Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-10-30
2000-05-23
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549511, C07D30514
Patent
active
060667478
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/US94/02382, dated Mar. 4, 1994.
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of taxol, baccatin III and 10-desacetyl-baccatin III derivatives or other taxanes having new C9 functional groups.
Taxol is a natural product extracted from the bark of yew trees. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is currently undergoing clinical trials against ovarian, breast and other types of cancer in the United States and France and preliminary results have confirmed it as a most promising chemotherapeutic agent. The structure of taxol and the numbering system conventionally used is shown below; this numbering system is also applicable to compounds used in the process of the present invention. ##STR1##
In Colin U.S. Pat. No. 4,814,470, it was reported that a taxol derivative, commonly referred to as taxotere, has an activity significantly greater than taxol. Taxotere has the following structure: ##STR2##
The tetracyclic core of taxol and taxotere bear a C9 keto substituent which, if modified, would lead to the preparation of a series of taxol analogs having improved water solubility. To date, however, the selective manipulation of the C9 keto group has presented a formidable problem.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a process for selectively manipulating the C9 keto substituent of baccatin III, 10-deactylbaccatin III and other taxanes; and the provision of such a process which is relatively straightforward.
Briefly, therefore, the present invention is directed to a process for the preparation of analogs or derivatives of taxol, baccatin III, 10-desacetyl baccatin III or other taxanes in which the C9 keto substituent is reduced to the corresponding hydroxy group. Optionally, the C9 hydroxy substituent may thereafter be selectively replaced by another functional group and/or other substituents of the taxane may be replaced by other functional groups to yield a taxane having the formula: ##STR3## wherein R.sub.1 is hydrogen, hydroxy, protected hydroxy or together with R.sub.14 forms a carbonate; forms an oxo; methylene, or together with R.sub.5a and the carbon atoms to which they are attached form an oxetane ring; hydroxy, --OCOR.sub.30, or together with R.sub.4 forms an oxo, oxirane or methylene; R.sub.5 forms an oxo, or together with R.sub.4 and the carbon atoms to which they are attached form an oxetane ring; protected hydroxy or together with R.sub.6a forms an oxo; hydroxy, protected hydroxy or together with R.sub.6 forms an oxo;
R.sub.7a is hydrogen, halogen, protected hydroxy, --OR.sub.28, or together with R.sub.7 forms an oxo; together with R.sub.10 forms an oxo; ##STR4## R.sub.14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R.sub.1 forms a carbonate; alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl; aryl, or heteroaryl; X.sub.10, or --SO.sub.2 X.sub.11 ; protecting group; protecting group; heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; alkyl, alkenyl alkynyl, aryl or heteroaryl; --NX.sub.8 X.sub.14 ; and
The present invention is additionally directed to a derivative of baccatin III or 10-desacetyl baccatin III having the following formula which is a key intermediate in the synthesis of a new series of tetracyclic taxanes ##STR5## wherein R.sub.2, R.sub.4a, R.sub.7a, R.sub.10a and R.sub.14 are as previously defined and R.sub.13 is hydroxy or protected hydroxy.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
As used herein "Ar" means aryl; "Ph" means phenyl; "Ac" means acetyl; "Et" means ethyl; "R" means alkyl unless otherwise defined; "tBu" means t-butyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "TPAP" me
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Holton Robert A.
Shindo Mitsuru
Somoza Carmon
Suzuki Yukio
Florida State University
Trinh Ba K.
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