Cyclothiocarbamate derivatives as progesterone receptor...

Details Cyclothiocarbamate derivatives as progesterone receptor... Cyclothiocarbamate derivatives as progesterone receptor...

2000-04-19

2002-08-20

Raymond, Richard L. (Department: 7694)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S070000, C544S092000

Reexamination Certificate

active

06436929

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to compounds which are agonists of the progesterone receptor, their preparation and utility. This invention also provides methods of using these compounds in the inducement of contraception and the treatment and/or prevention of dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, and prostate.
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, alternatively they may be used in conjunction with a PR antagonist. 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.
The compounds of this invention have been shown to act as competitive inhibitors of progesterone binding to the PR and act as agonists 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 describe in U.S. Pat. No. 5,688,810 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).
Sakata et al. (JP 07159917, CA 123:301431) teach that certain benzoxazin-2-thione compounds such as compound A can be used as photographic materials. Kim et al. disclose that some imidazole substituted benzothiazines, such as compound B, can be used as cardiotonics (U.S. Pat. No. 5,171,851 and EP 510235). More recently, Young et al. (WO95/20389) and Christ et al. (WO98/14436) claimed benzoxazin-2-thiones such as compound C as inhibitors of HIV reverse transcriptase.
Pflegel et al. (Pharmazie, 37(10), 714-717(1982)) disclosed quinazolin-2-thiones such as compound D in their study of polarography of heterocyclics, but disclosed no activity for compound D.
DESCRIPTION OF THE INVENTION
This invention provides compounds of the formula:
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 spirocyclic ring selected from a), b) or c), below, each spirocyclic ring being optionally substituted by from 1 to 3 substituents selected from H or C
1
-C
3
alkyl:
a) a 3 to 8 membered spirocyclic alkyl ring, preferably a 3 to 6 membered spirocyclic alkyl ring; or
b) a 3 to 8 membered spirocyclic alkenyl ring, preferably a 3 to 6 membered spirocyclic alkenyl ring; or
c) a 3 to 8 membered spirocyclic ring containing one to three heteroatoms selected from O, S and N, preferably a 3 to 6 membered spirocyclic ring containing one to three heteroatoms;
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
alkoxy, substituted C
1
to C
3
alkoxy, amino, 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, or COR
C
;
R
C
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
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 selected from H, halogen, CN, NO
2
, C
1
to C
6
alkyl, substituted 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
5
is selected from groups a), b), or c) below:
a) R
5
is a trisubstituted benzene ring containing the substituents X, Y and Z as shown below:
X is selected 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, 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 selected from the group of 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
5
is a five or six membered heterocyclic ring with 1, 2, or 3 ring heteroatoms selected from the group of O, S, S(O), S(O
2
) or NR
6
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
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
c) or R
5
is a six membered ring with the structure:
wherein
X
1
is N or CX
2
,
X
2
is halogen, CN, or NO
2
,
Q
1
is S, NR
7
, or CR
8
R
9
;
R
7
is selected from the group of CN, 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, or substituted heterocyclic, SO
2
CF
3
, OR
11
or NR
11
R
12
;
R
8
and R
9
are independent substituents selected from the group of H, C
1
to C
6
alkyl, su

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