Cyclic urea and cyclic amide derivatives

Details Cyclic urea and cyclic amide derivatives Cyclic urea and cyclic amide derivatives

2000-04-19

2002-04-09

Raymond, Richard L. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S070000, C544S071000, C544S092000

Reexamination Certificate

active

06369056

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 that 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).
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonist 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) 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. 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).
The patent by Christ et al. (WO 9814436) claims a cyclo amide such as compound A as inhibitors of HIV reverse transciptase. Other prior art includes pyridazine cyclo amide such as compound B by Turck et al. (
Tetrahedron,
49(3), 599-606 (1993)) and compounds such as C by Canonne et al. (
J. heterocyclic Chem.
26, 113(1989)). No activity data were reported in Turck's and Canonne' publications.
Regarding cyclic amides, Singh et al. and Kumar et al. (Singh et al.
J. Med. Chem.
37(2), 248-254(1994); Kumar et al.
J. Org. Chem.
57(25), 6995-6998(1992)) disclose compounds such as D and E claimed as cAMP PDE III inhibitors.
DESCRIPTION OF THE INVENTION
This invention provides compounds of Formula I:
wherein:
A, B and D are N or CH, with the proviso that A, B and D can not all be CH;
R
1
and R
2
are independent substituents 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, COR
A
, NR
B
COR
A
;
or R
1
and R
2
are fused to form a spirocyclic ring selected from a), b) or c), each spirocyclic ring optionally substituted by from 1 to 3 C
1
-C
3
alkyl groups:
a) a 3 to 8 membered spirocyclic alkyl ring;
b) a 3 to 8 membered spirocyclic alkenyl ring; 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, or COR
C
;
R
C
is H, C
1
to C
3
allyl, substituted C
1
to C
3
allyl, 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 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, 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
, C
1
to C
3
alkoxy, C
1
to C
3
alkyl, or C
1
to C
3
thioalkoxy;
or
R
4
is a five or six membered ring with 1, 2, or 3 heteroatoms from the group including O, S, SO, SO
2
or NR
5
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
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
amin

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