Taxane derivatives and drugs containing the same

Details Taxane derivatives and drugs containing the same Taxane derivatives and drugs containing the same

1999-01-14

2000-02-15

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

5142328, 514253, 514316, 514320, 544130, 544369, 544375, 544510, 546187, 546196, C07D30514, A61K 31335

Patent

active

060253851

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to taxane derivatives or salts thereof having excellent solubility in water, and also to drugs containing the same.


BACKGROUND ART

Taxol (registered trademark) (i) represented by the following formula (i): ##STR1## is a diterpenoid available by extraction from the bark of the Pacific yew tree, Taxus brevifolia, and was isolated and determined in structure for the first time by Wall, et al. (J. Am. Chem. Soc., 93, 2325, 1971). It has been reported to exhibit high efficacy against ovarian cancer and breast cancer (Ann. int. Med. 111, 273, 1989).
Formulation of Taxol into an injection however requires a special solvent, as it is a compound sparingly soluble in water. Taxol is therefore accompanied by problems in that the production of an injection is difficult and side effects may be induced by a solvent.
A great deal of work has therefore been conducted in recent years with a view to developing a water-soluble derivative of Taxol (Nicolaou, et al., Nature 364, 464, 1993). Under the current circumstances, however, no derivatives have been found yet to be equipped with satisfactory properties.
Accordingly, an object of the present invention is to provide a novel taxane derivative having improved water solubility and high antitumor activities.


DISCLOSURE OF THE INVENTION

With the foregoing circumstances in view, the present inventors have proceed with extensive research. As a result, it has been found that a compound represented by the below-described formula (1) and containing specific substituent(s) introduced at the 3'-position and/or 10-position of taxane (general name of the Taxol skeleton) has excellent antitumor activities, has water solubility extremely higher than Taxol and is hence useful as a drug, leading to the completion of the present invention.
The present invention therefore provides a taxane derivative represented by the following formula (1): ##STR2## wherein at least one of X and Y represents a group --CO--A--B in which A represents a single bond, a group --R--CO--, a group --R--OCO-- or a group --R--NHCO--, R representing a lower alkylene group or a phenylene group, B represents a group ##STR3## in which R.sup.1 represents a hydrogen atom, a substituted or unsubstituted alkyl group or an aralkyloxycarbonyl group, of a group ##STR4## in which R.sup.2 represents an amino group, a mono or di-alkylamino group, a piperidino group, a pyrrolidino group or a morpholino group, or a group ##STR5## in which R.sup.3 R.sup.5 and R.sup.6 each independently represent a hydrogen atom or a lower alkyl group and R.sup.4 represents a lower alkylene group, and the other represents a hydrogen atom, a lower alkanoyl group, a benzoyl group, an alkoxycarbonyl group or a trihalogenoalkoxycarbonyl group; Z represents a hydrogen atom, a trialkylsilyl group or a trihalogenoalkoxycarbonyl group; Ac represents an acetyl group, Bz represents a benzoyl group, and Ph represents a phenyl group; or a salt thereof.
Further, the present invention also provides a drug comprising the taxane derivative represented by the formula (1) or the salt thereof as an active ingredient.
Still further, the present invention also provides a drug composition comprising the taxane derivative represented by the formula (1) or the salt thereof and a pharmaceutically acceptable carrier.
Moreover, the present invention also provides use of the taxane derivative represented by the formula (1) or the salt thereof as a drug.
In addition, the present invention also provides a method for the treatment of a tumor, which comprises administering taxane derivative represented by the formula (1) or the salt thereof.


BEST MODES FOR CARRYING OUT THE INVENTION

The taxane derivative according to the present invention is characterized in that as is represented by the formula (1), one or both of the 31-amino group and the 10-oxy group are a group --CO--A--B or groups --CO--A--B. In each --CO--A--B, the lower alkylene group represented by R in A may be a linear or branched alkylene group having 1-6 carbon atoms, exa

REFERENCES:
patent: 5880131 (1999-03-01), Greenwald

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