Camptothecin derivatives

Details Camptothecin derivatives Camptothecin derivatives

1999-01-08

2003-01-28

Lukton, David (Department: 1653)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S279000, C514S283000, C514S002600, C514S018700, C514S019300, C530S333000, C530S322000

Reexamination Certificate

active

06512118

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel camptothecin derivative having enhanced antitumor activities. More particularly, the present invention relates to a novel camptothecin derivative which is prepared by combining an aminoalkoxy- or hydroxyalkoxy-camptothecin compound with a polysaccharide having carboxyl groups via an amino acid or a peptide, and a process for preparing the same. The camptothecin derivatives of the present invention can be delivered into a target region of the patient selectively and in much amount, so that they can show desired pharmacological activities at the desired region of the patient. Therefore, the antitumor activities of the camptothecin compounds are enormously enhanced and their side effects can be reduced, and hence, the camptothecin derivatives of the present invention are extremely useful as a medicaments.
PRIOR ART
Camptothecin is one plant alkaloids, and has the following formula:
and it has been known to show antileukemic and antitumor activities, and one camptothecin derivative, irinotecan hydrochloride {CPT-11, 7-ethyl-1-[4-(piperidino)-1-piperidino]carbonyloxycamptothecin}, has already been put on the market. However, CPT-11 shows potent antitumor activities in clinical use but also shows severe toxicity like other antitumor agents, so that CPT-11 has been restricted in its therapeutic use [cf. Cancer and Chemotherapy, vol. 21, p. 709 (1994)].
There have been synthesized various camptothecin compounds, and it has been reported that these camptothecin compounds show antitumor activities (Japanese Patent First Publication (Kokai) Nos. 279891/1989, 222048/1993, 87746/1994, 228141/1994, and Japanese Patent First Publication (Kohyo) Nos. 503505/1992, 502017/1992).
On the other hand, in order to enhance antitumor activities and also to reduce the side effects thereof as low as possible, these compounds having such severe side effects have been studied as to a kind of drug delivery system therefor, by which a necessary amount of a drug is selectively delivered into a target tissue. Especially, in the chemotherapy of cancers, it is a serious problem that there is no significant difference between tumor cells and normal cells in sensitivity against anticancer agents, and many studies on targeting-type drug delivery system for anticancer agents have been done in order to selectively deliver an anticancer agent into a cancer-bearing region, for example, doxorubicin-polysaccharide complex (WO 94/19376), doxorubicin-inclusive liposome (Enhancement of effects of anticancer agents and targeting therapy, p. 227 (1987), published by Science Forum Ltd.), dextran-binding mitomycin (Enhancement of effects of anticancer agents and targeting therapy, p. 278 (1987), published by Science Forum Ltd.).
As explained above, camptothecin compounds show excellent anti-tumor activities and are very useful as a medicament but they are strictly restricted in clinical use because of their severe side effects. Thus, it is desired to develop a new camptothecin derivative wherein the excellent pharmacological activities of camptothecin compounds are duly retained but undesirable severe side effects are suppressed.
Under the above mentioned circumstances, the present inventors have intensively studied in order to obtain an excellent camptothecin derivative without the drawback of the conventional camptothecin compounds by utilizing the techniques of the above mentioned drug delivery system, and finally have found that a novel camptothecin derivative having desired pharmacological effects can be obtained by combining a camptothecin compound having a reactive group with a polysaccharide having carboxyl groups via an amino acid or a peptide, and have accomplished the present invention.
BRIEF DESCRIPTION OF INVENTION
An object of the present invention is to provide a novel camptothecin derivative comprising the camptothecin compound [I] bound to a polysaccharide having carboxyl groups via an amino acid or a peptide, which has enhanced antitumor activities with less side effects.
Another object of the present invention is to provide a process for preparing these camptothecin derivative.
DETAILED DESCRIPTION OF INVENTION
The compound of the present invention is a camptothecin derivative comprising a camptothecin compound having an aminoalkoxy group or a hydroxyalkoxy group, represented by the formula [I]:
wherein R
1
, R
2
, R
3
, R
4
and R
5
are
(A) among R
1
, R
2
, R
3
, R
4
and R
5
, two groups being adjacent each other combine to form an alkylene group, or both are a hydrogen atom, and one of the remaining three groups of R
1
, R
2
, R
3
, R
4
and R
5
is a group of the formula: —X
n
-Alk
m
-R
6
, and the other two groups are a hydrogen atom, an alkyl group or a halogen atom, or
(B) among R
1
, R
2
, R
3
, R
4
and R
5
, two groups being adjacent each other combine to form an alkylene group, and one of the carbon atoms of said alkylene group is substituted by a group of the formula: —X
n
-Alk
m
-R
6
, and the remaining three groups of R
1
, R
2
, R
3
, R
4
and R
5
are a hydrogen atom, an alkyl group or a halogen atom, and
one or two methylene groups of the alkylene group in (A) or (B) may optionally be replaced by —O—, —S— or —NH—,
X is —O— or —NH—,
Alk is an alkylene group,
R
6
is —NH
2
, a group of the formula:
 or —OH,
m and n are both 0 or 1, or m is 1 and n is 0,
which camptothecin compound is bound to a polysaccharide having carboxyl groups via an amino acid or a peptide. The camptothecin derivative of the present invention shows extremely potent antitumor activities but show low toxicity.
The camptothecin derivative of the present invention includes compounds which are prepared by combining the camptothecin compound [I] with a polysaccharide having carboxyl groups via an amino acid or a peptide. For example, such camptothecin derivatives may be prepared by combining a part or all of the carboxyl groups of an amino acid or a peptide with R
6
of the compound [I] through acid-amide or ester bonds, followed by combining a part or all of the carboxyl groups of a polysaccharide with amino groups of said amino acid or said peptide through acid-amide bonds. More particularly, the camptothecin derivative of the present invention includes compounds which are prepared by combining the C-terminal carboxyl group of an amino acid or a peptide with R
6
of the compound [I] through an acid-amide or ester bond, followed by combining a part or all of the carboxyl groups of a polysaccharide with the N-terminal amino group of said amino acid or said peptide through acid-amide bonds.
Each substituent of the compound of the formula [I] of the present invention is explained below.
The alkylene group in the definition (A) formed by combining adjacent two groups of R
1
, R
2
, R
3
, R
4
and R
5
each other, wherein one or two methylene groups may optionally be replaced by —O—, —S— or —NH—, is formed by combining each other two substituents at 7- and 9-positions, 9- and 10-positions, 10- and 11-positions, or 11- and 12-positions of the formula [I], and the alkylene group includes a straight chain or branched chain alkylene group having 2 to 6 carbon atoms, for example, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, methylethylene, methyltrimethylene, etc.
The above alkylene group wherein one of the methylene groups is replaced by —O—, —S— or —NH— includes an alkylene group wherein a methylene group at the end or at any position other than the end is replaced by —O—, —S— or —NH—. For example, such alkylene group includes an alkyleneoxy group represented by the formula: —O-Alk′-(Alk′ is an alkylene group, hereinafter, the same) such as methyleneoxy, ethyleneoxy, trimethyleneoxy, tetramethyleneoxy, methylethyleneoxy; an alkyleneamino group represented by the formula: —NH-Alk′- such as methyleneamino, ethyleneamino, trimethyleneamino, tetramethyleneamino, methylethylene-amino; an alkylenethio group represe

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