Baccatin derivatives and a process for producing the same

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C549S511000

Reexamination Certificate

active

06410757

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a baccatin derivative and a process for producing the same, and in particular to a baccatin derivative of the general formula (I) comprising &bgr;-ketoester bound to a baccatin whose hydroxyl groups at the 7- and 10-positions are protected, as well as a process for producing the same. This material is useful for preparing taxoid compounds such as paclitaxel.
BACKGROUND OF THE INVENTION
Paclitaxel (trade name: Taxol) is one kind of anticancer agent taken from a
Taxus brevifolia
(yew tree) and it is known to be effective particularly against breast cancer and lung cancer. However, the amount of paclitaxel taken from the
Taxus brevifolia
is very small, and the problem of destruction of forests is caused by stripping the bark from the tree.
On the other hand, 10-deacetylbaccatin III can be taken again because this compound is obtained from leaves of the tree and it is useful as a precursor of paclitaxel or its derivative docetaxel (trade name: Taxotere).
For synthesis of the taxoid compounds, semi-synthetic methods are known, and the following methods have been reported: (a) a method by using &bgr;-lactam (European Patent No. 0400971), (b) a method by using an oxazoline compound (International Patent Kokai No. 504444/1995), (c) a method by using a thioester compound (International Patent Kokai No. 505360/1998), and (d) a method by using cinnamic acid (Tetrahedron, Vol. 42, p. 4451 (1986)). These methods are related to the esterification for binding a carboxylic acid compound to an unprotected hydroxyl group at the 13-position in baccatin, or to the esterification using an activated carboxylic acid (thioester).
In general, the preparation of ester compounds can be accomplished by a method of binding a carboxylic acid compound to an alcohol compound with a condensation agent such as dicyclohexylcarbodiimide or diisopropylcarbodiimide in the presence of abase such as pyridine or 4-dimethylaminopyridine; by a method of using an acid anhydride/acid halide; or by transesterification using an acid catalyst etc. For example, the transesterification using an ester compound and an alcohol compound is known as a general method as described in publications such as Chemical Review, Vol. 93, p. 1449 (1993) and Journal of Organic Chemistry, Vol. 50, p. 3618 (1985).
Up to now, the reaction of introducing a side-chain moiety onto a hydroxyl group at the 13-position is limited to the method of binding an carboxylic acid and an activated carboxylic acid (thioester) to the hydroxyl group as described above, and there has been no report on a method of introducing an ester compound as a precursor of a side-chain moiety into the hydroxyl group at the 13-position by transesterification. By introducing an ester compound as a precursor of a side-chain moiety, a compound having a different functional group to that of the conventional side-chain moiety can be easily prepared, and the possibility of obtaining a compound having a different physiological activity than ever before is suggested. In general, the transesterification is conducted in the presence of an acid catalyst such as sulfuric acid or p-toluenesulfonic acid, an amine base such as 4-dimethylaminopyridine or 1,8-diazabicyclo[5,4,0]undecene, or titanium tetraalkoxide etc., but even the transesterification where the reaction proceeds between alcohol and ester is also reported in e.g. Journal of the American Chemical Society, p. 4195 (1951).
SUMMARY OF THE INVENTION
In view of the circumstances described above, the inventors have extensively studied a method of introducing a side-chain moiety precursor by transesterification and attempted to develop a baccatin derivative having &bgr;-ketoester bound via an ester linkage to a hydroxyl group at the 13-position in baccatin and a process for producing the same.
As a result, the inventors have found that when &bgr;-ketoester is allowed to react with a baccatin in the presence of either a tin compound or an amine base preferably under reduced pressure, the &bgr;-ketoester is bound via an ester linkage to the baccatin by transesterification, and the present invention was thereby completed.
Further, the inventors have extensively studied a method of introducing a side-chain moiety precursor by transesterification in the absence of a catalyst and attempted to develop a baccatin derivative having a &bgr;-ketoester bound via an ester linkage to a hydroxyl group at the 13-position in baccatin, as well as a process for producing the same.
The present invention has the following aspects and embodiments:
(1) The first aspect of the present invention relates to a baccatin derivative represented by the general formula (I):
(wherein R
1
and R
2
simultaneously or independently represent a hydroxyl-protecting group, R
3
represents any one group selected from the group of an unsubstituted or substituted phenyl group, an unsubstituted or substituted furyl group, an unsubstituted or substituted pyridinyl group, an alkyl group, a hydroxyalkyl group, a halogenated alkyl group, a cyclic alkyl group and a thienyl group, R
5
represents a hydrogen atom or an alkyl group, Bz represents abenzoyl group, and Ac represents an acetyl group).
(2) The second aspect of the present invention relates to a process for producing a baccatin derivative represented by the general formula (I) described above, which comprises allowing a baccatin to react with a &bgr;-ketoester in the presence of a tin compound or an amine base, wherein the baccatin is represented by the general formula (II):
(wherein R
1
and R
2
simultaneously or independently represent a hydroxyl-protecting group, Bz represents a benzoyl group, and Ac represents an acetyl group).
(3) As the third aspect of the present invention, in (2) above, the reaction is conducted under reduced pressure.
(4) The forth aspect of the present invention also relates to a process for producing a baccatin derivative represented by the general formula (I) above, which comprises allowing a baccatin represented by the general formula (II) to react with a &bgr;-ketoester in the absence of a catalyst:
(wherein Rand R
2
simultaneously or independently represent a hydroxyl-protecting group, Bz represents a benzoyl group, and Ac represents an acetyl group).
(5) As the fifth aspect of the present invention, in (4) above, the reaction is conducted under reduced pressure.
(6) The sixth aspect of the present invention further relates to a baccatin derivative represented by the general formula (III):
(wherein R
1
and R
2
simultaneously or independently represent a hydroxyl-protecting group, n is an integer of 1 to 5, Bz represents a benzoyl group, and Ac represents an acetyl group)
(7) The seventh aspect of the present invention relates to use of a baccatin derivative represented by the general formula (I) described in (1) above or a baccatin derivative represented by the general formula (III) described in (6) above for producing taxoid compounds such as paclitaxel.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention is described in detail.
The baccatin used in the present invention can be 10-deacetylbaccatin III extracted from yew trees, a compound analogous thereto, or a compound obtained by synthesis from a low-molecular compound. In particular, 10-deacetylbaccatin III is suitable for efficiently achieving the present invention.
10-Deacetylbaccatin III used in the present invention, to which a protecting group was introduced, is represented by the general formula (II) above.
The hydroxyl-protecting group in the above formula includes protecting groups described in e.g. “New Course of Experimental Chemistry, 14, Organic Synthesis V, Chapter 11-1, compiled by the Chemical Society of Japan”. Specific protecting groups include triethylsilyl group, benzyloxycarbonyl group, acetyl group, allyloxycarbonyl group etc.
Then the &bgr;-ketoester used in the present invention is represented by any of the following formulae:
(wherein R
3
is a group selected from an unsubstituted or substituted phenyl group, an unsu

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Baccatin derivatives and a process for producing the same does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Baccatin derivatives and a process for producing the same, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Baccatin derivatives and a process for producing the same will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2916951

All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.