Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-17
2001-07-17
Gerstl, Robert (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
06262094
ABSTRACT:
SUMMARY OF THE INVENTION
This invention concerns a compound having the general formula I
where:
P—Q is a C, C double bond or an epoxide;
G is N
R is selected from the group of H, alkyl, and substituted alkyl;
R
1
is selected from the group consisting of
R
2
is
G
1
is selected from the group of H, halogen, CN, alkyl and substituted alkyl;
G
2
is selected from the group of H, alkyl, and substituted alkyl;
G
3
is selected from the group of O, S, and NZ
1
;
This application claims priority from German applications DE 199 07 588.3, filed Feb. 22, 1999 and DE 199 30 111.5, filed Jul. 1, 1999, incorporated herein by reference in their entirety.
BACKGROUND OF THE INVENTION
Epothilones are macrocyclic lactones with useful antifungal and cytotoxic properties. Their action, as in the case of Taxol
R
, is based on stabilization of the microtubuli as a result of which especially tumors and other rapidly dividing cells are inhibited. Typical epothilones carry a methylthiazolyl side chain, a 12,13-double bond (C, D), a 12,13-epoxide (A, B) and a proton (A, C) or a methyl group (B, D) on C-12; compare, for example: Review
Angew. Chem
. 1998, 110, 89-92 and 2120-2153 and Heterocycles 1998, 48, 2485-2488.
G
4
is selected from the group of H, alkyl, substituted alkyl, OZ
2
, NZ
2
Z
3
, Z
2
C═O, Z
4
SO
2
, and optionally substituted glycosyl;
G
5
is selected from the group of halogen, N
3
, NCS, SH, CN, NC, N(Z
1
)
3
+
, and heteroaryl;
G
6
is selected from the group of H, alkyl, substituted alkyl, CF
3
, OZ
5
, SZ
5
, and NZ
5
Z
6
;
G
7
is CZ
7
or N;
G
8
is selected from the group of H, halogen, alkyl, substituted alkyl, OZ
10
, SZ
10
, NZ
10
OZ
11
;
G
9
is selected from the group of O, S, —NH—NH— and —N═N—;
G
10
is N or CZ
12
;
G
11
is selected from the group of H
2
N, substituted H
2
N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z
1
, Z
6
, Z
9
, and Z
11
are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z
2
is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z
3
, Z
5
, Z
8
, and Z
10
are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z
4
is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z
7
is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ
8
, SZ
8
, and NZ
8
Z
9
; and
Z
12
is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R
1
is
G
1
, G
2
, G
3
and G
4
cannot simultaneously have the following meanings:
G
1
and G
2
=H, G
3
=O and G
4
=H or Z
2
C═O where Z
2
=alkyl group.
Further, the invention concerns a compound having general formula Ia
where the symbols have the following meaning:
P—Q is a C,C double bond or an epoxide,
R is a H atom or a methyl group,
G
1
is a H atom, an alkyl group, a substituted alkyl group or a halogen atom,
G
2
is a H atom, an alkyl group or a substituted alkyl group,
G
3
is an O atom, an S atom or an NZ
1
group with
Z
1
being a H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and
G
4
is a H atom, an alkyl group or a substituted alkyl group,
an OZ
2
group, an NZ
2
Z
3
group, a Z
2
C═O group, a Z
4
SO
2
group or an optionally substituted glycosyl group with
Z
2
being a H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group,
Z
3
a H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and
Z
4
an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group,
with the proviso that G
1
, G
2
, G
3
and G
4
cannot have simultaneously the following meanings: G
1
and G
2
=H atom, G
3
=O atom and G
4
=H atom or Z
2
C═O with Z
2
=alkyl group.
Further, the invention concerns a compound having general formula Ib
where the symbols have the following meaning:
P—Q is a C,C double bond or an epoxide,
R is a H atom or a methyl group,
G
1
is a H atom, an alkyl group, a substituted alkyl group or a halogen atom,
G
2
is a H atom, an alkyl group or a substituted alkyl group, and
G
5
is a halogen atom, an N
3
group, an NCS group, an SH group, an CN group, an NC group or a heterocyclic group.
Further, the invention concerns a compound having general formula IIa
where the symbols have the following meaning:
P—Q is a C,C double bond or an epoxide,
R is a H atom or a methyl group,
G
6
is a H atom, an alkyl group, a substituted alkyl group or a CF
3
, OZ
5
, SZ
5
or NZ
5
Z
6
group with
Z
5
being a H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and
Z
6
being a H atom, an alkyl group or a substituted alkyl group,
G
7
is a CZ
7
group or an N atom with
Z
7
being a H or halogen atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group, or an OZ
8
, SZ
8
or NZ
8
Z
9
group with
Z
8
being a H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and
Z
9
being a H atom or an alkyl group, and
G
8
is a H or a halogen atom, an alkyl group or an OZ
10
, SZ
10
or NZ
10
Z
11
group with
Z
10
being a H atom, an alkyl group, a substituted alkyl group, an acyl group, a substituted acyl group, an aryl group, or a substituted aryl group, and
Z
11
being a H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group.
Further, the invention concerns a compound having general formula IIb
where the symbols have the following meaning:
P—Q is a C,C double bond or an epoxide,
R is a H atom or a methyl group,
G
6
is a H atom, an alkyl group, a substituted alkyl group or a CF
3
, OZ
5
, SZ
5
or NZ
5
Z
6
group with
Z
5
being a H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and
Z
6
being a H atom, an alkyl group or a substituted alkyl group, and
G
9
is an O or S atom or an —N═N— group.
Further, the invention concerns a compound having general formula III
where the symbols have the following meaning:
P—Q is a C,C double bond or an epoxide,
R is a H atom or a methyl group,
G
10
is an N atom or a CZ
12
group with
Z
12
being a H atom or halogen atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group.
Further, the invention concerns a compound having general formula IV
where the symbols have the following meaning:
P—Q is a C,C double bond or an epoxide,
R is a hydrogen atom or a methyl group, and
G
11
is a H
2
N group, a substituted H
2
N group, an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group.
Further, the invention concerns an antifungal agent containing or consisting of a compound according to the invention, in addition to an optional carrier, diluent or additive.
Further, the invention concerns a therapeutic agent for the treatment of tumor diseases and growth disturbances, containing or consisting of a compound according to the invention, in addition to an optional carrier, diluent or additive.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term “pharmaceutically active agent” or “pharmaceutically active epothilone” refers to an epothilone that is pharmacologically active in treating cancer or other diseases described herein.
The term “alkyl” refers to optionally substituted, straight or branched chain saturated hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression “lower alkyl” refers to optionally substituted alkyl groups of 1 to 4 carbon atoms.
The term “substitut
Glaser Nicole
Hoefle Gerhard
Kim Soong-Hoon
Leibold Thomas
Vite Gregory
Bristol--Myers Squibb Company
Gerstl Robert
Patel Rena
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