Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-17
2004-02-17
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S278000, C514S312000, C544S333000, C546S018000, C546S158000
Reexamination Certificate
active
06693103
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to compounds which are agonists and antagonists of the progesterone receptor, their preparation and utility.
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 that 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 96/19997 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).
Jones, et al, (U.S. Pat. No. 5,688,810) describe the PR antagonist dihydroquinoline 1.
Jones, et al, described the enol ether 2 (U.S. Pat. No. 5,693,646) as a PR ligand.
Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as a PR ligand.
Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J. Med. Chem., 41, 291, 1998).
Zhi, et al, described the ether 7 as a PR antagonist (J. Med. Chem., 41, 291, 1998).
Combs, et al, disclosed the amide 8 as a ligand for the PR (J. Med. Chem., 38, 4880, 1995).
Perlman, et. al., described the vitamin D analog 9 as a PR ligand (
Tet. Letters,
35, 2295, 1994).
Hamann, et al, described the PR antagonist 10 (
Ann. NY. Acad. Sci.,
761, 383, 1995).
Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37, 16
th
Int. Cong. Het. Chem, Montana, 1997).
Kurihari, et. al., described the PR ligand 12 (
J. Antibiotics,
50, 360, 1997).
A number of publications reported the synthesis and utilities of benzodiazinones and benzoxazines. However, none of examples in this literature contained substituents necessary for the compounds to be active as progesterone receptor modulators. Included in this literature is the patent by Kubla et al. (U.S. Pat. No. 4,666,913) which claimed that the compound such as A and B could be used as cardiotonic agents. Ning et al. reported the synthesis of quinazolinones such as C.
Other prior art close to this invention is the literature which disclosed the benzoxazines. Among these publications, Gromachevskaya et al. (Chem. Heterocycl. Compd. (N.Y.), 33(10), 1209-1214 (1998)) studied the bromination process of certain benzoxazines such as compound D. Kobzina et al. (U.S. Pat. No. 3,917,592) claimed that compounds such as E can be used as a herbicidal agent.
Pflegel et al. (Pharmazie, 37(10), 714-717(1982)) disclosed quinazolin-2-thiones such as compound F in their study of polarography of heterocyclics. No activity of the compound F was mentioned.
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 agonists and/or 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.
The compounds in the present invention contain a pendent aromatic substituent. The aromatic substituents proved to be critical for the resultant compounds being active as progesterone receptor modulators and have broad structural diversity which may consists of aryl, substituted aryl, heteroaryl or substituted heteroaryl group.
This invention provides compounds of Formula I having the structure:
wherein:
R
1
, R
2
are independent substituents selected from the group which includes H, C
1
to C
6
alkyl, substituted C
1
to C
6
alkyl, C
2
to C
6
alkenyl, substituted C
2
to C
6
alkenyl, C
2
to C
6
alkynyl, substituted C
2
to C
6
alkynyl, C
3
to C
8
cycloalkyl, substituted C
3
to C
8
cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR
A
, or NR
B
COR
A
;
or R
1
and R
2
are fused to form:
a) an optionally substituted 3 to 8 membered spirocyclic alkyl ring;
b) an optionally substituted 3 to 8 membered spirocyclic alkenyl; or
c) an optionally substituted 3 to 8 membered heterocyclic ring containing one to three heteroatoms from the group including O, S and N; the spirocyclic rings of a), b) and c) being optionally substituted by from 1 to 4 groups selected from fluorine, C
1
to C
6
alkyl, C
1
to C
6
alkoxy, C
1
to C
6
thioalkyl, —CF
3
, —OH, —CN, NH
2
, —NH(C
1
to C
6
alkyl), or —N(C
1
to C
6
alkyl)
2
;
R
A
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, substituted C
1
to C
3
aminoalkyl,
R
B
is H, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl,
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, substituted C
1
to C
6
alkenyl, alkynyl, or substituted alkynyl, COR
C
,
R
C
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, substituted C
1
to C
3
aminoalkyl,
R
4
is H, halogen, CN, NO
2
, C
1
to C
6
alkyl, substituted C
1
to C
6
alkyl, alkynyl, or substituted alkynyl, C
1
to C
6
alkoxy, substituted C
1
to C
6
alkoxy, amino, C
1
to C
6
aminoalkyl, substituted C
1
to C
6
aminoalkyl,
R
5
is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below,
X is taken from the group including halogen, CN, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl, alkynyl, or substituted alkynyl, C
1
to C
3
alkoxy, substituted C
1
to C
3
alkoxy, C
1
to C
3
thioalkoxy, substituted C
1
to C
3
thioalkoxy, amino, 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
D
, OCOR
D
, or NR
E
COR
D
;
Edwards James P.
Fensome Andrew
Jones Todd K.
Tegley Christopher M.
Terefenko Eugene A.
Howson and Howson
Kifle Bruck
Mckenzie Thomas C
Wyeth
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