Taxoid anti-tumor agents, pharmaceutical compositions, and...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C549S511000, C514S449000

Reexamination Certificate

active

06458976

ABSTRACT:

FIELD OF INVENTION
The present invention relates to new taxoids possessing strong antitumor activities, the precursors of these antitumor taxoids, and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Taxol (paclitaxel), a complex diterpene, is currently considered the most exciting lead in cancer chemotherapy. Paclitaxel possesses high cytotoxicity and strong antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs. For example, paclitaxel has been approved by FDA in late 1992 for the treatment of advanced ovarian cancer and for breast cancer in 1994. Paclitaxel is currently in phase II and III clinical trial for lung cancer and other cancers.
Although paclitaxel is an extremely important “lead” in cancer chemotherapy, it is common that better drugs can be derived from naturally occurring lead compounds. In fact, French researchers have discovered that a modification of the C-13 side chain of paclitaxel brought about a new anticancer agent which seems to have antitumor activity superior to paclitaxel with better bioavailability. This synthetic compound was named “Taxotère (docetaxel)”, which has t-butoxycarbonyl instead of benzoyl on the amino group of (2R,3S)-phenylisoserine moiety at the C-13 position and a hydroxyl group instead of acetoxy group at C-10. Docetaxel is currently in phase II and III clinical trials in United States, Europe, and Japan, has shown excellent activity, especially against breast and lung cancers.
A recent report on clinical trials of paclitaxel and docetaxel has disclosed that paclitaxel causes, e.g., nerve damage, muscle pain or disturbances in heart rhythm, whereas docetaxel provokes, e.g., mouth sores and a plunge in white blood cells. Other less serious side effects also exist for these two drugs. Therefore, it is very important to develop new anti-cancer drugs different from these two drugs which have fewer undesirable side effects, better pharmacological properties, improved activity against drug-resistant tumors, and/or activity spectra against various tumor types.
It is an objective of the present invention to develop such new anti-tumor agents of paclitaxel class, i.e., taxoids, which have distinct structural differences from those of paclitaxel and docetaxel.
It is an object of the present invention to provide a series of new taxoids bearing a 1-propenyl, 2-methyl-1-propenyl, 2-methylpropyl, or trifluromethyl radical at the C-3′ position instead of a phenyl group, and which possess strong antitumor activities with better therapeutic profile, in particular against drug-resistant tumors. One of the serious drawbacks of both paclitaxel and docetaxel is the fact that these two drugs possess only a weak activity against drug-resistant tumors, e.g., adriamycin-resistant breast cancer. The new taxoids of the present invention have shown not only stronger antitumor activities against human ovarian, non-small cell lung, colon, and breast cancers than those of the two drugs, but also exhibit more than one order of magnitude better activity against adriamycin-resistant human breast cancer cells than those of the two drugs. Multi-drug-resistance (MDR) is a serious issue in clinical oncology, and thus the new taxoid antitumor agents of this invention will serve as important drugs to overcome this problem.
SUMMARY OF THE INVENTION
One aspect of the invention is a taxoid of the formula (I)
in which
R
1
is a C
3
-C
5
alkyl or alkenyl or trifluoromethyl radical;
R
2
is a C
3
-C
5
branched alkyl radical;
R
3
and R
4
are independently selected from hydrogen and hydroxyl protecting groups including functional groups which increase the water solubility of the taxoid antitumor agent;
R
5
represents a hydrogen or hydroxyl-protecting an acyl or alkoxycarbonyl or carbamoyl group;
R
6
represents an acyl radical,
which are useful as antitumor agents or their precursors.
Preferably, R
1
is selected from propyl, 2-methyl-1-propenyl, 1-methyl-1-propenyl, 2-methylpropyl, 1-methylpropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methylbutyl, 2-methylbutyl, isobutyl, 2-methylethyl, 3-methylbutyl, 2-butenyl, or trifluoromethyl radicals;
R
2
is selected from isopropyl, cyclopropyl, isobutyl, sec-butyl, 2-methylpropyl, 3-methylpropyl, tert-butyl, cyclobutyl, cyclopentyl, 1-ethylpropyl, or 1,1-dimethylpropyl radicals;
R
5
is selected from hydrogen, C
2
-C
6
acyl, C
1
-C
6
alkoxylcarbonyl, C
1
-C
6
N-alkylcarbamoyl, or C
1
-C
6
N,N-dialkylcarbamoyl radicals; and
R
6
is selected from benzoyl, fluorobenzoyl, chlorobenzoyl, azidobenzoyl, cyclohexanecarbonyl, acryloyl, crotonoyl, 1-methylacryloyl, 2-methyl-2-butenoyl, or 3-methyl-3-butenoyl radical.
More preferably, R
5
is selected from acetyl, propanoyl, cyclopropanecarbonyl, acryloyl, crotonoyl, 3,3-dimethylacryloyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, pyrrolidine-N-carbonyl, piperidine-N-carbonyl, morpholine-N-carbonyl, methoxycarbonyl, ethoxylcarbonyl, propoxylcarbonyl, butoxycarbonyl, cyclopentanecarbonyl, or cyclohexanecarbonyl radicals.
These new taxoids (I) are synthesized by the processes which comprise the coupling reactions of the baccatin of the formula (II)
wherein G
1
represents a hydroxyl protecting group, and R
5
and R
6
have been defined above, with the &bgr;-lactams of the formula (III)
wherein G is a hydroxyl protecting group such as ethoxyethyl (EE), triethylsilyl (TES), (tert-butyl)dimethylsilyl (TBS), and triisopropylsilyl (TIPS), and R
1
and R
2
have been defined above, in the presence of a base.
Another aspect of the invention is a taxoid of the formula (7):
wherein
R
1
is a branched or unbranched C
3
-C
5
alkyl or alkenyl radical, CF
2
H, or (S)-2,2-dimethylcyclopropyl; R
8
is a C
1
-C
4
alkyl radical; and R
7
is F, Cl, MeO, vinyl, Me, or N
3
.
R
1
is preferably a branched or unbranched C
4
alkyl or alkenyl radical, more preferably CH
2
CH(CH
3
)
2
or CH═C(CH
3
)
2
. R
7
is preferably MeO or N
3
.
In one embodiment, R
1
is CH
2
CH(CH
3
)
2
, R
7
is MeO, and R
8
is ethyl. In another embodiment, R
1
is CH═C(CH
3
)
2
, R
7
is MeO, and R
8
is ethyl. In yet another embodiment, R
1
is CH═C(CH
3
)
2
, R
7
is N
3
, and R
8
is ethyl.
The invention also encompasses a method for treating tumors which comprises administering to a patient an effective amount of the taxoid of formula (7). Preferably, the method treats leukemia, melanoma, breast, non-small cell lung, ovarian, and colon cancers.
Yet another aspect of the invention is a pharmaceutical composition having antineoplastic activity containing the taxoid of formula (7) and a physiologically acceptable carrier.
A further aspect of the invention is a method for preparing a taxoid of formula (7), including coupling a baccatin of formula (5) with a &bgr;-lactam of formula (6) in the presence of a base,
wherein G and G
1
, which may be the same or different, each represents a hydroxyl protecting group, and R
1
, R
7
, and R
8
are as defined for formula (7). Preferably, G and G
1
are independently ethoxyethyl (EE), triethylsilyl (TES), (tert-butyl)dimethylsilyl (TBS), or triisopropylsilyl (TIPS).
DETAILED DESCRIPTION OF THE INVENTION
New taxoids of the formula (I) hereinabove are useful as antitumor agents or their precursors. These taxoids possess strong antitumor activities against human breast, non-small cell lung, ovarian, and colon cancers including drug-resistant cancer cells, as well as leukemia and melanoma.
The new taxoids of the formula (I) are synthesized by modifying the baccatins of the formula (II)
wherein G
1
, R
5
, and R
6
have been defined above.
The baccatins (II) are coupled with the &bgr;-lactamis of the formula (III)
wherein G, R
1
, and R
2
have been defined hereinabove, to yield the new taxoids (I).
The &bgr;-lactams (III) are readily prepared via the &bgr;-lactams (IV) which are easily obtained through the chiral enolate-imine cyclocondensation method that has been developed in the present in

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Taxoid anti-tumor agents, pharmaceutical compositions, and... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Taxoid anti-tumor agents, pharmaceutical compositions, and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Taxoid anti-tumor agents, pharmaceutical compositions, and... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2969540

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.