2,5-pyridinedicarboxylic acid derivatives

Details 2,5-pyridinedicarboxylic acid derivatives 2,5-pyridinedicarboxylic acid derivatives

2000-11-07

2001-10-23

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C544S364000, C544S365000, C544S121000, C514S235800

Reexamination Certificate

active

06306860

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel 2,5-pyridinedicarboxylic acid derivatives and more particularly, to novel 2,5-pyridinedicarboxylic acid derivatives of the following formula 1 and its pharmaceutically acceptable salts as anti-viral agents, having inhibitory activities against the proliferation of virus such as hepatitis B virus and human immunodeficiency virus, including its preparing method:
wherein, R
1
represents hydroxy group, straight or branched alkyl group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with alkyl group of 1 to 3 carbon atoms, alkyl group of 1 to 3 carbon atoms substituted with cycloalkyl group of 3 to 6 carbon atoms, straight or branched hydroxyalkyl group of 1 to 6 carbon atoms, straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms, straight or branched alkoxy group of 1 to 4 carbon atoms, hydroxyalkoxy group of 2 to 4 carbon atoms, straight or branched alkoxyalkyl group of 2 to 6 carbon atoms, dialkoxyalkyl group of 3 to 6 carbon atoms, dialkylamino group of 2 to 4 carbon atoms, acetylamino group, vinyl group, or saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; hence, the heterocycle is unsubstituted or substituted with same or different 1~3 substituents selected from the group consisting of alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, hydroxyalkyl group of 1 to 3 carbon atoms, phenyl group, carbamoyl group and hydroxy group;
R
2
represents hydrogen atom, phenyl group, straight or branched alkyl group of 1 to 4 carbon atoms, straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, or alkoxyalkyl group of 2 to 4 carbon atoms;
R
3
represents 3-amino-2-pyridyl group
wherein, Q is hydrogen atom or straight or branched alkyl group of 1 to 4 carbon atoms), or 2-hydroxyethyl group;
n is an integer of 0 or 1~4;
meantime, the above R
1
that belong to branched hydroxyalkyl group may represent (R)- or (S)-type stereospecificity.
2. Description of the Related Art
About 300 million people around the world are infected with hepatitis caused by Hepatitis B virus (hereinafter referred to as “HBV”) as a main pathogen, being accompanied by acute or chronic hepatitis. In severe cases, it is reported that HBV is involved in transforming hepatitis into hepatic cirrhosis hepatocellular carcinoma. In spite of the fact that intensive research have focused on the correlation of liver disease associated with HBV and its molecular biological characteristics, some hepatitis B vaccines and diagnostic reagents have been developed but any effective drug for treating hepatitis B does not exist. Recently, results of some studies have indicated that some nucleoside compounds such as Lamivudine and Famvir, which have been known for AIDS or herpes zoster, are effective in suppressing the proliferation of HBV. However, it has been well known that further development of nucleoside compounds are restricted because of high treatment cost, adverse reaction, and toxicity.
Under such circumstances, there is an urgent need for the development of effective hepatitis B drug as non-nucleoside compound and in parallel with this trend, some patents related to quinolone compound [European Patent Publication Nos. 563732 and 563734] and iridoids compound [Korean Patent Unexamined Publication No. 94-18863] have been reported to have anti-HBV activities but with no significant development progress has been noticeable.
Meantime, the present applicant has filed patent application related to novel terephthalamide derivatives with antiviral activities as a non-nucleoside compound [Korean Pat. Appln. Nos. 96-72384 and 97-36589].
SUMMARY OF THE INVENTION
The novel 2,5-pyridinedicarboxylic acid derivatives of the present invention have unique chemical structure as non-nucleoside compounds, and show the anti-viral activities against HBV as well as human immunodeficiency virus (hereinafter referred to as “HIV”). Although HBV is different from HIV, they have the same replication processes, which are the reverse transcription from viral RNA and the digestion of RNA part of RNA-DNA hybrid intermediates. Since the novel 2,5-pyridinedicarboxylic acid derivatives according to the present invention of the formula 1 have mechanism to inhibit reverse transcription, it can be developed as anti-HBV or anti-HIV agents.
Therefore, an object of the present invention is to provide novel 2,5-pyridinedicarboxylic acid derivatives and its pharmaceutically acceptable salts which suppress very effectively the proliferation of various viruses such as HBV and HIV, including its preparing method.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to novel 2,5-pyridinedicarboxylic acid derivatives of the following formula 1 and its pharmaceutically acceptable salts.
wherein, R
1
represents hydroxy group, straight or branched alkyl group of 1 to 6 carbon atoms, cycloalkyl group of 3 to 6 carbon atoms unsubstituted or substituted with alkyl group of 1 to 3 carbon atoms, alkyl group of 1 to 3 carbon atoms substituted with cycloalkyl group of 3 to 6 carbon atoms, straight or branched hydroxyalkyl group of 1 to 6 carbon atoms, straight or branched dihydroxyalkyl group of 3 to 6 carbon atoms, straight or branched alkoxy group of 1 to 4 carbon atoms, hydroxyalkoxy group of 2 to 4 carbon atoms, straight or branched alkoxyalkyl group of 2 to 6 carbon atoms, dialkoxyalkyl group of 3 to 6 carbon atoms, dialkylamino group of 2 to 4 carbon atoms, acetylamino group, vinyl group, or saturated or unsaturated five or six membered heterocyclic ring having 1 to 3 hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur; hence, the heterocycle is unsubstituted or substituted with same or different 1~3 substituents selected from the group consisting of alkyl group of 1 to 3 carbon atoms, alkoxy group of 1 to 3 carbon atoms, hydroxyalkyl group of 1 to 3 carbon atoms, phenyl group, carbamoyl group and hydroxy group;
R
2
represents hydrogen atom, phenyl group, straight or branched alkyl group of 1 to 4 carbon atoms, straight or branched hydroxyalkyl group of 2 to 4 carbon atoms, or alkoxyalkyl group of 2 to 4 carbon atoms;
R
3
represents 3-amino-2-pyridyl group
wherein, Q is hydrogen atom or straight or branched alkyl group of 1 to 4 carbon atoms), or 2-hydroxyethyl group;
n is an integer of 0 or 1~4;
meantime, the above R
1
that belong to branched hydroxyalkyl group may represent (R)- or (S)-type stereospecificity.
The present invention is explained in more detail as set forth hereunder:
The preferred 2,5-pyridinedicarboxylic acid derivatives of the above formula 1 according to the present invention are represented by the following formula 1a or 1b:
wherein, R
1
, R
2
, Q and n are the same as defined above, respectively.
wherein, R
1
, R
2
and n are the same as defined above, respectively.
The more preferred compounds according to the present invention are represented by the formula 1a; wherein R
1
, R
2
, Q and n are as the follows:
In case where R
1
is hydroxy group, branched hydroxyalkyl group of 3 to 5 carbon atoms, or branched dihydroxyalkyl group of 3 to 5 carbon atoms; R
2
is hydrogen atom, methyl group, ethyl group, 2-hydroxyethyl group or phenyl group; and n is 0, 2 or 3;
in case where R
1
is straight or branched alkyl group of 2 to 4 carbon atoms, cyclopropyl group, cyclopentyl group, methoxy group, ethoxy group, 2-hydroxyethoxy group, branched alkoxyalkyl group of 4 to 5 carbon atoms, dialkoxyalkyl group of 3 to 5 carbon atoms or dialkylamino group of 2 to 4 carbon atoms; R
2
is hydrogen atom, methyl group, ethyl group, isopropyl group or 2-methoxyethyl group; n is an integer of 0 or 1~3;
in case where R
1
is five or six membered saturated heterocycle selected from the group consisting of dioxolan, tetrahydrofuran, tetrahydrofuranone, tetrahydrothiophenone, pyrrolidinone, morpholine, piperidine and p

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