Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-07
2004-11-09
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S253030, C514S232800, C546S084000, C544S126000, C544S361000
Reexamination Certificate
active
06815449
ABSTRACT:
TECHNICAL FIELD
The present invention relates to LK6-A derivatives which have immunosuppressive activity, cell growth inhibitory activity, anti-tumor activity, etc., and pharmaceutically acceptable salts thereof.
BACKGROUND ART
Cyclosporin A [Nature, Vol. 280, p. 148 (1978)], FK506 [Immunol. Today, Vol. 10, p. 6 (1989)], mizoribine [Transplantation Proceed., Vol. 11, p. 865, (1979)], azathioprine [New Eng. J. Med., Vol. 268, p. 1315 (1963)], 15-deoxyspergualin [Transplantation Proceed., Vol. 22, p. 1606 (1990)], etc., which are known as low-molecular immunosuppressive agents, are used as therapeutic agents for autoimmune diseases, allergic diseases, infections caused by organ transplantation, etc. or as rejection inhibitors in organ transplantation. However, they are not entirely satisfactory in respect of efficacy, side effect, etc.
Plakinidines [Tetrahedron Lett., Vol. 31, p. 3271 (1990)] are reported as compounds having the pyrrolo[4,3,2-de]quinoline skeleton, but their immunosuppressive activity has not been known. As the pyrrolo[4,3, 2-de]quinoline compound having immunosuppressive activity, LK6-A represented by the following formula (Japanese Published Unexamined Patent Application No. 151185/97) has been reported.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel LK6-A derivatives having excellent immunosuppressive activity, cell growth inhibitory activity, anti-tumor activity, etc. which are useful as therapeutic agents for autoimmune diseases, allergic diseases, and diseases caused by abnormal cell growth such as leukemia and cancers, or as rejection inhibitors in organ transplantation.
The present invention relates to LK6-A derivatives represented by general formula (I):
[wherein R
1
represents lower alkyl (the lower alkyl may be substituted by one to a substitutable number of, preferably 1-4 substituents which are the same or different and are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy and halogen), lower alkanoyl (the lower alkyl moiety of the lower alkanoyl may be substituted by one to a substitutable number of, preferably 1-4 substituents which are the same or different and are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy and halogen), carboxy, lower alkoxycarbonyl,
(wherein n represents 1 or 2) or COCH═CHR
9
{wherein R
9
represents substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or NR
10
R
11
(wherein R
10
and R
11
, which may be the same or different, each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryl-substituted lower alkyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted tetrahydropyranylmethyl, or R
10
and R
11
are combined together with the adjoining N to form a substituted or unsubstituted heterocyclic group)};
R
2
represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkanoyloxy, halogen, SR
12
(wherein R
12
represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl-substituted lower alkyl, substituted or unsubstituted tetrahydropyranyl, or substituted or unsubstituted tetrahydropyranylmethyl), NR
13
R
14
(wherein R
13
and R
14
have the same significances as the above R
10
and R
11
, respectively) or azido;
R
2′
represents hydrogen or is combined with R
3
to represent a bond;
R
3
represents substituted or unsubstituted lower alkanoyl or is combined with R
2′
to represent a bond;
R
4
and R
5
, which may be the same or different, each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl, or substituted or unsubstituted heteroaryl-substituted lower alkoxycarbonyl;
R
6
represents hydrogen or halogen; and
R
7
and R
8
, which may be the same or different, each represents hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkanoyl;
provided that a compound wherein R
1
represents (E)-3-methoxyacryloyl, R
2
, R
4
, R
5
and R
6
represent hydrogen, R
2′
and R
3
are combined together to represent a bond, R
7
represents hydrogen and R
8
is acetyl is excluded],
and pharmaceutically acceptable salts thereof.
Hereinafter, the compounds represented by general formula (I) are referred to as Compounds (I). The same shall apply to compounds of other formula numbers.
Preferred examples of the compounds of the present invention are shown in the following (a)-(h).
(a) Compound (I) in which R
1
represents COCH═CHR
9
(wherein R
9
has the same significance as defined above); R
2′
and R
3
are combined together to represent a bond; R
4
, R
5
and R
6
represent hydrogen; and R
7
and R
8
, which may be the same or different, each represents hydrogen or acetyl.
(b) Compound (I) in which R
1
represents lower alkyl (the lower alkyl may be substituted by one to a substitutable number of, preferably 1-4 substituents which are the same or different and are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy and halogen) or lower alkanoyl (the lower alkyl moiety of the lower alkanoyl may be substituted by one to a substitutable number of, preferably 1-4 substituents which are the same or different and are selected from the group consisting of lower alkyl, hydroxy, lower alkoxy and halogen); R
2′
and R
3
are combined together to represent a bond; R
4
, R
5
and R
6
represent hydrogen; and R
7
and R
8
, which may be the same or different, each represents hydrogen or acetyl.
(c) Compound (I) in which R
1
represents:
(wherein n has the same significance as defined above); R
2′
and R
3
are combined together to represent a bond; R
2
, R
4
, R
5
and R
6
represent hydrogen; and R
7
and R
8
, which may be the same or different, each represents hydrogen or acetyl.
(d) Compound (I) in which R
1
represents (E)-3-methoxyacryloyl; R
2′
and R
3
are combined together to represent a bond; R
4
represents hydrogen; and R
5
represents substituted or unsubstituted lower alkoxycarbonyl or substituted or unsubstituted aralkyloxycarbonyl.
(e) Compound (I) in which R
1
represents COCHR
15
CH(OCH
3
)
2
(wherein R
15
represents hydrogen or lower alkyl); R
2′
and R
3
are combined together to represent a bond; R
4
and R
5
, which may be the same or different, each represents hydrogen or lower alkyl; and R
7
and R
8
, which may be the same or different, each represents hydrogen, substituted or unsubstituted lower alkyl or acetyl.
(f) Compound (I) in which R
1
represents COCHR
15a
CH(OCH
3
)
2
(wherein R
15a
represents hydrogen or halogen); R
2′
and R
3
are combined together to represent a bond; R
4
and R
5
represent hydrogen; and R
7
and R
8
, which may be the same or different, each represents hydrogen or acetyl.
(g) Compound (I) in which R
1
represents 1-hydroxy-3-methoxypropyl; R
2′
and R
3
are combined together to represent a bond; R
4
and R
5
represent hydrogen; and R
7
and R
8
, which may be the same or different, each represents hydrogen or acetyl.
(h) Compound (I) in which R
2
represents hydrogen or substituted or unsubstituted lower alkanoyloxy; R
2′
represents hydrogen; R
3
represents substituted or unsubstituted
Akama Tsutomu
Hasegawa Atsuhiro
Ikeda Shun-ichi
Kanda Yutaka
Mochida Kenichi
Huang Evelyn Mei
Kyowa Hakko Kogyo Co. Ltd.
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