Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-01
2004-02-17
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S640000
Reexamination Certificate
active
06693126
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a composition for hepatoprotection and treatment of liver diseases comprising a dihydroxyphenyl derivative represented by the following formula (1) which has an excellent hepatoprotective and therapeutic activity for liver diseases:
in which
A and B independently of one another represent hydrogen, or together represent methylene group,
D represents hydrogen or lower alkoxy,
E represents acetylthioacetyl, or represents the following substituent (a-1) or (a-2):
wherein
represents single or double bond,
R
1
represents hydrogen, lower alkyl or N-acetylmethylaminomethyl,
R
2
represents hydrogen, or represents lower alkyl which is optionally substituted by hydroxycarbonyl, phenyl or 5- or 6-membered heteroaryl containing one or more hetero atoms selected from a group consisting of nitrogen and sulfur, wherein the heteroaryl can be substituted by lower alkyl,
R
3
represents hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbamoyl or lower alkenylcarbamoyl, or represents lower alkyl which is substituted by hydroxy, aryl(lower)alkoxy or 5- or 6-membered heteroaryl(lower)alkoxy containing nitrogen as the hetero atom,
R
4
represents hydrogen, or represents lower alkanoyl which is optionally substituted by halogen,
provided that R
4
does not exist when double bond is linked to the nitrogen atom in substituent (a-2).
The present invention also relates to a novel dihydroxyphenyl derivative having an excellent protective and therapeutic acitivity for liver which is left after known compounds are removed from the compound of formula (1) above, and to a process for preparing the same.
2. Description of the Prior Art
The liver has been known as an important organ wherein various metabolic activities are carried out. Acute or chronic lesions can be developed by a variety of factors including noxious materials such as virus, chemicals, etc., and undernourishment, which may cause liver injuries such as fatty liver, hepatitis, jaundice, cirrhotic liver, hepatic sclerosis, and liver cancer, etc. Recently, as the therapeutic agents for liver diseases, silymarin(see, Biotech, Therapeutics, 1993, 4, 263-270), malotilate(see, Japan, J. Exp. Med., 1986, 56, 235-245; Biochem, Biophy. Res. Comm., 1994, 200, 1414, 1994), DDB(see, Biochem. Biophy. Res. Comm., 1981, 103, 1131-1137), flumecinol(see, U.S. Pat. No. 4,039,589), etc. were reported, and yet which also have been proved to have demerits of their own. That is, silymarin has a low bioavailability and medicinal effect; malotilate exhibits a hematotoxicity and low bioavailability in oral administration and further it causes undesirable side effects due to its metabolite; flumecinol can be restrictively used to an infant; and DDB has a low bioavailability when administered orally. In addition, a dietary cure, symptomatic treatment, and medical therapies using steroids, immune-related agent, etc. are known, but the efficacy thereof as a therapeutic agent is immaterial. Further, the present inventors have identified the therapeutic effect of novel genipin derivatives to hepatitis.
While, the following compounds of formulas (2) to (4) may be mentioned as reference compounds having a similar structure to that of the compound of formula (1) according to the present invention and also similar use. First, the thiazofuran of formula (2) as a thiazole derivative acts as an inhibitor for purine biosynthesis, by which it exhibits a therapeutic effect to myelocytic leukemia. Therefore, it is now in a third clinical test by ICN company.
Also, the thiazoline derivative of the following formula (3) has been reported to have parasiticidal and fungicidal effects(see, Pharm. Acta. Helv. 1991, 66(8), 237-40), and the pidotimod of the following formula (4) which is a thiazolidine derivative has been marketed by Poli Industria Chimica since 1993 as an immuno-regulatory agent through the mechanism of PNP(purine nucleoside phosphorylase) inhibition.
in which
R represents phenyl, substituted phenyl, 2-furyl, 1-naphthyl or 4-pyridyl.
DISCLOSURE OF INVENTION
Under such a technical background as mentioned above, the present inventors have extensively studied to develop novel compounds which can be effectively used in the hepatoprotection and treatment of liver diseases. As a result, we have succeeded to identify that the compound of formula (1) according to the present invention exhibits a potent hepatoprotective and therapeutic activity for liver diseases, and further part of the compound of formula (1) is novel.
Therefore, it is an object of the present invention to provide a pharmaceutical composition for the hepatoprotection and treatment of liver diseases comprising as an active ingredient a dihydroxyphenyl derivative of formula (1), as defined below, pharmaceutically acceptable acid addition salt or stereochemical isomer thereof together with a pharmaceutically acceptable inert carrier.
in which
A and B independently of one another represent hydrogen, or together represent methylene group,
D represents hydrogen or lower alkoxy,
E represents acetylthioacetyl, or represents the following substituent (a-1) or (a-2):
wherein
represents single or double bond,
R
1
represents hydrogen, lower alkyl or N-acetylmethylaminomethyl,
R
2
represents hydrogen, or represents lower alkyl which is optionally substituted by hydroxycarbonyl, phenyl or 5- or 6-membered heteroaryl containing one or more hetero atoms selected from a group consisting of nitrogen and sulfur, wherein the heteroaryl can be substituted by lower alkyl,
R
3
represents hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbamoyl or lower alkenylcarbamoyl, or represents lower alkyl which is substituted by hydroxy, aryl(lower)alkoxy or 5- or 6-membered heteroaryl(lower)alkoxy containing nitrogen as the hetero atom,
R
4
represents hydrogen, or represents lower alkanoyl which is optionally substituted by halogen,
provided that R
4
does not exist when double bond is linked to the nitrogen atom in substituent (a-2).
Part of the compound of formula (1) which is left after known compounds are removed therefrom is novel, and therefore it is another object of the present invention to provide such a novel dihydroxyphenyl derivative and processes for the preparation thereof.
The novel dihydroxyphenyl derivative according to the present invention is the compound of formula (1) wherein
A and B independently of one another represent hydrogen, or together represent methylene group,
D represents hydrogen or lower alkoxy,
E represents acetylthioacetyl, or represents the following substituent (a-1) or (a-2):
wherein
represents single or double bond,
R
1
represents hydrogen, lower alkyl or N-acetylmethylaminomethyl,
R
2
represents hydrogen, or represents lower alkyl which is optionally substituted by hydroxycarbonyl, phenyl or 5- or 6-membered heteroaryl containing one or more hetero atoms selected from a group consisting of nitrogen and sulfur, wherein the heteroaryl can be substituted by lower alkyl,
R
3
represents hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbamoyl or lower alkenylcarbamoyl, or represents lower alkyl which is substituted by hydroxy, aryl(lower)alkoxy or 5- or 6-membered heteroaryl(lower)alkoxy containing nitrogen as the hetero atom,
R
4
represents hydrogen, or represents lower alkanoyl which is optionally substituted by halogen,
provided that
i) R
1
and R
2
are not hydrogen or methyl when D is hydrogen and E is substituent (a-1),
ii) R
3
is not hydrogen in the thiazoline ring of (a-2) when D is hydrogen and E is substituent (a-2), and
iii) R
4
does not exist when double bond is linked to the nitrogen atom in substituent (a-2).
BEST MODE FOR CARRYING OUT THE INVENTION
More preferred composition according to the present invention comprises a dihydroxyphenyl derivative represented by the following formula (1):
in which
A and B both represent hydrogen, or together represent a methylene group,
D represents hydrogen or C
1
-C
4
-alkoxy,
E represents the following substituent
Choi Hea-Jin
Chung Jea-Uk
Ha Jong-Ryul
Jeong Kwang-Won
Lee Su-Jin
Alexander John B.
Choongwae Pharm. Co., Ltd.
Corless Peter F.
Edwards & Angell LLP
Gerstl Robert
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