Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-07-10
2001-01-23
Trinh, Ba K. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S510000, C549S511000
Reexamination Certificate
active
06177456
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to novel monohalogenated cephalomannine derivatives, their preparation and methods of use as effective anticancer and antileukemic agents, and as alternatives to paclitaxel for use in bioactivity testing.
BACKGROUND OF THE INVENTION
Several important compounds from the taxane family of diterpenes have been identified as possessing strong antineoplastic activity against various cancers. For example, paclitaxel (1), having the following structure,
has been approved by the Food and Drug Administration for the treatment of ovarian and breast cancers and Karposi sarcoma, and is presently undergoing clinical trials for treatment of various other cancers, including lung and colon cancer.
Cephalomannine has been reported to be effective in causing remission of leukemic tumors (see U.S. Pat. No. 4,206,221) and is most often present with its structurally similar analog, paclitaxel. The structure of cephalomannine (2) is shown below:
Paclitaxel and cephalomannine are only some of the many natural products from the taxane family which can be found, for example, in the bark of the Pacific yew tree
Taxus brevifolia
and other yew species such as
T. baccata, T. cuspidata
, as well as
T. yvunnanensis
and other plant materials including
T. hicksii, T. densiforinis, T. gem, T. wardii, T. capitata, T. brownii
, and
T. dark green spreader
. These compounds can also be found in Cephalotaxus species, such as, for example,
Cephalotaxus manni
as well as cultured plant cells and fungi.
The supply of paclitaxel, cephalomannine and other important taxanes is, however, limited to a finite amount of yew trees and other vegetation in which they are present in small amounts. Thus, alternative compounds having paclitaxel-like or cephalomannine-like anti-tumor and/or anti-leukemic activity are highly desirable to increase the armamentarium of clinical therapeutic agents.
In U.S. application Ser. No. 08/654,424, filed May 29, 1996, and U.S. application Ser. No. 08/672,397, filed May 29, 1996, now U.S. Pat. Nos. 5,807,888 and 5,854,278 respectively, the entirety of each being incorporated by reference herein, the synthesis, separation and anticancer activity of several dihalocephalomannine diasteromers is provided. In this study, two diastereomeric 2″,3″-dibromocephalomannines and their two corresponding 7-epimers were obtained by treatment of extracts of
Taxus yunnanensis
with bromine solution, under mild conditions. Treatment of the same extract with chlorine solution yielded four diasteromeric 2″,3″-chlorocephalomannines. The diasteromeric mixtures were separated into the individual components by preparative HPLC on C
18
reversed-phase silica gel. A more efficient analytical separation was obtained on a pentafluorophenyl bonded phase. The compounds were isolated and fully identified by classic and modern methods. Slight differences were observed in the NMR spectra of the 7-epimers when compared to their 7&bgr;-OH analogs. On the basis of a comparison of physicochemical data, the bromo compounds were identified as (2″R,3″S)-dibromo-7-epi-cephalomannine (3), (2″S,3″R)-dibromo-7-epicephalomannine (4),(2″R,3″S)-dibromocephalomannine (5), (2″S,3″R)-dibromocephalomannine (6). The chloro compounds were identified as (2″R,3″R)-dichlorocephalomannine (7), (2″S,3″S)-dichlorocephalomannine (8), (2″R,3″S)-dichlorocephalomannine (9), and (2″S,3″R)-dichlorocephalomannine (10).
Cytotoxic activity was tested against the NCI 60 human tumor cell line panel in comparison with paclitaxel and results were obtained showing strong antineoplastic activity against several tumor lines, including, but not limited to, leukemia cell line HL-60 (TB); Non-Small Cell Cancer Line NCI-H522; Colon Cancer Cell Lines COO 205 and HT29; CNS Cancer Cell Lines SF-539 and SNB-75; Ovarian Cancer Cell Line OVCAR-3; Renal Cancer Cell Line RXF-393; and Breast Cancer Cell Lines MCF7, MDA-MB-231/ATCC, HS 578, MDA-MB-435 and MDA-N.
The structures of some of these dihalogenated cephalomannines are set forth below:
R
R
1
R
2
3
H
OH
4
H
OH
5
OH
H
6
OH
H
7
OH
H
8
OH
H
9
OH
H
10
OH
H
It would be highly desirable to provide additional new analogs of paclitaxel and cephalomannine having anti-neoplastic and/or anti-leukemic activity to add to the arsenal of bioactive and therapeutic compounds described above.
SUMMARY OF THE INVENTION
As discussed above, individual diastereomeric 2″3″-dichlorocephalomannine analogs have been isolated from extract of
Taxus yunnanensis
after chlorination of the extract. In accordance with the present invention, a more polar and more soluble monohalocephalomannine analog, 3″-monochlorocephalomannine, was discovered during separation and purification, which compound has the following structure:
Cytotoxic activity testing of the inventive analog against the NCI 60 human cell line panel in comparison with paclitaxel demonstrates strong anti-neoplastic and anti-leukemic efficacy of the novel compound.
The invention is more fully discussed in the following detailed description with preferred embodiments with accompanying Figures.
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Pandey Ramesh C.
Yankov Luben K.
Dorsey & Whitney LLP
Trinh Ba K.
Xechem International, Inc.
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