5-pyrimidinecarboxamide derivatives and the pharmaceutical...

Details 5-pyrimidinecarboxamide derivatives and the pharmaceutical... 5-pyrimidinecarboxamide derivatives and the pharmaceutical...

2002-05-24

2004-07-13

Balasubramanian, Venkataraman (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S317000, C548S362100

Reexamination Certificate

active

06762189

ABSTRACT:

This patent application claims a benefit of priority from Korean Patent Application No. 1999/53294 filed Nov. 27, 1999 and Korean Patent Application No. 1999/64402 filed Dec. 29, 1999 through PCT Application Serial No. PCT/KR00/01364 filed Nov. 27, 2000, the contents of each of which are incorporated herein by reference
TECHNICAL FIELD
The present invention relates to novel 5-pyrimidinecarboxamide derivatives and the pharmaceutical compositions containing said derivatives. More specifically, the present invention relates to novel 5-pyrimidinecarboxamide derivatives and their pharmaceutically acceptable salts represented below in formula 1, which have excellent inhibitory effect on proliferation of hepatitis B virus and of human immunodeficiency virus. The present invention also relates to the process for preparing compounds of formula 1 and to the pharmaceutical compositions containing said derivatives as effective ingredients against viruses.
Wherein,
R
1
is H, hydroxy, straight or branched alkyl group with C
1
~C
5
, straight or branched alkoxy group with C
1
~C
5
, straight or branched hydroxyalkyl group with C
2
~C
6
, dialkylamino group with C
2
~C
6
straight or branched alkyl group with C
2
~C
6
substituted with hydroxy or alkoxycarbonyl group with C
2
~C
5
, cycloalkyl group with C
3
~C
6
, or saturated or unsaturated 5 or 6 membered heterocyclic compounds containing 1 to 3 heteroatoms selected from N, O, and S, which may be unsubstituted or substituted with alkyl group of C
1
~C
3
; R
1
may or may not contain asymmetrical carbons;
R
2
is H or straight or branched alkyl group with C
1
~C
4
;
Or both R
1
and R
2
consist of 5 or 6 membered saturated heterocyclic ring containing 1~3 heteroatoms selected from N, O, and S, which is unsubstituted or substituted with straight or branched alkyl group with C
1
~C
5
or straight or branched hydroxyalkyl group with C
2
~C
5
;
n is an integer between 0 and 4;
R
3
is indazol-5-yl, or indazol-6-yl.
BACKGROUND ART
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 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 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 (EPO563732, EPO563734), 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.
AIDS is a disease inducing dramatic decrease in immune function in the body cells and causing various symptoms of infection rarely seen in normal human beings, which spread to the whole body. Human immunodeficiency virus (HIV; referred as “HIV” hereinafter) responsible for AIDS is known to mainly attack helper T cells, which is one of the T cells with regulatory function in the immune system. When helper T cells are infected with HIV virus and undergo necrosis, human immune system cannot function properly. Impairment in immune function subsequently results in fatal infection and development of malignant tumor. Since AIDS patient has been found in USA in 1981 for the first time, the number increased to more than 850,000 patients in 187 countries in 1993 (WHO 1993 report). WHO predicted that 30 to 40 million more people would be infected with HIV by the year 2000 and 10 to 20 million of them would develop the disease.
At the present time, drugs controlling proliferation of HIV have been most widely used for the treatment of AIDS. Of these, Zidovudine, which had been named Azidothymidine previously, is a drug developed in 1987. Didanosine was developed in 1991 as an alternative medicine for AIDS patients when Zidovudine was either ineffective or could not be used due to side effects. In addition, Zalcitabine was approved for concurrent use with Zidovudine in 1992. These drugs alleviate symptoms, slow down progression of the disease in the infected individuals to full-blown AIDS, and somewhat extend life span in the patients. These drugs, however, are not able to cure the patients completely and often develop problems such as resistance and side effects.
In light of these problems, 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 5-pyrimidinecarboxamide derivatives represented in formula 1 and completed the invention by showing their dramatic inhi

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