, KR
  • HBV polymerase was used which had been expressed in E. coli as stated above.
  • the method used in the present invention to measure in vitro reverse transcription 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
  • HBV polymerase To the wells coated with streptavidin, 20 ⁇ l of HBV polymerase, 20 ⁇ JL of reaction mixture (10 ⁇ M each of DIG-UTP and Biotin-UTP, 46 mM Tris-HCl, 266 mM KCI, 27.5 mM MgCl 2 , 9.2 mM DTT substrate/ primer hybrid), and 20 ⁇ l of test compound(added to 1, 0.1, and 0.01 ⁇ g/ml) 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
  • RNA was formed from RNA by the action of HCV
  • the compounds used in the experiments have higher than 100 ⁇ g/ml- for IC50 and are considered to have little cytotoxicity.
  • novel 2,4-difluorobenzamide derivatives represented by formula 1 of the present invention have the excellent 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

2,4-difluorobenzamide derivatives and their pharmaceutically acceptable salts, represented by following formula (1), 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

NOVEL 2,4-DIFLUOROBENZAMIDE DERIVATIVES AS ANTIVIRAL
AGENTS
TECHNICAL FIELD The present invention relates to novel 2,4-difluorobenzamide derivatives and their pharmaceutical compositions. More specifically, the present invention relates
to novel 2,4-difluorobenzamide 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 relates to a process for preparing compounds of formula 1, non- nucleoside, and their pharmaceutical compositions as an effective ingredient
against viruses,
Figure imgf000002_0001
(1) wherein Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a C2-C6 alkylamino group, a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; R2 is H, a straight or branched C1-C3 alkyl group; or Ri and R2 may comprise a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group; R3 is a 5- indazolyl or 6-indazolyl group; and n is an integer between 0 and 4.
BACKGROUND ART Hepatitis B virus (HBV; referred to 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. There have been many studies on the identification of 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 researches to find effective anti- hepatitis B agents.
HBV genome consists of four different genes that respectively code for polymerase (P), surface protein (S), core protein (C), and X protein. Of these proteins expressed from HBV genes, polymerase, surface protein, and core protein are structural proteins while X protein serves 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 the virus genome. This polypeptide includes sequences responsible for activities of a 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 subsequent extensive researches on the study of replication mechanism of HBV.
HBV enters liver when an antigenic protein on virion surface is recognized by a hepatic cell-specific receptor. Inside the liver cell, DNAs are synthesized by the action of HBV polymerase, attached to a 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 and viral proteins are synthesized from these mRNAs. 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 transcription 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, Scientific American, 264: 48-54, 1991).
Although HBV and HIV are different viruses, their replication mechanisms during the proliferation have some common steps, namely, the reverse transcription of virus RNA to form DNA and the removal of RNA strand from subsequently formed RNA-DNA hybrid.
Recently, nucleoside compounds such as lamivudine and famvir have been reported as useful inhibitors of HBV proliferation, although they have been originally developed as therapeutics for the treatment of acquired immune deficiency syndrome (AIDS; referred to as "AIDS" hereinafter) and herpes zoster infection (Gerin, J. L, Hepatology, 14: 198-199, 1991; Lok, A. S. P., J. Viral Hepatitis, 1: 105-124, 1994; Dienstag, J. L. et al, Neτυ 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 218052), and terephthalic amide derivatives (KR 98-53296A, KR 98-86363A, KR 99-87861 A). 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 to as "HCV" hereinafter) is a virus having a membrane, which belongs to the flaviviridae. HCV genome is single stranded (+)-RNA of 9.5 kb in length and expresses polyprotein consisting of 3010 amino acids. The HCV polyprotein is cleaved posttranslationally by cellular and viral protease to yield 3 structural proteins and 6 nonstructural proteins.
Both 5'- and 3' -terminus of the HCV genome contain an untranslated region(UTR), which has highly conserved nucleotide sequence of most genotypes. Recently, it was known that 5'-UTR is a 330~341 nucleotide sequence and 3'-UTR includes 98 nucleotides at the end of poly A, which is expected to play a role of RNA replication and translation of virus. Amino terminus 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 was 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, wherein 20% of which will further develop severe chronic liver disease within 5 years. Such a higher progression rate, rarely in RNA virus, shows that HCV is a major cause of 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 has not been under control.
From the point of retrospective studies, unlike HBV, HCV infection is distributed 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 a completely different family from that of HBV, it cannot be inhibited by means of HBV vaccine. The treatment of -interferon has been tried, but its antiviral effect depends on the genotype of HCV and it was not shown very effective. Since HCV was discovered in 1987, there has been attempted a lot of researches, but remarkably effective drug has not yet been developed. Interferon is the unique choice for the treatment so far, but it has confirmed that 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 are no effective antiviral agents with proliferation inhibitory activity against HCV.
Therefore, we, inventors of the present invention, tried to develop non-nucleoside 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 2,4-difluorobenzamide derivatives represented in formula 1 and completed the invention by showing their dramatic inhibitory effect on proliferation of HCV as well as of HBV.
It is an objective of the present invention to provide novel 2,4-difluorobenzamide derivatives, their pharmaceutically acceptable salts, and the process for preparing them.
It is a further objective of present invention to provide a pharmaceutically compositions 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 relates to novel 2,4-difluorobenzamide derivatives represented by the following formula 1 and their pharmaceutically acceptable salts,
Figure imgf000007_0001
(1) wherein Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a C2-C6 alkylamino group, a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from a group consisting of N, O and S;
R2 is H, a straight or branched C1-C3 alkyl group; or Ri and R2 may consist of saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from a group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group; R3 is a 5-indazolyl or 6-indazolyl group, and n is an integer between 0 and 4. More preferable compounds in accordance with the present invention are as follows;
2,4-diπuoro-N-(lH-5-indazolyl)-5-(2-morpholinoethyl) aminobenzamide (compound of example 1),
2,4-difluoro-N-(lH-6-indazolyl)-5-(2-morpholinoethyl) aminobenzamide
(compound of example 2),
2,4-difluoro-5-(2-hydiOxyethyl)amino-N-(lH-5-indazolyl) benzamide
(compound of example 3), 2,4-difluoro-5-(2-hy droxyethyl)amino-N-(lH-6-indazolyl) benzamide
(compound of example 4),
2,4-difluoro-5-(2-dimethylaminoethyl)amino-N-(lH-5-indazolyl)benzamide (compound of example 5),
2,4-difluoro-5-(2-dimethylaminoethyl)amino-N-(lH-6-indazolyl)benzamide (compound of example 6),
2,4-difluoro-N-(lH-5-indazolyl)-5-(2-(2-pyridyl)ethyl) aminobenzamide
(compound of example 7),
2,4-difluoro-N-(lH-6-indazolyl)-5-(2-(2-pyridyl)ethyl) aminobenzamide
(compound of example 8), 2,4-difluoro-iV-(lH-6-indazolyl)-5-(methyl-2-(2-pyridyl) ethyl) aminobenzamide (compound of example 9),
2,4-difluoro-5-(ethyl-(2-hydroxyethyl)amino)-N-(lH-6-indazolyl)benzamide (compound of example 10),
2,4-dmuoro-N-(lH-6-indazolyl)-5-(2-(4-sulfarnoyl phenyl)ethyl)aminobenzamide (compound of example 11),
2,4-difluoro-N-(lH-5-indazolyl)-5-(2-pyrrolidinoethyl) aminobenzamide
(compound of example 12), 2,4-difluoro-5-(3-(lH-l-imidazolyl)propyl)amino-N-(lH-5- indazolyl)benzamide (compound of example 13),
2,4-diπuoro-5-(3-(lH-l-imidazolyl)propyl)amino~ -(lH-6- indazolyl)benzamide (compound of example 14), 2,4-diπuoro-N-(lH-6-indazolyl)-5-isobutylamino benzamide (compound of example 15),
2,4-difluoro-N-(lH-5-indazolyl)-5-((2-pyridyl)methyl) aminobenzamide (compound of example 16),
2,4-dmuoro-N-(lH-6-indazolyl)-5-((2-pyridyl)methyl) aminobenzamide (compound of example 17),
2,4-difluoro-N-(lH-5-indazolyl)-5-piperazinobenzamide (compound of example 18),
2,4-difluoro-N-(lH-6-indazolyl)-5-piperazinobenzamide (compound of example 19), 2,4-difluoro-N-(lH-5-indazolyl)-5-(4-methylpiperazino) benzamide
(compound of example 20),
2,4-difluoro-N-(lH-6-indazolyl)-5-(4-methylpiperazino) benzamide (compound of example 21),
2,4-difluoro-5-(4-hydroxypiperidino)-N-(lH-5-indazolyl) benzamide (compound of example 22),
2,4-difluoro-5-(4-hydroxypiperidino)-N-(lH-6-indazolyl) benzamide (compound of example 23),
2,4-difluoro-5-(4-(2-hydroxyethyl)piperazino)-N-(lH-5-indazolyl)benzamide (compound of example 24), 2,4-difluoro-5-(4-(2-hydroxyethyl)piperazino)-N-(lH-6-indazolyl)benzamide
(compound of example 25),
2,4-difluoro-5-(3,5- 's-dimethyl)piperazino-N-(lH-5-indazolyl)benzamide (compound of example 26),
5-([l,4]-diazepano)-2,4-difluoro-N-(lH-5-indazolyl) benzamide (compound of example 27),
5-([l,4]-diazepano)-2,4-difiuoro-N-(lH-6-indazolyl) benzamide (compound of example 28 ),
2,4-difluoro-N-(lH-5-indazolyl)-5-(4-methyl-[l,4]-diazepano)benzamide (compound of example 29),
2,4-difluoro-N-(lH-6-indazolyl)-5-(4-methyl-[l,4]-diazepano)benzamide (compound of example 30), 2/4-difluoro-N-(lH-5-indazolyl)-5-(l-(2-methyl-4,5- dihydro)imidazolyl)benzamide (compound of example 31),
2/4-difluoro-N-(lH-5-indazolyl)-5-thiomorpholino benzamide (compound of example 32),
2,4-difluoro-5-(4-(4,6-dimethoxy-l,3,5-triazin-2-yl) piperazino)-N-(lH-5- indazolyl)benzamide (compound of example 33),
2,4-difluoro-N-(lH-6-indazolyl)-5-(4-((3-nitro)-2- pyridyl)piperazino)benzamide (compound of example 34),
5-(4-(6-cWoro-2-methylthio-4-pyrimidinyl)piperazino)-2,4-difluoro-]V"-(lH-6- indazolyl)benzamide (compound of example 35), 2,4-difluoro-N-(lH-5-indazolyl)-5-(4-(2-pyridyl) piperazino)benzamide
(compound of example 36),
The compounds represented by the 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. 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, tartaric 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 2,4- difluorobenzamide derivatives of formula 1, represented by the scheme 1 as follows,
Scheme 1
Figure imgf000011_0001
wherein Ri, R2, R3 and n are as defined in formula 1.
Chemical reagents used as starting and reaction materials in the scheme 1, namely, 2,4,5-trifluorobenzoyl chloride (2), 5-aminoindazole, 6-aminoindazole (3) and amine compounds (5), are commercially available and may be purchased or can be easily done by one with general knowledge in the technical field.
A detailed description of the method for preparing of 2,4-difluorobenzamide derivatives of the present invention is set forth hereunder.
In the step 1, 2,4,5-trifluorobenzamide derivatives (4) were prepared by reaction of 2,4,5-trifluorobenzoyl chloride (2) with 5-aminoindazole or 6-aminoindazole (3) in the presence of the base. At this time, it is preferably used tertiary organic base having weak basicity such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N- methylpiperidine, 4-dimethylaminopyridine, N,N-dimethylaniline, 2,6-lutidine, pyridine.
The preferred temperature is 0~5 °C and the preferred reaction time is 1-2 hrs. For a solvent, a single solvent selected from chloroform, methylene chloride, acetonitrile, tetrahydrofuran, methanol, ethanol is preferable. In the step 2, 2,4-difluorobenzamide derivatives (1) were prepared by reacting 2,4,5-trifluorobenzamide derivatives (4) obtained by step 1 with amine compound (5) 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. These amine compounds (5), for example, are ethanolamine, propanolamine, morpholine, piper azine, dimethylethylene diamine, hydroxypiperidine, etc. The base used in step 2 is the same as in the step 1 and tertiary organic base including l,8-diazabicyclo-[5.4.0]-undec-7-ene(DBU) is preferred. It is advisable to use the amine compound (5) a bit excess to increase the yield. And, the reaction solvent is single or mixed solvent selected from the group consisting of 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 (5) and is preferably 40 ~ 100 °C .
Furthermore, novel 2,4-difluorobenzamide derivatives represented by formula 1 of the present invention have the excellent inhibitory effect on proliferation of HBV and HCV may be useful as therapeutic agents for prevention and treatment of hepatitis B and C. The present invention provides the pharmaceutical compositions of therapeutics containing 2,4-difluorobenzamide derivatives and their pharmaceutically acceptable salts of formula 1 as effective ingredients to prevent and treat HBV and HCV.
For clinical use of drugs with the pharmaceutical compositions of the present invention, compounds of formula 1 may be mixed with a pharmaceutically acceptable carrier and made into various pharmaceutically acceptable forms; for example, tablets, troches, lozenge, suspensions, powder or granule, emulsion, hard or soft capsules, syrup or elixirs, etc.
It may comprise a binder such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose, gelatin), an excipient such as dicalcium phosphate, a disintegrator such as cornstarch, potato starch, and a lubricant such as magnesium stearate, calcium stearate, sodium stearoyl fumarate, polyethyleneglycol Wax to be prepared as tablets or capsules, etc. In case of capsules, it may comprise a liquid carrier such as fatty oil. The pharmaceutical composition of the present invention can be administered parenterally, by subcutaneous injection, intravenous injection, intramuscular injection and intrathoracic injection. For the preparation of parenteral formulation, the composition of formula 1 is mixed with water by adding a stabilizer or buffer to make a solution or a suspension, then prepare this in an ampul or a vial.
Effective dosage for the compound of formula 1 is generally 10~500mg/kg for adults, which may be divided into several doses, preferably into 1~6 doses per day, if deemed necessary consulted with a doctor or a pharmacist.
Hereinafter the present invention will be described 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 2,4,5~trifluoro- -(12J-5- indazolyl)benzamide
To the methylene chloride solution 100ml of 5-aminoindazole 5g was added triethylamine 6ml, the solution was cooled down to 5°C and then 4.6ml of 2,4,5- trifluorobenzoyl chloride was slowly added. The mixture was stirred for 1 hr at the same temperature and the solvent was removed. The residue was resolved in 150ml of methanol and 40ml of water was added to precipitate the product. The solid obtained by filtration under the reduced pressure was washed with the solution of methanol : water = 2:1. The desired compound(9.8g, 93%) was obtained by drying of the solid product at 50 °C in vacuo. m.p. : 232-239 °C Η-NMR (DMSO-dβ, ppm): 7.52(s, 2H), 7.70(m, IH), 7.82(m, IH), 8.05(s, IH), 8.21 (s, IH), 10.48(s, IH), 13.03(s, IH)
Preparation example 2>: preparation of 2,4,5-trifluoro- -(lH~6- indazolyl)benzamide
To the solution of 5g of 6-aminoindazole in 100ml of methylene chloride was added with 6ml of triethylamine. The solution was cooled down to 5 °C and then
4.6ml of 2,4,5-trifluorobenzoyl chloride was slowly added. After stirring for 1 hr at the same temperature, the solid precipitate was filtered under the reduced pressure and washed with 50ml of methylene chloride. The solid was resolved in 100ml of methanol and 50ml of water was added to precipitate the product. After filtration, the desired compound was obtained by first washing with methanol : water = 2 : 1 solution followed by drying at 50 °C in vacuo(9g, 86%). m.p. : 210-230 °C
Η-NMR (DMSO-dβ, ppm): 7.20(m, IH), 7.69(m, 2H), 7.82(m, IH), 7.99(s, IH), 8.21(s, IH), 12.98(s, IH)
<Example 1>: preparation of 2,4-difluoro-N-(lH-5-indazolyl)-5-(2- morpholinoethyl)aminobenzamide
To the solution of 0.3g of 2,4,5-trifluoro-N-(lH-5-indazolyl)benzamide obtained by preparation example 1 in 30 ml of acetonitrile was added 1ml of 4-(2- aminoethyl)morpholine. The solution was refluxed for 48 s and then the solution was cooled down to room temperature. The reaction mixture was stirred for 1 hr after 5ml of water was added. The product was filtered and dried under the reduced pressure (0.3g, 73%). m.p. : 250-251 °C
Η-NMR (DMSO-de, ppm): 2.36(m, 4H), 2.45(m, 2H), 3.20(m, 2H), 3.51(m, 4H), 6.08(s, IH), 6.59(m, IH), 7.33(m, IH), 7.42(m, IH), 7.47(m, IH), 7.97(s, IH), 8.12(s,
IH), 9.79(s, IH), 12.93(s, IH)
<Example 2>: preparation of 2,4-difl oro-N-(lH-6-indazolyl)-5-(2- morpholinoethyl)aminobenzamide
To the solution of 0.3g of 2,4,5-trifluoro-AT-(lH-6-indazolyl)benzamide obtained by preparation example 2 in 30 ml of acetonitrile were added 0.23ml of 1,8- diazabicyclo-[5.4.0]-undec-7-ene(DBU) and 0.9ml of 4-(2-aminoethyl)morpholine. The solution was refluxed for 60 s and the mixture was concentrated under the reduced pressure and stirred in 50ml of methanol for 2 s. The solid was filtered and dried in vacuo to give the desired compound(0.28g, 68%). m.p. : 240-243 °C
Η-NMR (DMSO-de, ppm): 3.14(m, 2H), 3.34(m, 2H), 3.55(m, 4H), 3.69(m, 2H), 3.96(m, 2H), 6.78(m, IH), 7.26(m, IH), 7.42(m, IH), 7.66(m, IH), 8.03(s, IH), 8.23(s, IH)
The examples 3—36 were prepared according to the synthetic method of examples 1 and 2. The table 1 showed yield, nomenclature, melting point, aminoindazole(3) used as starting material and amines(5) of compound 1-36. The table 2 is showed Η-NMR results of compound 1-36.
Table 1
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Table 2
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
The composition of the present invention, 2,4-difluorobenzamide derivatives and their pharmaceutically acceptable salts represented by formula 1 may be administered orally or parenterally. An injection for parenteral administration and tablet for oral administration were prepared according to Preparation as follows.
<Preparation 1> Preparation of Injection solution
Injection solution containing 50mg of an effective ingredient was made in following method. 5g of the compound of example 1, 0.6g of sodium chloride and O.lg of ascorbic acid were solved in distilled water to make the final volume of 100 ml. This solution was sterilized for 30 minutes at 20 °C .
<Preparation 2> Preparation of tablets Tablets containing effective ingredient 60mg were made as follows. lOOOg of the compound of example 1 was mixed with 175.9g of lactose, 180g of starch and 32g of colloidal silicic acid. 10% gelatin solution was added to this mixture and the mixture was ground, filtered by using a 14 mesh and dried. Finally, 160g of starch, 50g of talc and 5g of stearic acid magnesium salt were added to the mixture and tablet was formed.
<Experiment 1> Inhibitory effect on in vitro activities of HBV polymerase in reverse transcription
The following in vitro experiment was performed to determine the effect of the compounds of formula 1 on the activities of HBV polymerase during reverse transcription.
The present inventors filed an application for a patent concerning HBV polymerase genetically expressed in and separated from E.coli, the process of its preparation, and the method to measure the enzyme activities (KR 178,070, KR
185,276). 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 vitro reverse transcription 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 μJL of reaction mixture (10 μM each of DIG-UTP and Biotin-UTP, 46 mM Tris-HCl, 266 mM KCI, 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 μg/ml) 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 on the 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 compound Inhibitory activity on HBV-RT (%)
Figure imgf000026_0001
Figure imgf000027_0001
<Experiment 2> Inhibitory effect on the in vitro HCV activity in RNA-
dependant RNA-polymerase.
The following in vitro experiment was performed to determine inhibitory
effects of compounds of formula 1 on the activity in RNA-dependant RNA- polymerase.
To test in vitro 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 [0.25 M Tris-HCl (pH 7.5), 0.25 M NaCl, 0.025 M MgCl2, 0.25 M KCI, 0.005
M EDTA, 0.05 M DTT] were added to a well coated with streptavidin. 10 μl of. reaction mixture containing HCV 3'UTR-"X" RNA, DIG-UTP, biotin-UTP, ATP,
UTP, CTP and GTP were added and subsequently 5 μl test compounds(added to 10, 1 and 0.1 μl/ml) were added and allowed to react at 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
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
<Experiment 3> Cytotoxicity test
To determine if compounds of formula 1 exhibit cytotoxicity, in vitro tests were carried out using HepG2 cells with MTT analysis method as generally known and the results are shown in Table 5 as follows.
Table 5
Figure imgf000030_0002
As a result, the compounds used in the experiments have higher than 100 μg/ml- for IC50 and are considered to have little cytotoxicity.
INDUSTRIAL APPLICABILITY
As described above, novel 2,4-difluorobenzamide derivatives represented by formula 1 of the present invention have the excellent 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

CLAIMSWHAT IS CLAIMED IS;
1. 2,4-difluorobenzamide derivatives of formula 1 or their pharmaceutically acceptable salts.
Figure imgf000032_0001
(1) wherein Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a C2-Ce alkylamino group; a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; R2 is H, a straight or branched C1-C3 alkyl group; or
Ri and R2 may comprise a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group;
R3 is a 5-indazolyl or 6-indazolyl group; and n is an integer between 0 and 4.
2. The 2,4-difluorobenzamide derivatives or their pharmaceutically acceptable salts according to claim 1, wherein the 2,4-difluorobenzamide derivatives represented by formula 1 is:
2,4-difluoro-N-(lH-5-indazolyl)-5-(2-morpholinoethyl) aminobenzamide 2,4-difluoro-N-(lH-6-indazolyl)-5-(2-morpholinoethyl) aminobenzamide 2,4-difluoro-5-(2-hydroxyethyl)amino-N-(lH-5-indazolyl) benzamide 2,4-difluoro-5-(2-hydroxyethyl)amino-N-(lH-6-indazolyl) benzamide 2,4-difluoro-5-(2-dimethylaminoethyl)amino-N-(lH-5-indazolyl)benzamide 2,4-difluoro-5-(2-dimethylaminoethyl)amino-N-(lH-6-indazolyl)benzamide 2,4-difluoiO- -(lH-5-indazolyl)-5-(2-(2-pyridyl)ethyl) aminobenzamide
2,4-difluoro-N-(lH-6-indazolyl)-5-(2-(2-pyridyl)ethyl) aminobenzamide 2,4-dmuoro-N-(lH-6-indazolyl)-5-(methyl-2-(2-pyridyl) ethyl) aminobenzamide
2,4-difluoro-5-(ethyl-(2-hydroxyethyl)amino)-N-(lH-6-indazolyl)benzamide 2,4-difluoro-N-(lH-6-indazolyl)-5-(2-(4-sulf amoyl phenyl)ethyl)aminobenzamide
2,4-difluoro- -(lH-5-indazolyl)-5-(2-pyrrolidinoethyl) aminobenzamide 2,4-drfluoro-5-(3-(lH-l-imidazolyl)propyl)amino-N-(lH-5- indazolyl)benzamide 2,4-di£uoro-5-(3-(lH-l-imidazolyl)propyl)amino-N-(lH-6- indazolyl)benzamide
2,4-difluoro-N-(lH-6-indazolyl)-5-isobutylamino benzamide 2,4-difluoro-N-(lH-5-indazolyl)-5-((2-pyridyl)methyl) aminobenzamide 2,4-difluoro-N-(lH-6-indazolyl)-5-((2-pyridyl)methyl) aminobenzamide 2,4-difluoro-N-(lH-5-indazolyl)-5-piperazinobenzamide
2,4-difluoro-N-(lH-6-indazolyl)-5-piperazinobenzamide 2,4-difluoiO-N-(lH-5-indazolyl)-5-(4-methylpiperazino) benzamide 2,4-difluoro-N-(lH-6-indazolyl)-5-(4-methylpiperazino) benzamide 2,4-difluoro-5-(4-hydroxypiperidino)- -(lH-5-indazolyl) benzamide 2,4-difluoro-5-(4-hydroxypiperidino)- -(lH-6-indazolyl) benzamide
2,4-drfluoro-5-(4-(2-hydroxyethyl)piperazino)-N-(lH-5-indazolyl)benzamide 2,4-difluoro-5-(4-(2-hydroxyethyl)piperazino)-N-(lH-6-indazolyl)benzamide 2,4-difluoro-5-(3,5-czs-dimethyl)piperazino-N-(lH-5-indazolyl)benzamide 5-([l,4]-diazepano)-2,4-difluoro-N-(lH-5-indazolyl) benzamide 5-([l,4]-diazepano)-2,4-difluoro-N-(lH-6-indazolyl) benzamide 2,4-difluoro-N-(lH-5-indazolyl)-5-(4-methyl-[l,4]-diazepano)benzamide 2/4-difluoro-N-(lH-6-indazolyl)-5-(4-methyl-[l,4]-diazepano)benzamide
2,4-difluoro-N-(lH-5-indazolyl)-5-(l-(2-methyl-4,5- dihydro)imidazolyl)benzamide
2/4-difluoro-N-(lH-5-indazolyl)-5-thiomorpholino benzamide 2/4-difluoro-5-(4-(4,6-dimethoxy-l/3,5-triazin-2-yl)piperazino)-N-(lH-5- indazolyl)benzamide
2,4-diπuoro-N-(lH-6-indazolyl)-5-(4-((3-nitro)-2- pyridyl)piperazino)benzamide
5-(4-(6-chloro-2-methylthio-4-pyrimidinyl)piperazino)-2,4-difluoro-N-(lH-6- indazolyl)benzamide 2,4-difluoro-N-(lH-5-indazolyl)-5-(4-(2-pyridyl) piρerazino)benzamide
3. The process for preparing in the present invention comprises the following steps of:
1) Preparation of 2,4,5-trifluorobenzanide derivatives(4) substituted with aminoindazole by reacting 2,4,5-trifluorobenzoyl chloride ) with 5- aminoindazole or 6-aminoindazole(3) in the presence of a base; and,
2) Preparation of 2,4-difluorobenzamide derivatives(l) by reaction of the 2,4,5- trifluorobenzanide derivatives(4) prepared in step 1 with amine compounds(5), Scheme 1
Figure imgf000035_0001
wherein Ri is a straight or branched Cι-C alkyl group, a hydroxy group, a C2-C6 alkylamino group; a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; R2 is H, a straight or branched C1-C3 alkyl group; or
Ri and R2 may comprise a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched Ci- alkyl group, a C1-C3 hydroxy alkyl group; R3 is a 5-indazolyl or 6-indazolyl group; and n is an integer between 0 and 4.
4. A therapeutic agent or a preventive agent for hepatitis B with 2,4- difluorobenzamide derivatives of formula 1 and their pharmaceutically acceptable salts as an effective ingredient,
Figure imgf000035_0002
(1) wherein Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a C2-C6 alkylamino group; a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; R2 is H, a straight or branched C1-C3 alkyl group;or Ri and R2 may comprise a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group; R3 is a 5-indazolyl or 6-indazolyl group; and n is an integer between 0 and 4.
5. A therapeutic agent or a preventive agent for hepatitis C with , 2,4- difluorobenzamide derivatives of formula 1 and their pharmaceutically acceptable salts as an effective ingredient,
Figure imgf000036_0001
(1) wherein Ri is a straight or branched C1-C4 alkyl group, a hydroxy group, a O2-C6 alkylamino group; a 4-sulfamoylphenyl group, a saturated or unsaturated 5 or 6 membered heterocyclic compound containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; R2 is H, a straight or branched C1-C3 alkyl group; or
Ri and R2 may comprise a saturated or unsaturated 5, 6 or 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, which is unsubstituted or substituted with a hydroxy group, a. straight or branched C1-C4 alkyl group, a C1-C3 hydroxyalkyl group;
R3 is a 5-indazolyl or 6-indazolyl group; and n is an integer between 0 and 4.
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