Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-03
2003-07-08
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S204000
Reexamination Certificate
active
06589968
ABSTRACT:
TECHNICAL FIELD
The invention relates to epothilone compounds that are useful for the treatment of cancer and other conditions characterized by undesireable cellular proliferation. More particularly, the invention relates to 10,11-dehydroepothilones.
BACKGROUND ART
Epothilone A (R=H) and Epothilone B (R=CH
3
) are produced by
Sorangium cellulosum
strain So ce 90, the structures of which are shown below, and were the first of several epothilones to be isolated, synthesized, and characterized. Höfle et al., 1996,
Angew. Chem. Int. Ed. Engl.
35(13/14): 1567-1569.
Epothilone A and epothilone B possess many of the advantageous properties of paclitaxel (Taxol®, Bristol-Myers Squibb). As a result, there is significant interest in these and structurally related compounds as potential chemotherapeutic agents. The desoxy counterparts of epothilones A and B are known as epothilone C(R=H) and epothilone D(R=CH
3
), and exhibit similar anti-tumor activity but with less cytotoxicity. The structures of epothilones C and D are shown below.
Although other naturally occurring epothilones have been described, these compounds are produced in exceedingly small amounts. PCT publication WO 99/65913 describes 39 naturally occurring epothilones obtained from
Sorangium cellulosum
So ce 90 of which epothilones A, B, C, and D together account for approximately 98.9% of the total epothilones produced. The 35 other naturally occurring epothilone compounds together account for the remaining 1.1% and include epothilone C
6
(which may also be referred to as 10,11-dehydroepothilone C) and whose structure is shown below
The naturally occurring epothilones can be modified through semisynthesis. PCT publication WO 99/27890 describes conversion of epothilones A and B into their lactam analogs. PCT publication WO 99/54318 describes conversion of epothilones C and D into their 12,13-cyclopropane analogs.
Additional epothilone analogs may be produced through de novo synthesis. PCT publications WO 99/07692 and WO 00/00485 describe a synthetic route wherein the methyl group at C-6 is replaced by other aliphatic groups and unsaturation may be introduced at the 10,11-position. PCT publication WO 99/02514 describes total synthesis of lactam analogs of epothilones.
Due to the increasing interest in epothilones as anti-cancer agents, novel derivatives of these compounds are needed and desired to more fully develop their therapeutic potential. The present invention fulfils this need.
DISCLOSURE OF THE INVENTION
This invention relates to epothilone compounds that are useful for the treatment of cancer and other conditions characterized by undesireable cellular proliferation. More particularly, the invention relates to 10,11-dehydroepothilones.
In one aspect, the present invention provides a compound of the formula
known herein as 10,11-dehydroepothilone D.
In another aspect, the present invention provides compounds of the formula (I)
wherein:
R
1
, R
2
, and R
3
, are each independently H, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
R
4
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, C
1
-C
5
haloalkyl, aryl, —C(=O)R
6
, —C(=O)OR
6
, or —NR
6
R
7
where R
6
and R
7
are each independently hydrogen, C
1
-C
5
aliphatic, aryl or alkylaryl;
R
5
is H, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
W is O, NR
8
where R
8
is hydrogen, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
X is O, CH
2
or a carbon-carbon bond;
Y is absent or a C
1
-C
5
alkyl, C
2
-C
5
alkenyl, or C
2
-C
5
alkynyl; and
Ar is aryl; provided that when W is O at least one of R
1
, R
3
, or R
5
is other than H.
In one embodiment, the present invention provides compounds of the formula (II)
wherein:
R
1
, R
2
, and R
3
, are each independently H, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
R
4
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, C
1
-C
5
haloalkyl, aryl, —C(=O)R
6
, —C(=O)OR
6
, or —NR
6
R
7
where R
6
and R
7
are each independently hydrogen, C
1
-C
5
aliphatic, aryl or alkylaryl;
R
5
is H, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
W is NR
8
where R
8
is hydrogen, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
X is O, CH
2
or a carbon-carbon bond;
Y is absent or a C
1
-C
5
alkyl, C
2
-C
5
alkenyl, or C
2
-C
5
alkynyl; and
Ar is aryl.
In one embodiment of the invention, compounds of formula (III) are provided
wherein:
R
1
, R
2
, and R
3
, are each independently H, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
R
4
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, C
1
-C
5
haloalkyl, aryl, —C(=O)R
6
, —C(=O)OR
6
, or —NR
6
R
7
where R
6
and R
7
are each independently hydrogen, C
1
-C
5
aliphatic, aryl or alkylaryl;
R
5
is H, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
2
-C
5
alkenyl, or C
2
-C
5
alkynyl;
R
8
is H, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, aryl or alkylaryl;
X is O, CH
2
or a carbon-carbon bond; and
R
9
is selected from the group consisting of
where Z is O or S, and R
10
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, C
1
-C
5
fluoroalkyl, or C
1
-C
5
aminoalkyl.
In another embodiment of the invention, compounds of formula (III) are provided wherein:
R
1
, R
2
, and R
3
are each independently H, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, or alkylaryl;
R
4
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, or C
1
-C
5
haloalkyl;
R
5
is H, C
1
-C
5
alkyl, or C
1
-C
5
alkoxy;
R
8
is hydrogen or C
1
-C
5
alkyl;
X is O, CH
2
or a carbon-carbon bond; and
R
9
is selected from the group consisting of
where Z is O or S, and R
10
is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In one embodiment of the invention, compounds of formula (III) are provided wherein:
R
1
and R
3
are methyl;
R
2
is H;
R
4
is H, methyl, ethyl, fluoromethyl, or hydroxymethyl;
R
5
is H, methyl, ethyl, or methoxy;
R8 is hydrogen or methyl;
X is O, CH
2
or a carbon-carbon bond; and
R
9
is selected from the group consisting of
where Z is O or S, and R
10
is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (IV) are provided
wherein:
R
1
, R
2
, and R
3
are each independently hydrogen, C
1
-C
5
alkyl, C
2
-C
5
alkenyl, C
2
-C
5
alkynyl, or alkylaryl;
R
4
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, or C
1
-C
5
haloalkyl;
R
5
is H, C
1
-C
5
alkyl, C
1
-C
5
alkoxy, C
2
-C
5
alkenyl, or C
2
-C
5
alkynyl;
R
8
is hydrogen or C
1
-C
5
alkyl;
X is O, CH
2
or a carbon-carbon bond; and
R
9
is selected from the group consisting of
where Z is O or S, and R
10
is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (IV) are provided wherein:
R
1
and R
3
are H;
R2 is methyl;
R
4
is H, C
1
-C
5
alkyl, C
1
-C
5
hydroxyalkyl, or C
1
-C
5
haloalkyl;
R
5
is H, C
1
-C
5
alkyl, or C
1
-C
5
alkoxy;
R
8
is hydrogen or C
1
-C
5
alkyl;
X is O, CH
2
or a carbon-carbon bond; and
R
9
is selected from the group consisting of
where Z is O or S, and R
10
is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of formula (IV) are provided wherein:
R
1
and R
3
are H;
R2 is methyl;
R
4
is H, methyl, ethyl, fluoromethyl, or hydroxymethyl;
R
5
is H, methyl, ethyl, or methoxy;
R
8
is hydrogen or methyl;
X is O, CH
2
or a carbon-carbon bond; and
R
9
is selected from the group consisting of
where Z is O or S, and R
10
is H, methyl, hydroxymethyl, fluoromethyl, or aminomethyl.
In another embodiment of the invention, compounds of the formulas
are provided.
In another embodiment of the invention, the compound having the formula
is provided.
In one embodiment, the present invention provides compounds of the formula (V)
wherein:
R
1
, R
2
, and R
3
, are each independently H, C
1
-C
5
alkyl, C
2
-C
5
Arslanian Robert L.
Carney John R.
Metcalf Brian
Favorito Carolyn A.
Kaster Kevin
Kosan Biosciences, Inc.
Lentini David
McKane Joseph K.
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