Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-05
2001-07-17
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S283400, C546S283700, C546S284100, C549S387000, C549S396000, C514S463000, C514S469000, C514S338000
Reexamination Certificate
active
06262083
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel genipin derivatives represented by the following formulas (I)a, (I)b, (I)c and (I)d, which have a liver protection activity:
in which
R
1
represents lower alkyl;
R
2
represents lower alkyl, pyridylcarbonyl, benzyl or benzoyl;
R
3
represents formyl, hydroxymethyl, azidomethyl, 1-hydroxyethyl, acetyl, methyl, hydroxy, pyridylcarbonyl, cyclopropyl, aminomethyl substituted or unsubstituted by (1,3-benzodioxolan-5-yl)carbonyl or 3,4,5-trimethoxybenzoyl, 1,3-benzodioxolan-5-yl, ureidomethyl substituted or unsubstituted by 3,4,5-trimethoxyphenyl or 2-chloro-6-methyl-3-pyridyl, thiomethyl substituted or unsubstituted by acetyl or 2-acetylamino-2-ethoxycarbonylethyl, oxymethyl substituted or unsubstituted by benzoyl, pyridylcarbonyl or 3,4,5-trimethoxybenzoyl;
provided that R
3
is not formyl, hydroxymethyl, acetyl, methylaminomethyl, acetylthiomethyl, benzoyloxymethyl or pyridylcarbonyloxymethyl when R
1
is methyl.
in which
R
4
represents lower alkoxy, benzyloxy, benzoyloxy, phenylthio, C
1
~C
12
alkanoyloxy substituted or unsubstituted by t-butyl, phenyl, phenoxy, pyridyl or thienyl;
R
5
represents methoxycarbonyl, formyl, hydroxyiminomethyl, methoxyiminomethyl, hydroxymethyl, phenylthiomethyl or acetylthiomethyl;
provided that R
5
is not methoxycarbonyl when R
4
is acetyloxy.
in which
R
6
represents hydrogen atom, lower alkyl or alkalimetal;
R
7
represents lower alkyl or benzyl;
R
8
represents hydrogen atom or lower alkyl;
R
9
represents hydroxy, lower alkoxy, benzyloxy, nicotinoyloxy, isonicotinoyloxy, 2-pyridylmethoxy or hydroxycarbonylmethoxy;
provided that R
9
is not hydroxy or methoxy when R
6
is methyl and R
8
is hydrogen atom.
in which
R
10
represents lower alkyl;
R
11
represents lower alkyl or benzyl;
R
12
represents lower alkyl, pyridyl substituted or unsubstituted by halogen, pyridylamino substituted or unsubstituted by lower alkyl or halogen, 1,3-benzodioxolanyl;
R
13
and R
14
each independently represent a hydrogen atom or join together to form isopropylidene together; and
their pharmaceutically acceptable salts, or stereoisomers.
The present invention also relates to pharmaceutical compositions comprising as an active ingredient of the compound of formulas (I)a, (I)b, (I)c and (I)d, which can be effectively used for the liver protection activity.
BACKGROUND ART
It has been reported that the known iridoids genipin represented by the following formula (A) and aucubin represented by the following formula (B) 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).
Said genipin of formula (A) and aucubin of formula (B) 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 (Japanese Patent Laid-open No. 80/164625). However, these compounds may be decomposed with amino acid residues of proteins such as albumin. Such a series of reactions may induce some color change of urine, faeces, 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 (C) in addition to genipin and aucubin (see, WO 92/06061 and European Patent Laid-open No. EP-0505572):
in which
R
1
represents benzyloxyl, hydroxy, acetoxy or ethoxyethoxy, and
R
2
represents benzoyloxymethyl, methoxymethyl, t-butyldimethylsilyloxymethyl, carboxy or hydroxymethyl.
It is described in the above literatures that the compound of formula (C) 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 Laid-open No. 97-21072).
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 new compounds of formulas (I)a, (I)b, (I)c and (I)d according to the present invention. By determining the antiviral activity and cytotoxicity of the compounds, we have identified that compounds according to the present invention are so stable in vivo that they do not induce any side effects such as change to blue color, etc. and that they may be effectively used for liver protection since they have an excellent liver protection activity with little cytotoxicity.
Therefore, it is an object of the present invention to provide novel genipin derivatives represented by the following formulas (I)a, (I)b, (I)c and (I)d which have an excellent liver protection activity as well as little cytotoxicity:
in which
R
1
represents lower alkyl;
R
2
represents lower alkyl, pyridylcarbonyl, benzyl or benzoyl;
R
3
represents formyl, hydroxymethyl, azidomethyl, 1-hydroxyethyl, acetyl, methyl, hydroxy, pyridylcarbonyl, cyclopropyl, aminomethyl substituted or unsubstituted by (1,3-benzodioxolan-5-yl)carbonyl or 3,4,5-trimethoxybenzoyl, 1,3-benzodioxolan-5-yl, ureidomethyl substituted or unsubstituted by 3,4,5-trimethoxyphenyl or 2-chloro-6-methyl-3-pyridyl, thiomethyl substituted or unsubstituted by acetyl or 2-acetylamino-2-ethoxycarbonylethyl, oxymethyl substituted or unsubstituted by benzoyl, pyridylcarbonyl or 3,4,5-trimethoxybenzoyl;
provided that R
3
is not formyl, hydroxymethyl, acetyl, methylaminomethyl, acetylthiomethyl, benzoyloxymethyl or pyridylcarbonyloxymethyl when R
1
is methyl.
in which
R
4
represents lower alkoxy, benzyloxy, benzoyloxy, phenylthio, C
1
~C
12
alkanoyloxy substituted or unsubstituted by t-butyl, phenyl, phenoxy, pyridyl or thienyl;
R
5
represents methoxycarbonyl, formyl, hydroxyiminomethyl, methoxyiminomethyl, hydroxymethyl, phenylthiomethyl or acetylthiomethyl;
provided that R
5
is not methoxycarbonyl when R
4
is acetyloxy.
in which
R
6
represents hydrogen atom, lower alkyl or alkalimetal;
R
7
represents lower alkyl or benzyl;
R
8
represents hydrogen atom or lower alkyl;
R
9
represents hydroxy, lower alkoxy, benzyloxy, nicotinoyloxy, isonicotinoyloxy, 2-pyridylmethoxy or hydroxycarbonylmethoxy;
provided that R
9
is not hydroxy or methoxy when R
6
is methyl and R
8
is hydrogen atom.
in which
R
10
represents lower alkyl;
R
11
represents lower alkyl or benzyl;
R
12
represents lower alkyl, pyridyl substituted or unsubstituted by halogen, pyridylamino substituted or unsubstituted by lower alkyl or halogen, 1,3-benzodioxolanyl;
R
13
and R
14
each independently represent a hydrogen atom or join together to form isopropylidene.
And their pharmaceutically acceptable salts or stereoisomers.
It is another object of the present invention to provide pharmaceutical compositions for the liver protection comprising as active ingredients the compound of formulas (I)a, (I)b, (I)c and (I)d as defined above, together with pharmaceutically acceptable inert carriers.
BEST MODE FOR CARRYING OUT THE INVENTION
Among the compounds of formula (I)a having a potent liver protection activity, the preferred compounds include those wherein R
1
represents methyl, R
2
represents benzyl or methyl and R
3
represents 1-hydroxyethyl, aminomethyl, 3,4,5-trimethoxy benzoylaminomethyl, N-hydroxy-N-methylaminomethyl or 3,4,5-trimethoxyphenylureidomethyl.
Among the compounds of formula (I)b having a potent liver protection activity, the preferred compounds include those wherein R
4
represents acetyloxy when R
5
is acetylthiomethyl, formyl, hydroxyiminomethyl or methoxyiminomethyl; R
4
represents acetylt
Choi Hea-Jin
Chung Jea-Uk
Ha Jong-Ryul
Jeong Kwang-Won
Lee Kyoung-June
Birch & Stewart Kolasch & Birch, LLP
Choongwae Pharma Corporation
Davis Zinna Northington
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