6-methylnicotinamide derivatives as antiviral agents

Details 6-methylnicotinamide derivatives as antiviral agents 6-methylnicotinamide derivatives as antiviral agents

2002-10-10

2003-08-19

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S131000, C544S365000, C546S193000, C546S256000, C546S275700

Reexamination Certificate

active

06608058

ABSTRACT:

This patent application claims a benefit of priority from Korean Patent Application No. 2000/20137 filed Apr. 17, 2000 and Korean Patent Application No. 2000/31926 filed Jun. 10, 2000 through PCT Application Serial No. PCT/KRO1/00613 filed Apr. 13, 2001, the contents of each of which are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to novel 6-methylnicotinamide derivatives and pharmaceutical compositions containing said derivatives. More specifically, the present invention relates to novel 6-methylnicotinamide derivatives and their pharmaceutically acceptable salts represented below in formula 1, which have an excellent inhibitory effect on proliferation of hepatitis B virus(HBV), hepatitis C virus(HCV) and human immunodeficiency virus(HIV). The present invention also relates to the process for preparing compounds of formula 1 and the pharmaceutical compositions containing said derivatives as effective ingredients against viruses.
wherein,
R
1
is hydroxy group; straight or branched C
1
~C
5
alkyl group; C
3
~C
6
cycloalkyl group which is unsubstituted or substituted with hydroxy group, C
2
~C
6
dialkylamino group; saturated or unsaturated 5 or 6 membered heterocyclic compounds containing 1 to 2 heteroatoms selected from N, O and S which may be unsubstituted or substituted with C
1
~C
3
alkyl group; or
 m is an integer of 0 or 1,
R
2
is H or C
1
~C
4
alkyl group;
or R
1
and R
2
are joined to form a 5- or 6-membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O and S,
n is an integer from 0 to 4,
R
3
is 5-indazole or 6-indazole
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 has been much research about the molecular biological characteristics of HBV and their 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 channeled into research to find treatment for hepatitis B.
HBV genome consists of genes for polymerase (P), surface protein (pre-S1, 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 comprises 80% of the whole virus genome and produces a protein of 94 kD 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 much research in 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 HBV polymerase action, attached to short chain to form complete double helix for HBV genome. Completed 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 through the action of DNA dependent DNA polymerase, which in turn 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, the replication mechanisms during their 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 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 (Gerin, J. L,
Hepatology
, 14: 198-199, 1991; Lok, A. S. P.,
J. Viral Hepatitis
, 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, development 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 (EPO 563732, EPO 563734), iridos 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 treating hepatitis B have not been developed yet and therapeutic method mainly depends on symptomatic treatment.
Hepatitis C virus (referred as “HCV” hereinafter) is a virus of the flaviviridae family which has a membrane. HCV genome is single stranded (+)-RNA of 9.5 kb in length and express polyprotein comprising of 3010 amino acids. The HCV polyprotein is cleaved co- and post translationally by cellular and viral protease to yield 3 structural proteins and 6 nonstructural proteins. 5′- and 3′-terminus of the HCV genome contain untranslated region (UTR), which highly conserved nucleotide sequence of all most genotype. Recently, it is known that 5′-UTR is a 330~341 nucleotide sequences 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 post-translation of virus. Amino end part of HCV genome produces structural proteins Core, E1 and E2 and the other part comprise of non-structural protein. The core is the main structural component of the viral capsid and E1 and E2 comprises of a outer protein. These proteins are cleaved by signal peptidase in endoplasmic reticulum. Serin-type protease NS3 and cofactor NS4A are responsible for the cleavage of nonstructural protein. NS5B protein is a RNA-dependant RNA polymerase. This protein is the most importance enzyme involved 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 chonic 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 has not regulated yet.
From the view of retrospective studies, HCV infection uniformly distributes worldwide and 1.5-2% of the world's population is infected. Compared to HBV, HCV infection is generally developed in chronic hepatitis and has a high probability of progression to liver cirrhosis and liver cancer. Hepatitis C virus that belongs to completely different family cannot be inhibited using B-type vaccine an

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