Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-04-14
2000-12-19
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549396, A61K 31352, C07D31194
Patent
active
061628263
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application of International Application No. PCT/KR97/00188, filed Oct. 8, 1997.
TECHNICAL FIELD
The present invention relates to a novel genipin derivative represented by the following formula (1), which has an anti hepatitis B virus (HBV) activity: ##STR2## in which R.sub.1 represents lower alkyl, benzyl, or C.sub.1 -C.sub.12 alkanoyl which can be substituted with phenyl, phenoxy, pyridyl, t-butyl or thienyl, methoxyiminomethyl, lower alkylaminomethyl, acetylthiomethyl, mercaptomethyl, 2,2-dimethyl-1,3-dioxolan-5-ylmethyloxymethyl, 2,3-dihydroxypropyloxymethyl, 6-aminofuran-9-ylmethyl, 4-amino-2-hydroxy-5-methylpyrinmidin-1-ylmethyl, 2,4-dihydroxy-5-methylpyrimidin-1-ylmethyl, 5-hydroxymethyl-1,3-oxathiolan-2-yl, or C.sub.1 -C.sub.12 alkanoyloxymethyl which can be substituted with phenyl, phenoxy, pyridyl, t-butyl or thienyl, and methoxyiminomethyl, 4-methoxybenzyloxymethyl or acetyloxymethyl, provided that R.sub.3 is not methoxycarbonyl when R.sub.1 is lower alkyl and R.sub.2 is hydroxymethyl, formyl or hydroxyirinomethyl, its pharmaceutically acceptable salt, or stereoisomer.
The present invention also relates to a pharmaceutical composition comprising as an active ingredient the compound of formula (I), which can be effectively used for the treatment of hepatitis B.
BACKGROUND ART
It has been reported that the known iridoids genipin represented by the following formula (II) and aucubin represented by the following formula (III) are natural substances, and act as a therapeutic agent for hepatitis B through the mechanism to inhibit the HBV replication (see, Korean Patent Laid-open No. 94-1886). ##STR3##
Said genipin of formula (II) and aucubin of formula (III) have some in vivo activities such as liver-protection, inhibition of biosynthesis of RNA and protein, detoxification as well as antiviral activity. Particularly, it has been disclosed that genipin is also effective as an anti-tumor agent (see, Japanese Patent Laid-open No 80/164625). However, these compounds may be decomposed to dialdehydes in vivo and the dialdehydes thus produced may combine with amino acid residues of proteins such as albumin. Such a series of reactions may induce some color change of urine, faces, and various internal organs into blue as well as immunotoxicities.
Compounds having a similar structure to the compound according to the present invention include the compound represented by the following formula (IV) in addition to genipin and aucubin(see, WO 92/06061 and European Patent Laid-open No. EP-0505572): ##STR4## in which R.sub.1 represents benzoyloxy, hydroxy, acetoxy or ethoxyethoxy, and t-butyldimethylsilyloxymethyl, carboxy or hydroxymethyl.
It is described in the above literatures that the compound of formula (IV) above may be used effectively as a therapeutic agent for hyperlipemia or as a cholagogues.
On the other hand, the present inventors have synthesized a series of novel aucubin and genipin derivatives on the basis of the prior arts as mentioned above in order to develop compounds having a superior activity to the earlier compounds on inhibition against HBV. After the antiviral activity and little cytotoxicity of the novel compounds prepared were identified, the present inventors have filed a patent application on the novel compounds (see, Korean Patent Appln. No. 95-38181).
DISCLOSURE OF INVENTION
The present inventors have continuously and intensively studied to develop novel compounds having more improved properties, and as a result, have succeeded to synthesize the new compound of formula (I) according to the present invention. By determining the antiviral activity and cytotoxicity of the compound, we have identified that the compound according to the present invention is so stable in vivo that it does not induce any side effects such as change to blue color, etc. and that it may be effectively used for the treatment of hepatitis B since it has an excellent inhibitory activity against HBV with little cytotoxicity.
Therefore, it is an object of the present invention to provi
REFERENCES:
patent: 5459160 (1995-10-01), Fujii et al.
Wysokinska et al., Chem. Abstract 117:23243, 1992.
Nakane et al., Chem. Abstract 93:186574, 1980.
Chemical Abstracts, vol. 111, 1989, p. 417 Abstract No. 239518.
Cho In Koo
Choi Hea Jin
Choi Kun Hyock
Chung Dong Hoon
Chung Jea Uk
Choongwae Pharmaceutical Corporation
Corless Peter F.
O'Day Christine C.
Rao Deepak R.
Shah Mukund J.
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