9-desoxobaccatin III and analogs thereof

Details 9-desoxobaccatin III and analogs thereof 9-desoxobaccatin III and analogs thereof

2000-10-12

2001-09-18

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S511000

Reexamination Certificate

active

06291692

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of taxol, baccatin III and 10-desacetylbaccatin III derivatives or analogs 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.
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:
In copending application, U.S. Ser. No. 07/949,449, filed Sep. 22, 1992, it is reported that 10-desacetoxytaxol and related compounds also exhibit anti-tumor activity. Compounds disclosed in this copending application include:
Taxol, taxotere and other biologically active tetracyclic taxanes may be prepared semisynthetically from baccatin III and 10-desacetyl baccatin III as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012 or by the reaction of a &bgr;-lactam and a suitably protected baccatin III or 10-desacetylbaccatin III (“10-DAB”) derivative as set forth in U.S. Pat. No. 5,175,315 or copending U.S. patent application Ser. No. 07/949,107 (which is incorporated herein by reference). Baccatin III 1 and 10-DAB 2 can be separated from mixtures extracted from natural sources such as the needles, stems, bark or heartwood of numerous Taxus species and have the following structures.
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 and analogs or derivatives thereof; 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 or 10-desacetyl baccatin III 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 tetracyclic taxane may be replaced by other functional groups to yield a tetracyclic taxane having the formula
wherein
R
1
is H, —OH, protected hydroxy, or —OCOR
8
,
R
2
is H, —OH, or acyloxy,
R
3
is methyl,
R
4
is H, —OH or protected hydroxy;
R
5
is H or R
9
CO—,
R
6
is H or R
10
(CO—,
R
7
is H, a hydroxy protecting group, or
R
8
R
9
, and R
10
, are independently H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, moncyclic aryl, or monocyclic heteroaryl.
R
11
is —OR
16
, —SR
17,
or —NR
18
R
19
;
R
12
is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R
13
and R
14
are independently hydrogen, alkyl, or alkenyl, alkynyl, aryl, acyl or heteroaryl, provided R
13
and R
14
are not both acyl;
R
15
is —COR
20
, —CCOR
20
, —COSR
20
, —CONR
14
R
20
, or —SO
2
R
21
R
16
is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxy protecting group,
R
17
is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group,
R
18
is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R
19
is an amino protecting group;
R
20
is alkyl, alkenyl, alkynyl, aryl, or heteroaryl, and
R
21
is alkyl, alkenyl, alkynyl, aryl, heteroaryl, —OR
17
, or —NR
14
R
18
.
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
wherein R
1
, R
4
, R
5
and R
6
are as previously defined and R
7
is hydrogen or a hydroxy protecting group.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.


REFERENCES:
patent: 4814470 (1989-03-01), Colin et al.
patent: 4876399 (1989-10-01), Holton et al.
patent: 4921974 (1990-05-01), Duggan
patent: 4924011 (1990-05-01), Denis et al.
patent: 4924012 (1990-05-01), Colin et al.
patent: 5175315 (1992-12-01), Holton
patent: 5352806 (1994-10-01), Gunawardana et al.
patent: 5440056 (1995-08-01), Klein et al.
patent: 5468769 (1995-11-01), Klein et al.
patent: 5530020 (1996-06-01), Gunawardana et al.
patent: 5594157 (1997-01-01), Gunawardana et al.
patent: 5616740 (1997-04-01), Klein et al.
patent: WO 99/37631 (1999-07-01), None
Chen et al. “Taxol Structure-Activity Relationships: Synthesis and Biological Evaluation of 2-Deoxytaxol” Tetrahedron Letters, vol. 34, No. 20 (1993) pp. 3205-3206.
Denis et al. A Highly Efficient, Practical Approach to Natural Taxol, Journal of American Chemical Society, vol. 110, No. 17 (1988) pp. 5917-5919.
Farina et al. “The Chemistry of Taxanes: Unexpected Rearrangement of Baccatin III During Chemoselective Debenzoylation with Bu3SnOMe/LiCl” Tetrahedron Letters, vol. 33, No. 28 (1992) pp. 3979-3982.
Holton et al. “A Synthesis of Taxusin” Journal of American Chemical Society, vol. 110 (1988) pp. 6558-6560.
Kingston et al. “The Taxane Diterpenoids” Progress in the Chemistry of Organic Natural Products 61, (1993) pp. 73-75, Springer-Verlag, New York.
Klein et al. “Synthesis of 9-Dihydrotaxol: A Novel Bioactive Taxane” Tetrahedron Letters, vol. 34, No. 13 (1993) pp. 2047-2050.
Miller et al. “Antileukemic Alkaloids from Taxus Wallichiana Zucc” Journal of Organic Chemistry, vol. 45, No. 7 (1981) pp. 1469-1474.
Samaranayake et al. “Modified Taxols. 5.1 Reaction of Taxol with Electrophillic Reagents and Preparation of a Rearranged Taxol Derivative with Tubulin Assembly Activity 3” Journal of Organic Chemistry, vol. 56, No. 17 (1991) pp. 5114-5119.

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