3,3-substituted indoline derivatives

Details 3,3-substituted indoline derivatives 3,3-substituted indoline derivatives

2000-04-19

2002-07-09

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S278000, C514S314000, C514S339000, C546S159000, C546S278100, C548S245000

Reexamination Certificate

active

06417214

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, 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 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 96/19997, published 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 further 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).
Jones, et al, (U.S. Pat. No. 5,688,810) describe 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 at, described the PR antagonist K (Chen, et al, POI-37, 16
th
Int. Cong. Het. Chem., Montana, 1997).
Kurihari, et. at., described the PR ligand L (
J. Antibiotics,
50, 360, 1997).
Elliott (Smith Kline Beecham) claimed the generic indoline M as potential endothelin receptor antagonists (WO 94/14434). The patent does not claim indolines and lacks the appropriate 5-aryl substitution, i.e. CN and NO
2
.
wherein: R
4
=H, Ar, R
11
, OH, 1-5 C alkoxy (opt. substd. by OH, OMe or halogen), —S(O)
q
R
11
, N(R
6
)
2
, XR
11
, halogen or NHCOR
6
; X=(CH
2
)
n
, O, NR
6
or S(O)
q
; n=0-6; q=0-2; R
6
=H or 1-4 C alkyl; R
11
=1-8 C alkyl, 2-8 C alkenyl or 2-8 C alkynyl (all optionally substituted); Ar=(i) opt. substd. phenyl or benzo-fused gp. of (a) or (b); or (ii) napthyl, indoyl, pyridyl, thienyl, oxazolindyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, pyrrolyl or pyrimidyl, all opt. substd. by one or more R
1
or R
2
groups.
DESCRIPTION OF THE INVENTION
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 and/or prevention of fibroids, including uterine fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy. This invention also particularly relates to methods of using these compounds in the inducement of contraception and the treatment and/or prevention of benign and malignant neoplastic disease. Such diseases may include, without limitation, benign prostatic hypertrophy, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, meningioma and other hormone-dependent tumors.
Compounds of this invention include compounds of the formula I:
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
—; —CH
2
CH
2
N(H or alkyl)CH
2
CH
2
—;
n is an integer from 0 to 5;
m is an integer from 1 to 4;
p is an integer from 1 to 4;
or R
1
and R
2
together comprise a double bond to ═C(CH
3
)
2
; ═C(C
3
-C
6
cycloalkyl), ═O, or ═C(cycloether), wherein cycloether is selected from tetrahydrofuranyl or hexahydropyranyl;
R
3
is 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
=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
=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, 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 independent substituents taken from the group including 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 ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO
2
or NR
6
and containing one or two independent substituents from the group including 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

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