Triterpene derivatives and remedies for liver diseases

Details Triterpene derivatives and remedies for liver diseases Triterpene derivatives and remedies for liver diseases

1998-08-26

2001-03-13

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C560S249000, C514S894000, C514S529000, C514S700000, C568S875000, C568S326000

Reexamination Certificate

active

06201018

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions, for hepatic disorders, comprising triterpene derivatives or salts thereof as an active ingredient. The present invention also relates to novel triterpene derivatives.
2. Background 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 hepatic diseases, alimentary therapy, rest cure, and other therapies using glycyrrhizin preparations, adrenocortical steroids, interferon and the like have hitherto been employed. These therapies, however, cannot be said to be satisfactorily effective for the treatment of 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 and are known as prophylactic and pharmaceutical compositions for immunological diseases and thrombosis (Japanese Patent Laid-Open No. 85344/1986). However, there is no report which discloses that the triterpene derivatives are effective as a pharmaceutical composition for treating hepatic disorders.
SUMMARY OF THE INVENTION
The present inventors have now found that certain triterpene derivatives are effective for treating hepatic disorders. Further, they have succeeded in synthesis of novel triterpene derivatives. The present invention has been made based on such novel finding.
According to the first aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder comprising as an active ingredient a triterpene derivative represented by the following formula (I) or a salt thereof:
wherein
R
1
represents
a hydroxyl group,
arylmethyloxy,
lower alkoxy, or
lower alkanoyloxy;
R
2
represents
lower alkyl,
lower alkenyl,
—CH
2
OR
5
wherein R
5
represents a hydrogen atom, arylmethyl, lower alkyl, or lower alkanoyl, formyl,
—COOR
6
wherein R
6
represents a hydrogen atom or lower 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, lower alkyl, aryl, or lower alkanoyl;
or R
1
and R
2
may combine with each other to form —O— C(R
9
)R
10
—C—CH
2
— wherein R
9
and R
10
, which may be the same or different, represent a hydrogen atom, lower alkyl, or aryl;
R
3
and R
4
, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
lower alkyl,
lower alkenyl,
aryl,
hydroxymethyl,
—N(R
11
)R
12
wherein R
11
and R
12
which may be the same or different, represent a hydrogen atom, lower alkyl, or lower alkanoyl,
formyl,
—COOR
6
wherein R
6
is as defined above,
—OR
13
wherein R
13
represents lower alkyl, cyclo-lower alkyl, aralkyl, lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, lower alkenylcarbonyl, or aryl-lower alkenylcarbonyl;
or R
3
and R
4
may combine with each other to form oxo, hydroxyimino, or alkylidene; and
X represents O, CH
2
, or NH.
According to the second aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (II) or a salt thereof:
wherein
R
16
represents
a hydroxyl group,
arylmethyloxy,
lower alkoxy, or
lower alkanoyloxy;
R
17
represents
lower alkyl,
lower alkenyl
—CH
20
R
5
wherein R
5
is as defined above, formyl,
—COOR
6
wherein R
6
is as defined above,
—CH
2
OCON(R
9
)R
10
wherein R
9
and R
10
are as defined above,
—CON(R
29
)R
30
wherein R
29
and R
30
, which may be the same or different, represent a hydrogen atom, lower alkyl, lower alkanoyl, aryl, or aralkyl;
—CH
2
N(R
7
)R
8
wherein R
7
and R
8
are as defined above;
—C(R
6
)
20
H wherein R
6
is as defined above;
—COR
6
wherein R
6
is as defined above;
—CH═CHR
6
wherein R
6
is as defined above;
or R
16
and R
17
may combine with each other to form —O— C(R
9
)R
10
—O—CH
2
— wherein R
9
and R
10
are as defined above;
R
18
and R
19
, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
arylmethyloxy,
lower alkyl,
—N(R
11
)R
12
wherein R
11
and R
12
are as defined above,
—COOR
6
wherein R
6
is as defined above,
—OR
13
wherein R
13
is as defined above,
—O—(CH
2
)
m
—R
22
wherein
R
22
represents
amino,
—NH—COOR
23
wherein R
23
represents arylmethyl or lower alkyl,
a hydroxyl group,
arylmethyloxy, or
—COOR
24
wherein R
24
represents a hydrogen atom, lower alkyl, or arylmethyl, and
m is an integer of 1 to 4,
—OCOCH(R
25
)(CH
2
)
n
—R
22
wherein R
22
is as defined above, R
25
represents a hydrogen atom, lower alkyl, aralkyl, or aryl, and n is an integer of 0 to 3,
—OCOCH═CH—COOR
6
wherein R
6
is as defined above, or —OCON(R
29
)R
30
wherein R
29
and R
30
are as defined above;
or R
18
and R
19
may combine with each other to form oxo,
R
20
and R
21
respectively represent the same meanings as R
18
and R
19
, provided that R
20
and R
21
do not represent a hydrogen atom;
or R
18
and R
20
may combine with each other to form —O— [C(R
9
)R
10
]
p
—O— wherein R
9
and R
10
are as defined above and p is an integer of 1 to 3, or —OCO[C(R
9
)R
10
]
q
—OCO— wherein R
9
and R
10
are as defined above and q is an integer of 0 to 2; and
Y represents O, CH
2
, NH, or a single bond to form a double bond in the ring with Y bonded thereto.
According to the third aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (III) or a salt thereof:
wherein
R
1
, R
2
, and Y are as defined above; and
R
27
represents
—O—(CH
2
)
m
—R wherein R
22
and m are as defined above,
—OCOCH(R
25
)(CH
2
)
n
—R
22
wherein R
22
, R
25
, and n are as defined above,
—OCON(R
29
)R
30
wherein R
29
and R
30
are as defined above,
—OCO—(CH
2
)n-R
16
wherein R
16
is as defined above, or
—OCOCH═CH—COOR
6
wherein R
6
is as defined above.
According to the fourth aspect of the present invention, there is provided a pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (IV) or a salt thereof:
wherein
R
1
, R R
19
, and Y are as defined above; and
R
28
represents
—CON(R
29
)R
30
wherein R
29
and R
30
are as defined above,
—C(R
6
)
2
OH wherein R
6
is as defined above,
—COR
6a
wherein R
6
a represents lower alkyl, or
—CH═CHR
6
wherein R
6
is as defined above.
The first group of novel compounds according to the present invention is triterpene derivatives represented by the following formula (Ia) or salts thereof:
wherein
R
1
represents a hydroxyl group, lower alkoxy, or lower alkanoyloxy;
R
2
represents hydroxymethyl, lower alkoxymethyl, lower alkanoyloxymethyl, or carboxyl;
or R
1
and R
2
may combine with each other to form —O—C(R
14
)R
15
—O—CH
2
— wherein R
14
and R
15
, which may be the same or different, represent a hydrogen atom or lower alkyl;
R
3
and R
4
, which may be the same or different, represent
a hydrogen atom,
a hydroxyl group,
lower alkyl,
lower alkenyl,
aryl,
hydroxymethyl,
—N(R
11
)R
12
wherein R
11
and R
12
, which may be the same or different, represent a hydrogen atom, lower alkyl, or lower alkanoyl,
formyl,
—COOR
6
wherein R
6
is as defined above,
—OR
13
wherein R
13
represents lower alkyl, cyclo-lower alkyl, aralkyl, lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, lower alkenylcarbonyl, or aryl-lower alkenylcarbo

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