Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-19
2002-05-21
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S408000, C548S409000, C548S410000
Reexamination Certificate
active
06391907
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds which are antagonists of the progesterone receptor, their preparation and utility.
BACKGROUND OF THE INVENTION
Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (R. M. Evans, Science, 240, 889, 1998). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, have been made which also serve as ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. Once bound to the DNA the complex modulates the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR antagonists may be used in contraception. In this context they may be administered alone (Ulmann, et al,
Ann. N.Y. Acad. Sci.,
261, 248, 1995), in combination with a PR agonist (Kekkonen, et al,
Fertility and Sterility,
60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (WO 96/1997 A1 Jul. 4, 1996).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. Pr antagonists may also be useful for the treatment of non-malignant chronic conditions such as fibroids (Murphy, et al,
J. Clin. Endo. Metab.,
76, 513, 1993) and endometriosis (Kettel, et al,
Fertility and Sterility,
56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al,
Ann. N.Y. Acad. Sci.,
761, 224, 1995).
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as antagonists in functional models, either/or in-vitro and in-vivo. These compounds may be used for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Described by Jones, et al, (U.S. Pat. No. 5,688,810) is the PR antagonist dihydroquinoline A.
Jones, et al, described the enol ether B (U.S. Pat. No. 5,693,646) as a PR ligand.
Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as a PR ligand.
Zhi, et al, described lactones D, E and F as PR antagonists (J. Med. Chem., 41, 291, 1998).
Zhi, et al, described the ether G as a PR antagonist (J. Med. Chem., 41, 291, 1998).
Combs, et al., disclosed the amide H as a ligand for the PR (
J. Med. Chem.,
38, 4880, 1995).
Perlman, et. al., described the vitamin D analog I as a PR ligand (
Tet. Letters,
35, 2295, 1994).
Hamann, et al, described the PR antagonist J (
Ann. N.Y Acad. Sci.,
761, 383, 1995).
Chen, et al, described the PR antagonist K (Chen, et al, POI-37, 16
th
Int. Cong. Het. Chem., Montana, 1997).
Kurihari, et. al., described the PR ligand L (
J. Antibiotics,
50, 360, 1997).
Kuhla, et al, disclosed the oxindole M as having cardiotonic activity (WO 86/03749).
Weber, teaches the oxindole N for cardiovascular indications (WO 91/06545).
Fischer, et al, describe a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516).
Singh, et al, described the PDE III inhibitor P (
J. Med. Chem.,
37, 248, 1994).
Andreani, et al, described the cytotoxic agent Q (
Acta. Pharn. Nord.,
2, 407, 1990).
Binder, et al, described structure R which is an intermediate for preparing COX II inhibitors (WO 97/13767).
Walsh described the oxindole S as an intermediate (U.S. Pat. Nos. 4,440,785, 4,670,566).
Bohm, et al, claim the oxindole T as cardiovascular agents (WO 91/06545).
Bohm, et al, include the generic structure U (WO 91/04974).
JP 63112584 A contains the generic structure V:
Boar, et al, described the dioxolane W as an intermediate for preparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).
Kende, et al, described methodology for preparing 3,3-substituted oxindoles, e.g. X, that was utilized in the present invention (Synth. Commun., 12, 1, 1982).
DESCRIPTION OF THE INVENTION
This invention comprises compounds of the Formula 1:
wherein:
R
1
and R
2
are chosen independently from H, alkyl, substituted alkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionally substituted aryl; heteroaryl; optionally substituted heteroaryl; alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl;
or R
1
and R
2
are joined to form a ring comprising one of the following:
—CH
2
(CH
2
)
n
CH
2
—; —CH
2
CH
2
CMe
2
CH
2
CH
2
—; —O(CH
2
)
m
CH
2
—; O(CH
2
)
p
O;
—CH
2
CH
2
OCH
2
CH
2
—; or —CH
2
CH
2
N(H or alkyl)CH
2
CH
2
—;
or R
1
and R
2
comprise a double bond to CMe
2
, C(cycloalkyl), O, or C(cyloether);
n is an integer from 0 to 5;
m is an integer from 1 to 4;
p is an integer from 1 to 4;
R
3
is selected from H, OH, NH
2
, C
1
to C
6
alkyl, substituted C
1
to C
6
alkyl, C
3
to C
6
alkenyl, alkynyl or substituted alkynyl, or COR
A
;
R
A
is selected from H, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl, C
1
to C
3
alkoxy, substituted C
1
to C
3
alkoxy, C
1
to C
3
aminoalkyl, or substituted C
1
to C
3
aminoalkyl;
R
4
is selected from H, halogen, CN, NH
2
, C
1
to C
6
alkyl, substituted C
1
to C
6
alkyl, C
1
to C
6
alkoxy, substituted C
1
to C
6
alkoxy, C
1
to C
6
aminoalkyl, or substituted C
1
to C
6
aminoalkyl;
R
5
is selected from the groups a), b) or c):
a) R
5
is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below:
wherein:
X is selected from the group of halogen, OH, CN, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl C
1
to C
3
alkoxy, substituted C
1
to C
3
alkoxy, C
1
to C
3
thioalkyl, substituted C
1
to C
3
thioalkyl, S(O)alkyl, S(O)
2
alkyl, C
1
to C
3
aminoalkyl, substituted C
1
to C
3
aminoalkyl, NO
2
, C
1
to C
3
perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, COR
B
, OCOR
B
, or NR
C
COR
B
;
R
B
is H, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl, aryl, substituted aryl, C
1
to C
3
alkoxy, substituted C
1
to C
3
alkoxy, C
1
to C
3
aminoalkyl, or substituted C
1
to C
3
aminoalkyl;
R
C
is H, C
1
to C
3
alkyl, or substituted C
1
to C
3
alkyl;
Y and Z are independently selected from H, halogen, CN, NO
2
, C
1
to C
3
alkoxy, C
1
to C
3
alkyl, or C
1
to C
3
thioalkyl; or
b) R
5
is a five or six membered heterocyclic ring with 1, 2, or 3 heteroatoms selected from O, S, SO, SO
2
or NR
6
and containing one or two independent substituents from the group of H, halogen, CN, NO
2
and C
1
to C
3
alkyl, C
1
to C
3
alkoxy, C
1
to C
3
aminoalkyl, COR
D
, or NR
E
COR
D
;
R
D
is H, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl, aryl, substituted aryl, C
1
to C
3
alkoxy, substituted C
1
to C
3
alkoxy, C
1
to C
3
aminoalkyl, or substituted C
1
to C
3
aminoalkyl;
R
E
is H, C
1
to C
3
alkyl, or substituted C
1
to C
3
alkyl;
R
6
is H, or C
1
to C
3
alkyl; or
c) R
5
is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from halogen, lower alkyl, CN, NO
2
, lower alkoxy, or CF
3
;
or a pharmaceutically acceptable salt thereof.
A preferred set of compounds of this invention is depicted by structure 2, 2a:
wherein:
R
5
is a disubs
Bender Reinhold H. W.
Edwards James P.
Fensome Andrew
Jones Todd K.
Miller Lori L.
American Home Products Corporation
Howson and Howson
Powers Fiona T.
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