Cyclocarbamate derivatives as progesterone receptor modulators

Details Cyclocarbamate derivatives as progesterone receptor modulators Cyclocarbamate derivatives as progesterone receptor modulators

2003-03-12

2004-03-30

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S228200, C514S212020, C514S217050, C514S217060, C514S211150, C514S211080

Reexamination Certificate

active

06713478

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 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 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).
Compounds of the prior art are described by Jones, et al, (U.S. Pat. No. 5,688,810) is 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. 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).
Narr et al. (German Patent, DE 3633861, CA 109:22973) claimed that imidazobenzoxazinones, e.g. A, as cardotonics; Benzoxazin-2-ones, such as brofoxine (B), being active as an anxiolytic was reported by Hartmann et al. (
Proc. West. Pharmacol. Soc.
21, 51-55 (1978)); More recently, a number of patents (e.g. Young et al. WO95/20389; Christ et al. WO98/14436) claimed quinazolin-2-ones and benzoxazin-2-ones such as compound C1 and C2 as inhibitors of HIV reverse transcriptase.
DESCRIPTION OF THE INVENTION
This invention relates to compounds that are antagonists of the progesterone receptor, their preparation and utility.
This invention provides compounds of Formula (I):
wherein:
R
1
and R
2
are independent substituents selected from the group of 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, or substituted C
1
to C
3
aminoalkyl;
R
B
is H, C
1
to C
3
alkyl, or 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, or 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, or substituted C
1
to C
6
aminoalkyl;
R
5
is selected from a) or b)
a) R
5
is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below:
wherein:
X is taken from the group including halogen, CN, C
1
to C
3
alkyl, substituted C
1
to C
3
alkyl, alkenyl, substituted alkenyl, alkynyl, 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
;
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
Y and Z are independent substituents taken from the group including H, halogen, CN, NO
2
, amino, aminoalkyl, C
1
to C
3
alkoxy, C
1
to C
3
alkyl, or C
1
to C
3
thioalkoxy; 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
, amino, and C
1
to C
3
alkyl, C
1
to C
3
alkoxy, C
1
to C
3
aminoalkyl, COR
F
, or NR
G
COR
F
;
R
F
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
G
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 pharmaceutically acceptable salt thereof.
Preferred compounds of this invention include those of Formula I
wherein:
R
1
is 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, COR
A
, or NR
B
COR
A
;
R
2
is 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
3
to C
8
cycloalkyl, substituted C
3
to C
8
cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR
A
, or

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