Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Patent
1998-02-05
2000-06-13
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
544148, 544368, 5462837, 548526, 549432, C07D49308, C07D30514
Patent
active
060751401
DESCRIPTION:
BRIEF SUMMARY
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. ##STR2##
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: ##STR3## 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.TM.) represented by the following structural formula: ##STR4## 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.TM. 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 .alpha.-configuration hydroxyl group at the 9-position has been obtained from a natural source, and various 9-position .alpha.-hydroxyl group type derivatives obtained by chemical modification of the compound have been reported (for example, see J. Med. Chem., 37, 2655 (1994)). Also, it is known that a compound having a .beta.-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 .beta.-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 .beta.-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: ##STR5## wherein R.sup.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; 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; alkoxyl group, a group --O--R.sup.31, an acyloxy group or a group --O--CO--R.sup.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 heterocycl
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Ishiyama Takashi
Soga Tsunehiko
Terasawa Hirofumi
Daiichi Pharmaceutical Co. Ltd.
Rao Deepak
Raymond Richard L.
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