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
2002-01-15
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S207000
Reexamination Certificate
active
06339098
ABSTRACT:
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. 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 or ablates that risk.
PR antagonists may also 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 960704).
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).
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 (
Tetrahedron. Lett.
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
Cong. Het. Chem., Montana, 1997).
Kurihari et al described the PR ligand L (
J. Antibiotics
50, 360, 1997).
There are several examples of 2,1-benzisothiazoline 2,2-dioxides (‘sultams’) in the chemical and patent literature which contain no reference to progesterone activity, and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline 2,2-dioxide, i.e., M (and derivatives, e.g., N), that was used in the present invention (
J. Heterocycl. Chem.
23(6), 1645-9, 1986).
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines, e.g., O, which are useful as central nervous depressants (U.S. Pat. No. 3,635,964).
Kamireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q, useful for controlling undesired vegetation (WO 95/33746).
DETAILED DESCRIPTION OF THE INVENTION
This invention provides progesterone receptor antagonists of Formula 1 having the structure
wherein
R
1
, and R
2
are each, independently, hydrogen, alky, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary, arylalkyl, heteroarylalkyl, and alkynyl; or
R
1
and R
2
are taken together form a ring and together contain —CH
2
(CH
2
)
n
CH
2
—, —CH
2
CH
2
CMe
2
CH
2
CH
2
—, —O(CH
2
)
p
CH
2
—, O(CH2)
q
O—, —CH
2
CH
2
OCH
2
CH
2
—, —CH
2
CH
2
NR
7
CH
2
CH
2
—; or
R
1
and R
2
are a double bond, said double bond having two methyl groups bonded to the terminal end, having a cycloalkyl group bonded to the terminal end, having an oxygen bonded to the terminal end, or having a cycloether bonded to the terminal end;
R
7
is hydrogen or alkyl of 1-6 carbon atoms;
n=1-5;
p=1-4;
q=1-4;
R
3
is hydrogen, hydroxyl, NH
2
, alkyl, substituted alkyl, alkenyl, alkynyl, substituted_or, COR
A
;
R
A
is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R
4
is hydrogen, halogen, —CN, —NH
2
, alkyl, substituted alkyl, alkoxy, alkoxy, aminoalkyl, or substituted aminoalkyl;
R
5
is a trisubstituted phenyl ring having the structure,
X is halogen, OH, —CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)
2
alkyl, aminoalkyl, substituted aminoalkyl, —NO
2
, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, —COR
B
, —OCOR
B
, or —NR
C
COR
B
;
R
B
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R
c
is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, —CN, —NO
2
, alkoxy, alkyl, or thioalkyl; or
R
5
is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO
2
and NR
6
with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO
2
alkyl, alkoxy, aminoalkyl, COR
D
, and NR
E
COR
D
;
R
D
is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R
E
is hydrogen, alkyl, or substituted alkyl;
R
6
is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR
6
is bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, which are useful for contraception, in the treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate cancer, and post menopausal hormone replacement therapy.
Preferred compounds of this invention are those having the structure:
wherein
R
1
and R
2
are taken together form a ring and together contain —CH
2
(CH
2
)
n
CH
2
—;
n=2-3;
R
3
is hydrogen;
R
4
is hydrogen;
R
5
is a trisubstituted phenyl ring having the structure,
X is halogen, OH, —CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)
2
alkyl, aminoalkyl, substituted aminoalkyl, —NO
2
, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3 heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, —CN, —NO
2
, alkoxy, alkyl, or thioalkyl; or
R
5
is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from the group consisting of O, S, and NR
6
with said ring carbons being optionally substituted with one or two substituents independently selected from the group consisting of hydrogen, halogen, CN, NO
2
, alkyl, or alkoxy;
R
6
is hydrogen, alkyl, alkoxyca
Collins Mark A.
Edwards James P.
Jones Todd K.
Mackner Valerie A.
Tegley Christopher M.
American Home Products Corporation
Howson & Howson
Stockton Laura L.
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