Thio-oxindole derivatives

Details Thio-oxindole derivatives Thio-oxindole derivatives

2000-04-19

2002-03-12

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...

C514S278000, C514S409000, C544S230000, C546S015000, C546S017000, C548S411000

Reexamination Certificate

active

06355648

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compounds which are agonists 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, 1988). 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. This complex binds to specific gene promoters present in the cell's DNA. 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 agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, typically in the presence of an ER agonist, alternatively they may be used in conjunction with a PR antagonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists These compounds may be used for contraception and post menopausal hormone replacement therapy.
Jones, et al, described in U.S. Pat. No. 5,688,810 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, taught the oxindole M as a cardiotonic (WO 86/03749).
Weber, described the oxindole N for cardiovascular indications (WO 91/06545).
Fischer, et al, claim a preparation for making compounds which include the generic structure O (U.S. Pat. No. 5,453,516).
R=various
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 (A. H. Robins) described the oxindole S as an intermediate (U.S. Pat. No. 4,440,785, U.S. Pat. No. 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 63112585 A contains the generic structure V:
Boar, et al, described the dioxolane W as an intermediate for preparation of acetylcholinesterase 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 provides compounds of the formulae 1 or 2:
wherein:
R
1
and R
2
are chosen independently from the group of 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
—;
m is an integer from 1 to 4;
n is an integer from 1 to 5;
p is an integer from 1 to 4;
or R
1
and R
2
together comprise a double bond to one of the following:
CMe
2
; C(cycloalkyl), O, C(cycloether);
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:
X is selected from 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, CONH
2
, CSNH
2
, CONHalkyl, CSNHalkyl, CON(alkyl)
2
, CSN(alkyl)
2
, COR
B
, OCOR
B
, NR
C
COR
B
;
R
B
is selected from 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
;
Q
1
is S, NR
7
, CR
8
R
9
;
R
7
is selected from the group including CN, C
1
to C
6
alkyl, substituted C
1
to C
6
alkyl, C
3
to C
8
cycloalkyl, substituted C
3
to C
8
cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, aroyl, substituted aroyl, SO
2
CF
3
, OR
11
or NR
11
R
12
;
R
8
and R
9
are independent substituents selected from the group of H, C
1
to C
6
alkyl, substituted C
1
to C
6
alkyl, C
3
to C
8
cycloalkyl, substituted C
3
to C
8
cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO
2
, CN, or CO
2
R
10
,
R
10
is C
1
to C
3
alkyl; or
CR
8
R
9
comprises a six membered ring as shown by the structure below
Q
2
is selected from the moieties:
R
11
, R
12
and R
13
are independently selected from H, C
1
to C
6
alkyl, substituted C
1
to

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