Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-06
2004-01-13
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S338000, C514S449000, C514S463000, C549S440000, C549S441000, C549S444000, C549S446000, C549S510000, C549S511000
Reexamination Certificate
active
06677456
ABSTRACT:
TECHNICAL FIELD
This invention relates to a taxol derivative which can be administered orally and has an antitumor activity.
BACKGROUND ART
Taxol is a natural substance represented by the following chemical structural formula, which can be obtained in a small amount from a bark or other parts of
Taxus brevifolia
.
It is known that taxol has an antitumor activity, and its action mechanism is considered to be based on its action to inhibit depolymerization of microtubules in cell division, so that its clinical application is expected as an antitumor agent having an action mechanism which is different from the conventional antitumor agents.
Taxol has so far been obtained from a natural source but only in an extremely small amount. However, taxol derivatives synthesized using a taxol precursor 10-O-deacetylbaccatine III represented by the following formula, which can be obtained from leaves and other parts of Taxus plants in a relatively large amount, have been reported.
Among them, a compound (taxotere, hereinafter referred to as “compound A”) having a structure of the following formula (A) has been drawing attention as a compound having an antitumor activity equal to or higher than that of taxol, and its development as an antitumor agent is in progress.
The present inventors have reported that a compound obtained by converting a hydroxyl group formed by reduction of the 9-position ketone and a hydroxyl group of the 10-position into a cyclic acetal form has a strong antitumor activity (JP-A-9-12578 (the term “JP-A” as used herein refers to a “published unexamined Japanese patent application”) and EP 0 826 688 A1.
Taxol, taxotere and the compound disclosed in JP-A-9-12578 are promising as antitumor agents. However, efficacy of these compounds by oral administration is not known. Regarding the compounds disclosed in Examples of JP-A-9-12578, it has a drawback from the toxicity point of view. From the viewpoint, for example, of lightening the burden on patients at the time of administration and of medical economy, a taxol derivative which can be orally administered is in demand.
As a result of extensive investigation to obtain a taxol derivative which can ensure high safety suited for oral administration while maintaining a high antitumor activity and improving the toxicity problem, the present inventors have conducted extensive studies and obtained a compound (hereinafter, referred to as “compound B”) of the following formula (B) capable of showing a significant antitumor activity even by its oral administration for example in an antitumor test using mice.
The toxicity problem of this compound was improved in comparison with the compounds disclosed in Examples of JP-A-9-12578. However, its applicability to oral administration in human was not able to be assured, because it was revealed by an in vitro metabolism test using human liver microsome that this compound undergoes its metabolism rapidly in human liver microsome.
DISCLOSURE OF INVENTION
With the aim of inhibiting modification of compounds by their metabolism, the inventors have carried out a new drug design study and found that a compound in which a substituent group is introduced into pyridine ring of the 13-position side chain hardly undergoes its metabolism in human liver microsome and can ensure safety suited for oral administration, while maintaining its antitumor activity and also improving the toxicity problem, thus resulting in the accomplishment of the invention.
Accordingly, the invention provides a compound represented by the following formula (I) or a salt thereof, a medicament which comprises the compound of the following formula (I) or a salt thereof and an antitumor agent which contains the compound of the following formula (I) or a salt thereof.
The invention also provides an intermediate (hereinafter, referred to as “intermediate of the invention”) represented by the following formula (III) for use in the production of the taxol derivative, and use thereof.
In the following formula (I), R
1
is dimethylaminomethyl group or morpholinomethyl group and R
2
is a halogen atom or an alkoxy group having from 1 to 6 carbon atoms. Preferred examples of R
2
include methoxy group, fluorine atom and chlorine atom, more preferably fluorine atom and methoxy group.
Particularly preferred is a compound represented by the following formula (II), namely (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylidenedioxy]-5,20-epoxy-1-hydroxytax-11-en-13-yl(2R,3S)-3-(tert-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate,
or a salt thereof.
Also in the above-mentioned intermediate of formula (III), R
3
is dimethylaminomethyl group, morpholinomethyl group or vinyl group, R
4
is hydroxyl group which may have a protecting group and R
5
is an alkoxy group having from 1 to 6 carbon atoms or a halogen atom. In addition, the part of dotted line between the 6-position and 7-position of a partial structure in the intermediate of formula (III), shown by formula:
means that the bond of the part may be a double bond.
In the intermediate of formula (III), examples of the protecting group of R
4
include a trialkylsilyl group, benzyl group, a substituted benzyl group, 1-ethoxyethyl group, benzyloxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group. Preferred among them are a trialkylsilyl group such as triisopropylsilyl group, tertiary butyldimethylsilyl group or triethylsilyl group and benzyl group, and particularly preferred are triisopropylsilyl group and benzyl group.
The production intermediate of the taxol derivative of the invention can be used by optionally selecting it in response to the final product of interest. For example, for the production of a compound represented by formula (II):
or a salt thereof, it is desirable to use a compound represented by formula (IV):
(wherein R
6
is triisopropylsilyl group, tertiary butyldimethylsilyl group, triethylsilyl group or benzyl group) or a salt thereof, a compound represented by formula (V):
(wherein R
7
is triisopropylsilyl group, tertiary butyldimethylsilyl group, triethylsilyl group or benzyl group) or a salt thereof, or a compound represented by formula (VI):
(wherein R
8
is triisopropylsilyl group, tertiary butyldimethylsilyl group, triethylsilyl group or benzyl group) or a salt thereof.
Compound (I) can be synthesized through the following steps 1), 2), 3), 4) and 5):
1) a step of reacting a compound of formula (III′):
with a compound formula (IV′):
thereby obtaining a compound of the following formula (VI′);
2) a step of converting the vinyl group of the resulting compound (VI′) into an aldehyde group;
3) a step of converting the aldehyde group into a dimethylaminomethyl or morpholinomethyl group;
4) a step converting, when the bond between the 6-carbon atom and 7-carbon atom is a double bond, the bond into a single bond; and
5) a step of removing, when R
33
is hydroxyl group having a protecting group, the protecting group.
In compound (III′), R
33
means hydroxyl group which may have a protecting group. Here, R
33
at the 3-position on the &bgr;-lactam ring is in a cis configuration relative to the pyridyl group at the 4-position. Examples of the protecting group of R
33
include substituted silyl, benzyl, substituted benzyl, 1-ethoxyethyl, benzyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl groups. The substituted silyl group has, for example, an alkyl group, an aryl group or an aralkyl group as a substituent. Examples of the substituted silyl group include trimethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tribenzylsilyl and tert-butyldiphenylsilyl groups. The substituted benzyl group has, for example, a halogen atom, an alkyl group, an alkoxy group or a nitro group as a substituent and examples of the substituted benzyl group include paranitrobenzyl and paramethoxybenzyl groups. Preferred examples of the protecting group of R
33
include trialkylsilyl groups such as triisopropylsilyl, tert-butyldimethylsilyl and triethy
Soga Tsunehiko
Takeda Yasuyuki
Uoto Kouichi
Daiichi Pharmaceutical Co. Ltd.
Sughrue & Mion, PLLC
Trinh Ba K.
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