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
2002-04-30
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S386000, C514S387000, C514S376000, C514S367000, C514S224200, C514S224500, C514S229800, C514S230500, C514S249000, C514S250000, C544S032000, C544S051000, C544S089000, C544S092000, C544S345000, C544S354000, C548S302100, C548S304400, C548S304700, C549S031000, C549S032000, C549S033000, C564S229000
Reexamination Certificate
active
06380235
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compounds which are agonists and 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 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/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).
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.
Jones, et al, (U.S. Pat. No. 5,688,810) disclose 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).
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. N.Y. 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).
Among the examples of the prior art, Ueda et al. (EP 22317) claimed benzothiazoline and benzoxazoline compounds of formula A as the inhibitors of aldose reductase. The benzimidazolinone derivatives such as compound B were disclosed by Hara et al. (EP 454330) and claimed as lung surfactant secretion promoters. In their preparation of benzoimidazole and analogues as antiulcer and cardiovascular agents, Bru-Magniez et al. (EP 385850) synthesized the benzoimidazolinones such as compound C. Used as cAMP PDE III inhibitors, benzoimidazolinones, benzoxazolinones, and benzothiazolinones as shown in formula D were reported by Singh et al (
J. Med. Chem.,
37, 248-254 (1994)).
The compounds in the present invention contain a pendent aromatic substituent and other substructural features. The aromatic substituents and those substructural features proved to be critical for the resultant compounds being active as progesterone receptor modulators.
Related to quinoxalin-2-ones, European patent (Ganzer et al. EP 311135) discloses the compounds such as E as herbicides.
DESCRIPTION OF THE INVENTION
This invention provides compounds of the formula:
wherein:
A is O, S, or NR
4
;
B is a bond between A and C═Q, or the moiety CR
5
R
6
;
R
4
, R
5
, R
6
are independently selected from 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, cyclic alkyl constructed by fusing R
4
and R
5
to from a 5 to 7 membered ring;
R
1
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, substituted C
1
to C
6
alkenyl, alkynyl, substituted alkynyl, or COR
A
;
R
A
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
akoxy, substituted C
1
to C
3
alkoxy, C
1
to C
3
aminoalkyl, or substituted C
1
to C
3
aminoalkyl;
R
2
selected from H, halogen, CN, NO,
2
, C
1
C
6
alkyl, subsituted 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
3
is selected from a) or b):
a) R
3
is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below:
X is selected from the group of halogen, 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
thioalkoxy, substituted C
1
to C
3
thioalkoxy, 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
thioalkoxy; or
b) R
3
is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O S, SO, SO
2
or NR
7
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
7
is H, or C
1
to C
3
alkyl;
Q is O, S, NR
8
, or CR
9
R
10
;
R
8
is selected from the group of CN, C
1
to C
6
alkyl, s
Bender Reinhold H. W.
Edwards James P.
Jones Todd K.
Tegley Christopher M.
Wrobel Jay E.
American Home Products Corporation
Howson and Howson
Raymond Richard L.
Truong Tamthom N.
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