Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-20
2002-04-02
Trinh, Ba K. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S510000, C549S511000
Reexamination Certificate
active
06365750
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel oxazolidines which find utility as intermediates in the preparation of C-13 acyloxy sidechain-bearing taxanes such as paclitaxel and analogs thereof. The present invention also relates to novel methods of preparing the oxazolidines, as well as to novel methods of coupling the oxazolidines to form the aforementioned sidechain-bearing taxanes.
BACKGROUND OF THE INVENTION
Taxanes are diterpene compounds finding utility in the pharmaceutical field. For example, paclitaxel (Taxol®), a taxane having the structure:
where Ph is phenyl, Ac is acetyl and Bz is benzoyl, has been found to be an effective anticancer agent. The compound taxotere, having the following structure, has also been reported for anticancer use:
Naturally occurring taxanes such as paclitaxel may be found in plant materials, and have been isolated therefrom. Such taxanes may, however, be present in plant materials in relatively small amounts so that, in the case of paclitaxel, for example, large numbers of the slow-growing yew trees forming a source for the compound may be required. The art has thus continued to search for synthetic, including semi-synthetic routes for the preparation of naturally occurring taxanes such as paclitaxel, as well as routes for the preparation of pharmaceutically useful analogs thereof. In particular, efficient. methods for the addition of a C-13 acyloxy sidechain to a taxane core are sought as the presence of the C-13 acyloxy sidechain imparts pharmacological activity or provides a taxane more readily converted to one having such pharmacological activity.
SUMMARY OF THE INVENTION
The present invention provides novel oxazolidine compounds useful as intermediates for the preparation of C-13 acyloxy sidechain-bearing taxanes. Novel methods for coupling the oxazolidine intermediates of the invention with taxanes containing a hydroxyl group directly bonded at C-13 to provide the aforementioned C-13 acyloxy sidechain-bearing taxanes are also provided, as are methods of preparing the novel oxazolidines of the present invention.
In particular, novel oxazolidines of the formulae I and II are provided:
where
R
1
is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl;
R
1*
is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl, with the proviso that R
1*
is not tert-butoxycarbonyl when R
2
is aryl;
R
2
is aryl, heterocyclo or alkyl;
R
4
is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclo;
R
5
and R
6
are (a) each independently alkyl; or (b) together with the carbon atom to which they are bonded, form a cycloalkyl, cycloalkenyl or heterocyclo group; and
R
8
is alkyl or aryl;
and salts thereof.
The novel oxazolidines of the present invention are useful as intermediates in the preparation of C-13 acyloxy sidechain-bearing taxanes such as paclitaxel and analogs thereof. Thus, the present invention further provides novel methods for coupling the intermediates of the formulae I and II with a taxane containing a hydroxyl group directly bonded at C-13 to provide C-13 acyloxy sidechain-bearing taxanes of the following formula VI:
where R
1
is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl; R
2
is aryl, heterocyclo or alkyl; and T is a taxane moiety directly bonded at C-13 of said moiety. Coupling may be achieved by the methods described following.
In one embodiment of the invention, a compound of the formula VI or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a compound of the following formula III or salt thereof:
with a compound of the following formula IV:
HO—T (IV),
in the presence of a coupling agent, to form a compound of the following formula V or salt thereof:
where R
1
, R
2
, R
5
, R
6
and T are as defined above; and
(b) contacting said compound of the formula V or salt thereof with a ring-opening agent to form said compound of the formula VI or salt thereof. Each of the steps (a) (when R
1
is R
1*
) and (b) of this method are themselves novel methods. Additionally, the compounds of the formulae III and V and salts thereof are novel when R
1
is R
1*
.
Compounds of the formula III include compounds of the formula I where R
4
is hydrogen. A compound of the formula I where R
4
is other than hydrogen may be converted to a compound of the formula III where R
1
is R
1*
by a novel method comprising the step of hydrolyzing said compound of the formula I where R
4
is other than hydrogen to form said compound of the formula III. Any compound capable of effecting the hydrolysis may be employed as the hydrolyzing agent. Exemplary hydrolyzing agents include aqueous bases such as aqueous hydroxides (e.g., metal hydroxides such as barium hydroxide, or preferably, alkali metal hydroxides such as lithium, sodium or potassium hydroxide). Contact with a base provides a carboxylic acid salt of a compound of the formula III. Further contact with an acid, preferably a mineral acid such as HCl, provides a compound of the formula III where R
4
is hydrogen, that is, which contains a free carboxylic acid group. Compounds of the formula III where R
1
is other than R
1*
may be prepared by methods analogous to those methods described herein for the preparation of compounds of the formula III where R
1
is R
1*
.
In another embodiment of the invention, a compound of the formula VI or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a compound of the following formula VII or salt thereof:
with a compound of the following formula IV:
HO—T (IV),
in the presence of a coupling agent, to form a compound of the following formula VIII or salt thereof:
where R
1
, R
2
, R
8
and T are as defined above; and
(b) contacting said compound of the formula VIII or salt thereof with a ring-opening agent to form said compound of the formula VI or salt thereof. Each of the steps (a) and (b) of this method are themselves novel methods. Additionally, the compounds of the formulae VII and VIII and salts thereof are novel.
Compounds of the formula VII are compounds of the formula II where R
4
is hydrogen. A compound of the formula II where R
4
is other than hydrogen may be converted to a compound of the formula VII by a novel method comprising the step of hydrolyzing said compound of the formula II where R
4
is other than hydrogen to form said compound of the formula VII. Hydrolysis of a compound of the formula II to form a compound of the formula VII may be conducted as described above for the hydrolysis of a compound of the formula I where R
4
is other than hydrogen to form a compound of the formula III.
The ring of the present oxazolidine compounds is numbered herein as follows:
With respect to the 4- and 5-position carbon atoms, the oxazolidine compounds of the formulae I and II may exist as the four stereoisomers Ia or iIa, Ib or IIb, Ic or IIc and Id or IId, respectively, as follows:
As the stereochemistry of taxanes may affect their pharmaceutical activity, it is desirable to employ oxazolidine intermediates which will provide the final taxane product with the stereochemistry sought. While the use of stereoisomeric mixtures of a compound of the formula I or II is contemplated herein, the use of a single stereoisomer providing the desired stereochemistry in the final product may achieve a more efficient use of the starting materials and less complicated separation and purification procedures.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is described further as follows.
The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 12 carbons in the normal chain. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include one or mo
Thottathil John K.
Trifunovich Ivan D.
Bristol Myers Squibb Comp.
Lopez Gabriel
Trinh Ba K.
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