Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-23
2004-07-20
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
06765015
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to novel halogenated paclitaxel analogs and derivatives, processes for their preparation and use as effective anti-tumor agents.
BACKGROUND OF THE INVENTION
Several important compounds from the taxane family of terpenes have been identified as possessing strong anti-neoplastic 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 cancer and breast cancer, 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. yunnanensis
and other plant materials including
T. hicksii, T. densiformis, 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 activity are highly desirable to increase the armamentarium of clinical therapeutic agents.
In the 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 5,824,278 respectively, the entirety of each being incorporated by reference herein, the synthesis, separation and anticancer activity of several dihalocephalomannine diastereomers 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 diastereomeric 2″, 3″-chlorocephalomannines. The diastereomeric mixtures were separated into the individual components by preparative HPLC on C
18
reversed-phase silica gel. A more efficient analytical separation seas obtained on a penta-fluorophenyl bonded phase. The compounds were isolated and fully identified by classic and modem 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 physico-chemical data, the bromo compounds were identified as (2″R,3″S)-dibromo-7-epi-cephalomannine (3), (2″S,3″R)-dibromo-7-epi-cephalomannine (4), (2″R,3″S)-dibromo-cephalomannine (5), (2″S,3″R)-dibromocephalomannine (6). The chloro compounds were identifed 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 Lung 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
SUMMARY OF THE INVENTION
In accordance with the present invention, there are now provided several novel halogenated derivatives of paclitaxel and cephalomannine for use as anticancer agents, which have structures selected from the next two general formulas A and B:
For General Formula A:
wherein R
1
is mono or dihalogenated acyl group, aroyl group (Table 1), alkyloxy-carbonyl group or aryloxy-carbonyl group (Table 2) and R
3
is hydrogen or halogenated group, and R
2
is hydrogen or acetyl groups;
wherein R
4
is PhCO or Me
3
COCO or CH
3
CH═C(CH
3
)CO, R
3
is a halogenated group (Tables 1 and 2);
For general formula B:
wherein R
1
is mono or dihalogenated acyl group or aroyl group (Table 1), alkyloxy-carbonyl group or aryloxy-carbonyl group (Table 2) and R
2
is hydrogen or acetyl group, and R
5
is any group from Table 3;
R
6
is H or Me;
wherein
R
1
is a group selected from Table 1 (groups 1 to 40);
and R
2
is H or Ac;
TABLE 1
Structures of Halogenated Acyl and Aroyl Groups
Group 1
Group 2
Group 3
Group 4
Group 5
Group 6
Group 7
Group 8
Group 9
Group 10
Group 11
Group 12
Group 13
Group 14
Group 15
Group 16
Group 17
Group 18
Group 19
Group 20
Group 21
Group 22
Group 23
Group 24
Group 25
Group 26
Group 27
Group 28
Group 29
Group 30
Group 31
Group 32
Group 33
Group 34
Group 35
Group 36
Group 37
Group 38
Group 39
Group 40
X: halogen (Cl or Br or I or F)
X
1
: one type of halogen
X
2
: other type of halogen
TABLE 2
Structures of Halogenated Alkyloxy- and Aryloxy- Carbonyl Groups
Group 41
Group 42
Group 43
Group 44
Group 45
Group 46
Group 47
Group 48
Group 49
Group 50
Group 51
Group 52
Group 53
Group 54
Group 55
Group 56
Group 57
Group 58
Group 59
Group 60
Group 61
Group 62
Group 63
Group 64
Group 65
Group 66
Group 67
Group 68
Group 69
Group 70
Group 71
Group 72
Group 73
Group 74
Group 75
Group 76
Group 77
Group 78
Group 79
Group 80
Group 81
Group 82
Group 83
Group 84
Group 85
Group 86
Group 87
Group 88
Group 89
Group 90
Group 91
Group 92
Group 93
Group 94
Group 95
X: halogen (Cl or Br or I or F)
X
1
: one type of halogen
X
2
: other type of halogen
TABLE 3
Group Structures of Amino Acids and Their Codes Used in This Patent
Me
Ac
Ph
Bz
G
1
G
2
G
3
G
4
G
5
G
6
G
7
G
8
G
9
G
10
G
11
G
12
G
13
wherein
R
1
is a group selected from Table 2 (groups 41 to 95);
R
2
is H or Ac;
wherein
R
3
is a group selected from Table 1 (groups 1 to 40);
and R
2
is H or Ac, and R
4
is PhCO or Me
3
COCO or CH
3
CH═C(CH
3
)CO;
wherein
R
3
is a group selected from Table 2, (groups 41 to 95),
R
2
is Ac or H, and R
4
is PhCO or Me
3
COCO or CH
3
CH═C(CH
3
)CO;
wherein
R
1
is a group selected from Table 1 (groups 1 to 40);
R
2
is H or Ac;
R
3
is a group selected from Table 2 (groups 41 to 95);
wherein
R
1
is a group selected from Table 2 (groups 41 to 95);
R
2
is H or Ac;
R
3
is a group selected from Table 1 (groups 1 to 40);
wherein
R
1
is a group selected from Table 1 (groups 1 to 40);
R
2
is H or Ac;
R
3
is a group selected from Table 1 (groups 1 to 40);
wherein
R
1
is a group from Table 2 (groups 41 to 95);
R
2
is H or Ac;
R
3
is a group selected from Table 2 (groups 41 to 95);
wherein
R
1
is a group selected from Table 1 (groups 1 to 40);
R
2
is H or Ac;
R
5
is H or Me or Ac or Ph or Bz or G
1
or G
2
or G
3
or G
4
or G
5
or G
6
or G
7
or G
8
or G
9
G
10
or G
11
or G
12
or G
13
;
R
6
is H, only in the case when R
5
is G
10
the group R
6
is H or Me;
wherein
R
1
is a group selected from Table 2 (groups 55 to 95);
R
2
is H or Ac;
R
5
is H or Me or Ac or Ph or Bz or G
1
or G
2
or G
3
or G
4
or G
5
or G
6
or G
7
or G
8
or G
9
G
10
or G
11
or G
12
or G
13
;
R
6
is H, only in the
Pandey Ramesh C.
Yankov Luben K.
Drehkoff W. Dennis
Ladas & Parry
Trinh Ba K.
Xechem International, Inc.
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