Pentacyclic compound

Details Pentacyclic compound Pentacyclic compound

2001-01-16

2003-04-08

Rao, Deepak R. (Department: 1624)

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

Organic compounds

Chalcogen in the nitrogen containing substituent

C544S148000, C544S368000, C546S283700, C548S526000, C549S482000, C549S510000

Reexamination Certificate

active

06545151

ABSTRACT:

TECHNICAL FIELD
This invention relates to a novel taxol derivative having an antitumor activity.
BACKGROUND ART
Taxol is a natural compound having the following chemical structure, which can be obtained in a small amount from a trunk or the like of
Taxus brevifolia
.
It is known that taxol has an antitumor activity and its action mechanism is based on the depolymerization inhibition action of microtubule during cell division, so that its clinical application is expected as an antitumor agent which is different from the general antitumor agents.
Though taxol can be obtained only in an extremely small amount from a natural source, reports have been published recently on the synthesis of taxol derivatives using a starting material 10-O-deacethylbaccatin III represented by the following structural formula:
which is a taxol precursor that can be obtained in a relatively large amount from leaves and the like of taxaceous trees (cf. JP-A-3-505725; the term “JP-A” as used herein means an “unexamined published Japanese patent application”). Of such derivatives, a compound (Taxotere™) represented by the following structural formula:
has been drawing attention as a compound which has an antitumor activity similar to or higher than that of taxol and is now under development as an antitumor agent.
Though taxol and Taxotere™ are promising compounds as antitumor agents, their clinical tests have revealed that they have low efficacy-on digestive organ cancers, especially large bowel cancers, so that great concern has been directed toward the development of a derivative having more strong antitumor effects.
DISCLOSURE OF THE INVENTION
The 9-position of taxol derivatives is generally a keto group, but some derivatives in which this position is reduced are also known. A compound having an &agr;-configuration hydroxyl group at the 9-position has been obtained from a natural source, and various 9-position &agr;-hydroxyl group type derivatives obtained by chemical modification of the compound have been reported (for example, see
J. Bed. Chem
., 37, 2655 (1994)). Also, it is known that a compound having a &bgr;-configuration hydroxyl group at the 9-position can be synthesized chemically by reducing 10-O-deacethylbaccatin III using a reducing agent, and various 9-position &bgr;-hydroxyl group type derivatives obtained by chemical modification of the compound have been reported (for example, see WO 94/20088).
As a result of extensive investigation, the inventors of the present invention have found that the antitumor activity of the aforementioned 9-position &bgr;-hydroxyl group type taxol derivative sharply increases when its 9-position hydroxyl group and 10-position hydroxyl group are converted into cyclic acetal type. The present invention has been accomplished on the basis of this finding.
Accordingly, present invention relates to a compound represented by the following general formula (I) or a salt thereof:
wherein
R
1
represents a phenyl group, which may have one or more substituent(s) selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group;
R
2
represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or an alkoxyl group, in which these. alkyl, alkenyl, alkynyl, cycloalkyl and alkoxyl groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group, an an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group;
R
3
represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group, a group —O—R
31
, an acyloxy group or a group —O—CO—R
31
, in which the alkoxyl and acyloxy groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cycloalkyl group, an alkoxyl group, an aryl group, an aryloxy group, an amino group, an alkylamino group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group and a heterocyclic group (the heterocyclic group may have one or more alkyl group(s) on the constituent atoms of its ring),
wherein R
31
represents an alkylamino group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, in which these alkylamino, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclic groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group, an acyloxy group and a nitrogen-containing heterocyclic group having a size of three- to eight-membered ring (the nitrogen-containing heterocyclic group may have one or more alkyl group(s) on the constituent atoms of its ring),
or R
3
may form a three-membered ring together with the methyl group linked to a carbon atom adjacent to the carbon atom to which R
3
is linked;
R
4
and R
5
each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or a heterocyclic group, in which these alkyl, alkenyl, alkynyl, aryl and heterocyclic groups may have one or more substituent(s) selected from the group consisting of an alkoxyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group and a nitrogen-containing saturated heterocyclic group having a size of five- or six-membered ring represented by the following formula:
wherein X represents an oxygen atom, a sulfur atom, CH
2
, CH—Y, NH or N—Y, in which Y is an alkyl group, (the heterocyclic group may have one or more alkyl group(s) on a carbon atom as a constituent atom of its ring), or R
4
and R
5
may form a thiocarbonyl group or a carbonyl group together with the carbon atom linked thereto;
Z
1
represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group;
Z
2
represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group;
Z
3
represents an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or a heterocyclic group, in which these alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclic groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group; and
Z
4
represents an alkyl group, an aryl group or an alkoxyl group, in which these alkyl, aryl and alkoxyl groups may have one or more substituent(s) selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, an alkylaminoalkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group;
with the proviso that the dotted line of the following moiety:
means that the corresponding bonding of the moiety may be a double bond, but R
3
is not a hydroxyl group in that case.
Further, the present invention relates to a compound having a configuration represented by the following general formula (Ia) or a salt thereof:
wherein R
1
, R
2
, R
3
, R
4
, R
5
, Z
1
, Z
2
, Z
3
and Z
4
are as defined above.
Firstly, the terms used herein are described.
The term “C
1
-C
6
” as used herein means 1 to 6 carbon atoms, for example, “C
2
-C
6
alkenyl group” means an alkenyl group having 2 to 6 carbon atoms.
Each of “alkyl group”, “alkenyl group” and “alkynyl group” may be either straight chain or branched chain, preferably having 1 carbon atom (2 carbon atoms in the case of alkenyl and alkynyl groups) to

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