Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-01
2001-10-23
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S049000, C549S200000, C552S261000, C560S116000, C568S579000
Reexamination Certificate
active
06306862
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
The present invention relates to triterpene derivatives usable as therapeutic agents for hepatic disorders.
2. Description of the Related Art
A liver is an important organ which has various functions necessary for maintaining life of a living body, such as detoxication, various metabolisms, and storage of substances. It, however, often undergoes acute or chronic damage due to viruses, drugs, alcohols and other various causes. This induces viral hepatitis, drug-induced hepatopathy, alcoholic hepatopathy, fatty liver, and, in addition, diseases such as cirrhosis and hepatic cancer.
For treating such disorders, alimentary therapy, rest cure, and other therapies using glycyrrhizin preparations, adrenocortical steroids, interferons and the like have hitherto been employed. These therapies, however, may not be satisfactorily effective for the treatment of the hepatic disorders. Glycyrrhizin and interferon are intravenously administered and, hence, unsuitable for prolonged administration. Further, the interferon and steroids have a problem of side effect.
Some triterpene derivatives have anticomplementary activity and platelet aggregation inhibitory activity. Thus, they are known as prophylactic and therapeutic agents for immunological diseases and thrombosis (Japanese Patent Laid-Open No. 85344/1986). Further, triterpene derivatives are disclosed, for example, in Japanese Patent Laid-Open No. 37749/1986, Chem. Pharm. Bull., 36, 153 (1988), Chem. Pharm. Bull., 24, 121 (1976), Chem. Pharm. Bull., 30, 2294 (1982), Chem. Pharm. Bull., 33, 4267 (1985), Chem. Pharm. Bull., 31, 664 (1983), Chem. Pharm. Bull., 31, 674 (1983), Phytochemistry 27, 3563 (1988), Planta Medica 46, 52 (1982), J. Chem. Soc., and Chem. Comm., 785 (1982).
However, so far as the present inventors know, there is no report which discloses that the triterpene derivatives are effective as a therapeutic agent for treating hepatic disorders.
SUMMARY OF THE INVENTION
The present inventors have now found that triterpene derivatives are effective for treating hepatic disorders. Further, they have succeeded in synthesis of novel triterpene derivatives. The present invention is based on such novel finding.
Thus, according to one aspect of the present invention, there is provided a therapeutic agent for a hepatic disorder, comprising a triterpene derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R
1
represents a hydroxyl group,
C
1-6
alkoxy,
C
1-6
alkylcarbonyloxy, or aralkyloxy which may be optionally substituted;
R
2
represents C
1-6
alkyl,
—CH
2
OR
5
wherein R
5
represents a hydrogen atom, C
1-6
alkyl, aralkyl which may be optionally substituted, or C
1-6
alkylcarbonyl,
formyl,
—COOR
6
wherein R
6
represents a hydrogen atom or C
1-6
alkyl), or
—CH
2
N(R
7
)R
8
wherein R
7
and R
8
, which may be the same or different, represent a hydrogen atom or C
1-6
alkyl; or
R
1
and R
2
may combine with each other to form —O—CR
9
(R
10
)—OCH
2
— wherein R
9
and R
10
, which may be the same or different, represent a hydrogen atom, C
1-6
alkyl, or aryl;
R
3
and R
4
, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
C
1-6
alkyl,
hydroxy C
1-6
alkyl,
formyl,
—COOR
11
wherein R
11
represents a hydrogen atom or C
1-6
alkyl, or
—OR
12
wherein R
12
represents C
1-6
alkyl, aralkyl which may be optionally substituted, C
1-6
alkylcarbonyl, arylcarbonyl which may be optionally substituted, C
2-6
alkenyl, C
2-6
alkenylcarbonyl, or arylalkenylcarbonyl which may be optionally substituted; or
R
3
and R
4
combine with each other to form a methylene group;
— — —
represents a single or double bond, provided that, when
— — —
represents a double bond, R
4
is absent.
The novel triterpene derivative according to another aspect of the present invention is represented by the formula (II) or a pharmaceutically acceptable salt thereof:
wherein
R
1
represents a hydroxyl group,
C
1-6
alkoxy,
C
1-6
alkylcarbonyloxy, or
aralkyloxy which may be optionally substituted;
R
2
represents C
1-6
alkyl,
—CH
2
OR
5
wherein R
5
represents a hydrogen atom, C
1-6
alkyl, aralkyl which may be optionally substituted, or C
1-6
alkylcarbonyl,
formyl,
—COOR
6
wherein R
6
represents a hydrogen atom or C
1-6
alkyl), or
—CH
2
N(R
7
)R
8
wherein R
7
and R
8
, which may be the same or different, represent a hydrogen atom or C
1-6
alkyl; or
R
1
and R
2
may combine with each other to form —O—CR
9
(R
10
)—OCH
2
— wherein R
9
and R
10
, which may be the same or different, represent a hydrogen atom, a C
1-6
alkyl group, or aryl which may be optionally substituted;
R
3
and R
4
, which may be the same or different, represent
C
1-6
alkyl,
hydroxy C
1-6
alkyl,
formyl,
—COOR
11
wherein R
11
represents a hydrogen atom or C
1-6
alkyl, or
—OR
12
wherein R
12
represents C
1-6
alkyl, aralkyl which may be optionally substituted, arylcarbonyl which may be optionally substituted, C
2-6
alkenyl, C
2-6
alkenylcarbonyl, or arylalkenylcarbonyl which may be optionally substituted; or
R
3
and R
4
may combine with each other to form a methylene group;
— — —
represents a single or double bond, provided that, when
— — —
represents a double bond, R
4
is absent;
when R
1
and R
2
may combine with each other to form -—O—CR
9
(R
10
)—OCH
2
— wherein any one of R
9
and R
10
represents aryl, R
3
and R
4
may further represent a hydrogen atom, a hydroxyl group, or aralkyloxy;
when any one of R
3
and R
4
represents a C
1-6
alkyl group, the other may further represent a hydroxyl group; and
when R
2
represents —CH
2
OR
5
, R
3
and R
4
may further represent a hydrogen atom.
Further, novel compounds provided by the present invention are:
a compound represented by the formula (II) wherein R
1
represents a hydroxyl group, R
2
represents —COOO—C
1-6
alkyl, R
3
represents a hydrogen atom and R
4
represents a hydroxyl group;
a compound represented by the formula (II) wherein R
1
represents C
1-6
alkoxy, R
2
represents —CH
2
OH, R
3
represents a hydrogen atom and R
4
represents a hydroxyl group,
a compound represented by the formula (II) wherein R
1
represents aralkyloxy, R
2
represents formyl, carboxyl, —COO—C
1-6
alkyl, or —CH
2
OR
5
, wherein R
5
represents a hydrogen atom, C
1-6
alkyl, or C
1-6
alkylcarbonyl, R
3
represents a hydrogen atom and R
4
represents aralkyloxy which may be optionally substituted; and
a compound represented by the formula (II) wherein R
1
represents a hydroxyl group or C
1-6
alkoxy, R
2
represents aralkyloxymethyl which may be optionally substituted, R
3
represents a hydrogen atom and R
4
represents aralkyloxy which may be optionally substituted.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Therapeutic Agent for Hepatic Disorders/Compounds of Formula (I)
The compounds represented by the formula (I) and salts thereof are effective for the treatment of hepatic disorders. Hepatic disorders, to which the compounds represented by the formula (I) can be applied, include acute and chronic viral hepatitis, and drug-induced, toxic, alcoholic, intrahepatic cholestasis, and inborn metabolic error hepatopathy. The term “hepatopathy” used herein refers to inflammatory diseases and, depending upon the progress of symptom, is used as a term include also fatty liver, cirrhosis, and hepatoma.
Specifically, the triterpene derivatives represented by the formula (I), when incubated together with human hepatoma cells (Hep G2) in the presence of aflatoxin B
1
(hepatopathy-inducing substance), has an inhibitory activity against necrosis of such cells.
As used herein, the term “alkyl” as a group or a part of a group means both straight and branched chain alkyls.
Specific examples of this group include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, and t-butyl. The term “halogen atom” means a fluorine, chlorine, bromine, or iodine atom. The term “aryl” as a group or a part of a group preferably means phenyl, naphthyl, tolyl, methoxyphenyl or the like. The te
Kuzuhara Hiroyuki
Minowa Nobuto
Nishiyama Shoji
Sasaki Kazue
Killos Paul J.
Meiji Seika Kaisha Ltd.
Oh Taylor V.
Wenderoth , Lind & Ponack, L.L.P.
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