Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-11
2004-10-19
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S545000
Reexamination Certificate
active
06806266
ABSTRACT:
TECHNICAL FIELD
The present invention relates to staurosporin derivatives or pharmaceutically acceptable salts thereof, which are useful for the treatment of tumors. Further, the present invention relates to enhancers for activity of an antitumor agent.
BACKGROUND ART
As staurosporin derivatives effective for the treatment of tumors, UCN-1 in WO89/7105, CGP41251 in EP657164A, etc. are described.
The staurosporin derivatives as described in the above two literatures, Japanese Published unexamined Application No.62-220196, WO94/20106, WO95/32974, WO95/32975, WO95/32976, EP624590A, etc. are characterized in that in the general formula (I) described below, both of R
2
and R
3
are hydrogen.
As the staurosporin derivatives wherein in the general formula (I) described below, at least one of R
2
and R
3
is not hydrogen, compounds described in Japanese Published Unexamined Application No.3-72485, Japanese. Published. Unexamined Application No.3-220194 and Japanese Published Unexamined Application No. 4-364186, compounds described in WO94/6799, and compounds described in WO97/5141 are known. However, Japanese Published Unexamined Application No.3-72485, Japanese Published Unexamined Application No.3-220194 and Japanese Published Unexamined Application No.4-364186 disclose only compounds wherein in the general formula (I) described below, R
1
is hydrogen, and R
2
and R
3
are hydrogen, nitro, amino, formyl, carboxy, lower alkoxycarbonyl, hydroxymethyl or hydroxy, and these compounds are used for inhibition of platelet aggregation, and their effect on the treatment of malignant tumors is not shown. WO94/6799 disclose only compounds wherein in the general formula (I) described below, R
1
is hydrogen, and R
2
and R
3
are hydrogen, halogen, formyl, lower alkanoyl or lower alkoxy, and these compounds are used for the treatment of thrombocytopenia, and their effect on the treatment of malignant tumors is not shown. Further, the compounds described in WO97/5141 are characterized in that in the general formula (I) described below, compounds are the derivatives which have a ketone or an oxime at the 11-position, and there are neither specific compounds nor synthetic intermediates thereof wherein in the general formula (I) described below, at least one of R
2
and R
3
is not hydrogen.
On the other hand, it is known that some of these compounds in the prior art have strong affinity for human &agr;
1
acidic glycoprotein (hereinafter referred to as h&agr;
1
AGP), which is contained in human plasma [Pharmacogenetics, 6, 411 (1996)]. The pharmacokinetics etc. of such compounds can be influenced by the strong affinity for h&agr;
1
AGP and the expected efficacy of the compounds upon administration into humans can also be influenced. Thus, staurosporin derivatives with low affinity for h&agr;
1
AGP are desired. The above-described staurosporin derivatives wherein in the general formula (I) described below, both of R
2
and R
3
are hydrogen are shown to have strong bonding to h&agr;
1
AGP [Abstracts of 118
th
The Pharmaceutical Society of Japan Annual Meeting, 4, 43 (1998)].
On the other hand, it is known that UCN-01 shows a synergistic effect when combined with known anticancer agents having actions on DNA or antimetabolites, such as Cisplatin, Mitomycin C or 5-Fluorouracil, in vitro and in vivo [Proc. Am. Assoc. Cancer Res., 33, 514 (Publication No. 3072) (1992) and Cancer Chemotherapy Pharmacology, 32, 183 (1993)]. The mechanism of bringing about the is estimated as follows: when DNA in cancer cells is damaged by anticancer agents having actions on DNA or by antimetabolites, the cancer cells act for repairing the DNA damage by stopping their cell cycle at the G2 or S stage (accumulation action at the G2 or S stage), and UCN-01 abrogates this accumulation action, thus promoting progress of the cell cycle, thereby depriving the cancer cells of a chance to repair the DNA damage and leading the cancer cells to apoptosis [Clinical Cancer Res., 2, 791 (1996), Cell Growth and Differentiation, 8, 779 (1997), J. Natl. Cancer Inst., 88, 956 (1996), Proc. Am. Assoc. Cancer Res., 39, 70 (Publication No. 476) (1998)]. This action is called abrogation action on accumulation action at the G2 or S stage, and caffeine is known as a known chemical having this abrogation action, but its concentration for inducing action is as very high as mmol/L level, and so there is little clinical usefulness. [Cancer Res., 55, 1643 (1995)].
Among such compounds, UCN-01, which can abrogate accumulation action at the G2 or S stage at a low concentration of 100 mmol/L or less, is considered to be the strongest abrogation inducer known so far.
On the other hand, UCN-01 binds strongly to h&agr;
1
AGP to lose its biological activity, thus making administration of a large amount of UCN-01 clinically necessary and simultaneously necessitating attention to the interaction among chemicals on h&agr;
1
AGP, and therefore it is anticipated that the possibility of using UCN-01 as an abrogation inducer on accumulation action at the G2 and S stage is limited [Cancer Res., 58, 3248 (1998)].
Accordingly, there is demand for enhancers for activity of antitumor agents, which are capable of exerting abrogation action on accumulation action at the G2 and S stage while preventing binding to a series of h&agr;
1
AGPs.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide staurosporin derivatives or pharmaceutically acceptable salts thereof, which are useful for the treatment of tumors. Another object is to provide enhancers for activity of antitumor agents.
The present invention relates to antitumor agents comprising a staurosporin derivative or a pharmaceutically acceptable salt thereof, as an active ingredient, which is represented by the general formula (I):
wherein
R
1
represents hydrogen, hydroxy, or lower alkoxy;
R
2
represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkadienyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, halogen, nitro, formyl, COR
6
<wherein R
6
represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, NR
7
R
8
{wherein R
7
and R
8
are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or are combined with their adjacent N to form a substituted or unsubstituted heterocyclic group (the heterocyclic group formed by R
7
and R
8
together with their adjacent N may contain an oxygen atom, a sulfur atom, or another nitrogen atom)}, OR
9
(wherein R
9
represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, or substituted or unsubstituted aryl), or SR
10
(wherein R
10
represents substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl)>, NR
11
R
12
<wherein R
11
and R
12
are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, COR
13
{wherein R
13
represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, lower alkoxycarbonyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, OR
9A
(wherein R
9A
has the same meaning as defined for R
9
above) NR
7A
R
8A
(wherein R
7A
and R
8A
have the same meaning as defined for R
7
and R
8
above, respectively)}, CSR
13A
(wherein R
13A
has the same meaning as defined for R
13
above), SO
2
R
13B
(wherein R
13B
has the same meaning as defined for R
13
above), or a residue of an amino acid, excluding a hydroxyl group in a carboxylic group of the amino acid (a functional group in th
Akinaga Shiro
Akiyama Tadakazu
Amishiro Nobuyoshi
Fuse Eiichi
Kanai Fumihiko
Fitzpatrick ,Cella, Harper & Scinto
Kifle Bruck
Kyowa Hakko Kogyo Co. Ltd.
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