U.S. patent application number 11/985808 was filed with the patent office on 2008-05-22 for 5-aryl indan-1 one and analogs useful as progesterone receptor modulators.
This patent application is currently assigned to Wyeth. Invention is credited to Jeffrey Curtis Kern, Eugene Anthony Terefenko, Eugene John Trybulski, Puwen Zhang.
Application Number | 20080119537 11/985808 |
Document ID | / |
Family ID | 37885073 |
Filed Date | 2008-05-22 |
United States Patent
Application |
20080119537 |
Kind Code |
A1 |
Zhang; Puwen ; et
al. |
May 22, 2008 |
5-Aryl indan-1 one and analogs useful as progesterone receptor
modulators
Abstract
Compounds of formula I or II and pharmaceutical compositions and
kits containing these compounds are provided. Also provided are
methods of inducing contraception, providing hormone replacement
therapy, treating cycle-related symptoms, or treating or preventing
benign or malignant neoplastic disease using the compounds of
formula I, formula II, or formula III. ##STR1##
Inventors: |
Zhang; Puwen; (Audubon,
PA) ; Kern; Jeffrey Curtis; (Gilbertsville, PA)
; Terefenko; Eugene Anthony; (Center Valley, PA) ;
Trybulski; Eugene John; (Huntingdon Valley, PA) |
Correspondence
Address: |
HOWSON AND HOWSON/WYETH;CATHY A. KODROFF
SUITE 210
501 OFFICE CENTER DRIVE
FT WASHINGTON
PA
19034
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
37885073 |
Appl. No.: |
11/985808 |
Filed: |
November 16, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11522862 |
Sep 18, 2006 |
7319152 |
|
|
11985808 |
Nov 16, 2007 |
|
|
|
60718355 |
Sep 19, 2005 |
|
|
|
Current U.S.
Class: |
514/427 ;
514/681; 548/561; 568/327 |
Current CPC
Class: |
C07D 207/34 20130101;
C07D 333/22 20130101; C07D 333/28 20130101; A61P 15/18 20180101;
C07D 261/08 20130101 |
Class at
Publication: |
514/427 ;
548/561; 568/327; 514/681 |
International
Class: |
A61K 31/40 20060101
A61K031/40; C07D 207/30 20060101 C07D207/30; A61K 31/122 20060101
A61K031/122; A61P 15/18 20060101 A61P015/18; C07C 49/297 20060101
C07C049/297 |
Claims
1. A compound of formula (I) or (II): (I) a compound of formula
(I): ##STR39## wherein: R.sub.1 and R.sub.2 are, independently,
selected from the group consisting of H, halogen, C.sub.1 to
C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6
alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl,
aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
provided that both R.sub.1 and R.sub.2 are not H; or R.sub.1 and
R.sub.2 are fused to form (a), (b), or (c): (a) a carbon-based 3 to
6 membered saturated spirocyclic ring; (b) a carbon-based 3 to 6
membered spirocyclic ring having in its backbone one or more
carbon-carbon double bonds; or (c) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone 1 to 3 heteroatoms selected
from the group consisting of O, S, SO, SO.sub.2, and NR.sup.C;
wherein rings (a)-(c) are optionally substituted by 1 to 3
substituents selected from the group consisting of F, Cl, and
C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i) or (ii): (i) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from the group consisting of O, S, SO, and
SO.sub.2 and substituted with 0 to 3 substituents selected from the
group consisting of H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4
alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; or
(ii) a 5 or 6 membered heteroaryl ring containing in its backbone 1
or 3 NR.sup.C heteroatoms and substituted with 0 to 3 substituents
selected from the group consisting of H, halogen, CN, NO.sub.2, OH,
amino, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1
to C.sub.4 alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and
NR.sup.CCOR.sup.D; R.sup.C is absent, H, C.sub.1 to C.sub.4 alkyl,
substituted C.sub.1 to C.sub.4 alkyl, CN, or COR.sup.D; R.sup.D is
H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, or C.sub.1
to C.sub.4 alkylamino; R.sub.4 is H, halogen, CN, OH, NO.sub.2,
alkoxy, or lower alkyl; R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are,
independently, H, F, or C.sub.1 to C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof; or (II) a compound of
formula (II): ##STR40## wherein: (i) R.sub.1 and R.sub.2 are,
independently, heteroaryl or substituted heteroaryl; or R.sub.1 and
R.sub.2 are fused to form a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone 1 to 3 heteroatoms selected
from the group consisting of O, S, SO, SO.sub.2, and NR.sup.C,
wherein the carbon-based ring is optionally substituted by 1 to 3
substituents selected from the group consisting of F, Cl, and
C.sub.1 to C.sub.3 alkyl; R.sub.3 is a saturated 5 or 6 membered
heteroaryl ring containing in its backbone 1 to 3 heteroatoms
selected from the group consisting of O, S, SO, SO.sub.2, and
NR.sup.C and substituted with 0 to 3 substituents selected from the
group consisting of H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4
alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; or
R.sup.C is absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1
to C.sub.4 alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4
alkylamino; R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or
lower alkyl; R.sub.5 and R.sub.6, are, independently, H, F, or
C.sub.1 to C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof; or (ii) R.sub.1 and R.sub.2 are, independently, selected
from the group consisting of H, halogen, C.sub.1 to C.sub.6 alkyl,
CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to
C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted
aryl, heteroaryl, and substituted heteroaryl; provided that both
R.sub.1 and R.sub.2 are not H; or R.sub.1 and R.sub.2 are fused to
form (a), (b), or (c): (a) a carbon-based 3 to 6 membered saturated
spirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone one or more carbon-carbon double bonds;
or (c) a carbon-based 3 to 6 membered spirocyclic ring having in
its backbone 1 to 3 heteroatoms selected from the group consisting
of O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from the
group consisting of F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is
a saturated 6 membered heteroaryl ring containing in its backbone 1
to 3 heteroatoms selected from the group consisting of O, S, SO,
SO.sub.2, and NR.sup.C and substituted with 0 to 3 substituents
selected from the group consisting of H, halogen, CN, NO.sub.2, OH,
amino, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1
to C.sub.4 alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and
NR.sup.CCOR.sup.D; or R.sup.C is absent, H, C.sub.1 to C.sub.4
alkyl, substituted C.sub.1 to C.sub.4 alkyl, CN, or COR.sup.D;
R.sup.D is H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy,
or C.sub.1 to C.sub.4 alkylamino; R.sub.4 is H, halogen, CN, OH,
NO.sub.2, alkoxy, or lower alkyl; R.sub.5 and R.sub.6 are,
independently, H, F, or C.sub.1 to C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, which is of formula I and
comprises
1-methyl-5-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrrole-2-carboni-
trile.
3. A pharmaceutical composition comprising a compound of claim 1 or
a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier or excipient.
4. A method of inducing contraception, providing hormone
replacement therapy, or treating cycle-related symptoms, or
treating or preventing benign or malignant neoplastic disease,
comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of claim 1.
5. A method of providing hormone replacement therapy or treating
cycle-related symptoms, comprising administering to a mammal in
need thereof a pharmaceutically effective amount of a compound of
formula III: ##STR41## wherein: R.sub.2 is selected from the group
consisting of H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; R.sub.3 is aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; R.sub.4 is
H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.9 is H,
F, or C.sub.1 to C.sub.3 alkyl; or a pharmaceutically acceptable
salt thereof.
6. A method of inducing contraception or treating or preventing
benign or malignant neoplastic disease, comprising administering to
a mammal in need thereof a pharmaceutically effective amount of a
compound of formula III: ##STR42## wherein: R.sub.2 is selected
from the group consisting of H, halogen, C.sub.1 to C.sub.6 alkyl,
CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to
C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted
aryl, heteroaryl, and substituted heteroaryl; R.sub.3 is heteroaryl
or substituted heteroaryl; R.sub.4 is H, halogen, CN, OH, NO.sub.2,
alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1 to C.sub.3
alkyl; or a pharmaceutically acceptable salt thereof.
7. A method of contraception which comprises administering to a
female of child bearing age for 28 consecutive days: (a) a first
phase of from 14 to 24 daily dosage units of a progestational agent
equal in progestational activity to about 35 to about 100 .mu.g
levonorgestrel; (b) a second phase of from 1 to 11 daily dosage
units, at a daily dosage of from about 2 to 50 mg, of a compound of
the structure: ##STR43## wherein: (I) R.sub.2 is selected from the
group consisting of H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; R.sub.3 is heteroaryl or
substituted heteroaryl; R.sub.4 is H, halogen, CN, OH, NO.sub.2,
alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1 to C.sub.3
alkyl; or a pharmaceutically acceptable salt thereof; or (II)
R.sub.2 is selected from the group consisting of H, halogen,
C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to
C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8
cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted
heteroaryl; R.sub.3 is heteroaryl or substituted heteroaryl;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.9 is H, F, or C.sub.1 to C.sub.3 alkyl; or a pharmaceutically
acceptable salt thereof; and (c) optionally, a third phase of daily
dosage units of an orally and pharmaceutically acceptable placebo
for the remaining days of the 28 consecutive days in which no
antiprogestin, progestin or estrogen is administered; wherein the
total daily dosage units of the first, second and third phases
equals 28.
8. A pharmaceutically useful kit adapted for daily oral
administration which comprises: (a) a first phase of from 14 to 21
daily dosage units of a progestational agent equal in
progestational activity to about 35 to about 150 .mu.g
levonorgestrel; (b) a second phase of from 1 to 11 daily dosage
units of a compound of the structure: ##STR44## wherein: (I)
R.sub.2 is selected from the group consisting of H, halogen,
C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to
C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8
cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted
heteroaryl; R.sub.3 is heteroaryl or substituted heteroaryl;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.9 is H, F, or C.sub.1 to C.sub.3alkyl; or a pharmaceutically
acceptable salt thereof; or (II) R.sub.2 is selected from the group
consisting of H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; R.sub.3 is heteroaryl or
substituted heteroaryl; R.sub.4 is H, halogen, CN, OH, NO.sub.2,
alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1 to C.sub.3
alkyl; or a pharmaceutically acceptable salt thereof; and wherein,
each daily dosage unit contains said compound at a daily dosage of
from about 2 to 50 mg; and (c) a third phase of daily dosage units
of an orally and pharmaceutically acceptable placebo; wherein the
total number of the daily dosage units in the first phase, second
phase and third phase equals 28.
9. A pharmaceutical composition comprising a compound of formula II
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier or excipient, wherein said
compound of formula II is: ##STR45## wherein: R.sub.1 and R.sub.2
are, independently, selected from the group consisting of H,
halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3,
C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to
C.sub.8 cycloalkyl, aryl, and substituted aryl; provided that both
R.sub.1 and R.sub.2 are not H; or R.sub.1 and R.sub.2 are fused to
form (a) or (b): (a) a carbon-based 3 to 6 membered saturated
spirocyclic ring; or (b) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone one or more carbon-carbon double bonds;
wherein rings (a)-(b) are optionally substituted by 1 to 3
substituents selected from the group consisting of F, Cl, and
C.sub.1 to C.sub.3 alkyl; R.sub.3 is a saturated 5 membered
heteroaryl ring containing in its backbone 1 to 3 heteroatoms
selected from the group consisting of O, S, SO, SO.sub.2, and
NR.sup.C and substituted with 0 to 3 substituents selected from the
group consisting of H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4
alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; or
R.sup.C is absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1
to C.sub.4 alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4
alkylamino; R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or
lower alkyl; R.sub.5 and R.sub.6 are, independently, H, F, or
C.sub.1 to C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
10. A method of inducing contraception, providing hormone
replacement therapy, treating cycle-related symptoms, or treating
or preventing benign or malignant neoplastic disease, comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of formula II: ##STR46## wherein:
R.sub.1 and R.sub.2 are, independently, selected from the group
consisting of H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, and substituted aryl;
provided that both R.sub.1 and R.sub.2 are not H; or R.sub.1 and
R.sub.2 are fused to form (a) or (b): (a) a carbon-based 3 to 6
membered saturated spirocyclic ring; or (b) a carbon-based 3 to 6
membered spirocyclic ring having in its backbone one or more
carbon-carbon double bonds; wherein rings (a)-(b) are optionally
substituted by 1 to 3 substituents selected from the group
consisting of F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is a
saturated 5 membered heteroaryl ring containing in its backbone 1
to 3 heteroatoms selected from the group consisting of O, S, SO,
SO.sub.2, and NR.sup.C and substituted with 0 to 3 substituents
selected from the group consisting of H, halogen, CN, NO.sub.2, OH,
amino, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1
to C.sub.4 alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and
NR.sup.CCOR.sup.D; or R.sup.C is absent, H, C.sub.1 to C.sub.4
alkyl, substituted C.sub.1 to C.sub.4 alkyl, CN, or COR.sup.D;
R.sup.D is H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy,
or C.sub.1 to C.sub.4 alkylamino; R.sub.4 is H, halogen, CN, OH,
NO.sub.2, alkoxy, or lower alkyl; R.sub.5 and R.sub.6 are,
independently, H, F, or C.sub.1 to C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 11/522,862, filed Sep. 18, 2006, which claims the benefit
of the priority of prior U.S. Provisional Patent Application No.
60/718,355, filed Sep. 19, 2005, now abandoned.
BACKGROUND OF THE INVENTION
[0002] This invention relates to agonists and antagonists of the
progesterone receptor, their preparation and utility.
[0003] Intracellular receptors (IR) form a class of structurally
related gene regulators known as "ligand dependent transcription
factors" (Mangelsdorf, D. J. etc. Cell, 83, 835, 1995). The steroid
receptor family is a subset of the IR family, including the
progesterone receptor (PR), estrogen receptor (ER), androgen
receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid
receptor (MR).
[0004] 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 PR
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 the
protein encoded by that gene.
[0005] 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.
[0006] 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, either along or in the presence of an
ER agonist. ER agonists are used to treat the symptoms of
menopause, TABLE-US-00001 Express Mail No. EO 940 621 492 US 1
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.
[0007] 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 (U.S.
Pat. No. 5,719,136).
[0008] PR antagonists may also be useful for the treatment of
hormone dependent breast cancers (Horwitz, et al, Horm. Cancer,
283, 1996, 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
uterine fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513,
1993) and endometriosis (Kettel, et al., Fertility and Sterility,
56, 402, 1991).
[0009] 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).
[0010] 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).
[0011] What is needed in the art are alternative progesterone
receptor modulators.
SUMMARY OF THE INVENTION
[0012] In one aspect, a compound of formula I is provided, wherein
R.sub.1-R.sub.8 are defined below. ##STR2##
[0013] In another aspect, a compound of formula II is provided,
wherein R.sub.1-R.sub.6 are defined below. ##STR3##
[0014] In a further aspect, methods of inducing contraception,
providing hormone replacement therapy, treating cycle-related
symptoms, or treating or preventing benign or malignant neoplastic
disease are provided using compounds of formula I or II.
[0015] In yet another aspect, methods of inducing contraception,
providing hormone replacement therapy, treating cycle-related
symptoms, or treating or preventing benign or malignant neoplastic
disease are provided using compounds of formula III, wherein
R.sub.2-R.sub.4 and R.sub.9 are defined below: ##STR4##
[0016] Other aspects and advantages will be readily apparent from
the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Novel progesterone receptor (PR) modulators and uses of the
same in treating a variety of conditions are provided. The novel
compounds have been shown to act as competitive inhibitors of
progesterone binding to the PR and act as PR modulators in
functional models. These PR modulators are thereby effective as PR
agonists or PR antagonists.
[0018] As used herein, the terms "anti-progestational agent",
"anti-progestin" and "progesterone receptor antagonist" are
understood to be synonymous. Similarly, "progestin",
"progestational agent", and "progesterone receptor agonist" are
understood to refer to compounds of the same activity.
[0019] A compound of formula I is provided: ##STR5## wherein,
R.sub.1 and R.sub.2 are, independently, selected from among H,
halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3,
C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; provided that both R.sub.1 and R.sub.2 are
not H; or R.sub.1 and R.sub.2 are fused to form (a), (b), or (c):
(a) a carbon-based 3 to 6 membered saturated spirocyclic ring; (b)
a carbon-based 3 to 6 membered spirocyclic ring having in its
backbone one or more carbon-carbon double bonds; or (c) a
carbon-based 3 to 6 membered spirocyclic ring having in its
backbone 1 to 3 heteroatoms selected from among O, S, SO, SO.sub.2,
and NR.sup.C; wherein rings (a)-(c) are optionally substituted by 1
to 3 substituents selected from among F, Cl, and C.sub.1 to C.sub.3
alkyl; R.sub.3 is (i) or (ii): (i) a 5 or 6 membered heteroaryl
ring containing in its backbone 1 to 3 heteroatoms selected from
among O, S, SO, and SO.sub.2 and substituted with 0 to 3
substituents selected from among H, halogen, CN, NO.sub.2, OH,
amino, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1
to C.sub.4 alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and
NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered heteroaryl ring
containing in its backbone 1 or 3 NR.sup.C heteroatoms and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is absent, H, C.sub.1 to
C.sub.4 alkyl, substituted C.sub.1 to C.sub.4 alkyl, CN, or
COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to
C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino; R.sub.4 is H,
halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.5,
R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, or C.sub.1
to C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
[0020] A compound of formula II is provided: ##STR6## wherein,
R.sub.1 and R.sub.2 are, independently, selected from among H,
halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3,
C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; provided that both R.sub.1 and R.sub.2 are
not H; or R.sub.1 and R.sub.2 are fused to form (a), (b), or (c):
(a) a carbon-based 3 to 6 membered saturated spirocyclic ring; (b)
a carbon-based 3 to 6 membered spirocyclic ring having in its
backbone one or more carbon-carbon double bonds; or (c) a
carbon-based 3 to 6 membered spirocyclic ring having in its
backbone 1 to 3 heteroatoms selected from among O, S, SO, SO.sub.2,
and NR.sup.C; wherein rings (a)-(c) are optionally substituted by 1
to 3 substituents selected from among F, Cl, and C.sub.1 to C.sub.3
alkyl; R.sub.3 is a saturated 5 or 6 membered heteroaryl ring
containing in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C and substituted with 0 to 3
substituents selected from among H, halogen, CN, NO.sub.2, OH,
amino, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1
to C.sub.4 alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and
NR.sup.CCOR.sup.D; or R.sup.C is absent, H, C.sub.1 to C.sub.4
alkyl, substituted C.sub.1 to C.sub.4 alkyl, CN, or COR.sup.D;
R.sup.D is H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy,
or C.sub.1 to C.sub.4 alkylamino; R.sub.4 is H, halogen, CN, OH,
NO.sub.2, alkoxy, or lower alkyl; R.sub.5 and R.sub.6 are,
independently, H, F, or C.sub.1 to C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
[0021] In one embodiment, in the compound of formula I or II,
R.sub.1 and R.sub.2 are, independently, H or C.sub.1 to C.sub.6
alkyl; R.sub.3 is a 5 membered heteroaryl ring containing in its
backbone 1 NR.sup.C heteroatom and substituted with 0 to 3
substituents selected from among H, CN, and C.sub.1 to C.sub.3
alkyl; R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are H.
[0022] In another embodiment, in the compound of formula I or II,
R.sub.3 is 1-methyl-2-cyanopyrrole,
1-methyl-2-cyano-4-acetylpyrrole or 2-chlorothiophene.
[0023] In a further embodiment, in the compound of formula I or II,
R.sub.3 is 1-methyl-2-cyanopyrrole.
[0024] In yet another embodiment, in the compound of formula I or
II, R.sub.1 is heteroaryl or aryl.
[0025] In still a further embodiment, in the compound of formula I
or II, R.sub.3 is of the structure: ##STR7## wherein, U is O, S, or
NR.sup.C; R.sup.C is H, C.sub.1 to C.sub.4 alkyl, or COR.sup.D;
R.sup.D is C.sub.1 to C.sub.4 alkyl; X' is selected from among
halogen, CN, NO.sub.2, C.sub.1 to C.sub.3 alkyl, and C.sub.1 to
C.sub.3 alkoxy; and Y' is selected from among H and C.sub.1 to
C.sub.4 alkyl.
[0026] In another embodiment, in the compound of formula I or II,
R.sub.3 is of the structure: ##STR8## wherein, X.sup.1 is halogen,
CN, C.sub.1 to C.sub.3 alkoxy, or NO.sub.2.
[0027] In still a further embodiment, the compound of formula I is
1-methyl-5-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrrole-2-carboni-
trile.
[0028] In yet another embodiment, in the compound of formula I or
II, R.sub.1 and R.sub.2 are fused to form any of rings (a), (b), or
(c).
[0029] In a further embodiment, the compound of formula II is
5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one;
1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbon-
itrile;
5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrro-
le-2-carbonitrile;
1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile;
4-acetyl-1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbon-
itrile; 5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one;
5-(5-chlorothien-2-yl)-3,3-dimethylindan-1-one; and
3,3-dimethyl-5-thien-3-yl-indan-1-one, or a pharmaceutically
acceptable salt thereof.
[0030] The term "alkyl" is used herein to refer to both straight-
and branched-chain saturated aliphatic hydrocarbon groups having 1
to about 8 carbon atoms, and desirably 1 to about 6 carbon atoms
(i.e., C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5 or C.sub.6).
Similarly, the term "lower alkyl" is used herein to refer to alkyl
groups as just described, but having 1 to about 3 carbon atoms.
Unless otherwise specified, the alkyl groups are not
substituted.
[0031] The term "cycloalkyl" is used herein to an alkyl group as
just described, but cyclic in structure and having 3 to about 8
carbon atoms. In one embodiment, a cycloalkyl group has 3 to about
8 carbon atoms. In another embodiment, a cycloalkyl group has about
3 to about 6 carbon atoms (i.e., C.sub.3, C.sub.4, C.sub.5 or
C.sub.6).
[0032] The term "alkenyl" is used herein to refer to both straight-
and branched-chain alkyl groups having one or more carbon-carbon
double bonds and containing about 3 to about 8 carbon atoms. In one
embodiment, the term alkenyl refers to an alkyl group having 1 or 2
carbon-carbon double bonds. In a further embodiment, an alkenyl
group has about 2 to about 8 carbon atoms. In another embodiment,
an alkenyl group has about 2 to about 6 carbon atoms. Unless
otherwise specified, the alkenyl groups are not substituted.
[0033] The term "alkynyl" is used herein to refer to both straight-
and branched-chain alkyl groups having one or more carbon-carbon
triple bond and having about 3 to about 8 carbon atoms. In one
embodiment, the term alkynyl refers to an alkyl group having 1 or 2
carbon-carbon triple bonds and having about 3 to about 6 carbon
atoms. Unless otherwise specified, the alkynyl groups are not
substituted.
[0034] The terms "substituted alkyl", "substituted alkenyl",
"substituted alkynyl", and "substituted cycloalkyl" refer to alkyl,
alkenyl, alkynyl, and cycloalkyl groups, respectively, having one
or more substituents including, without limitation, halogen, CN,
OH, NO.sub.2, amino, aryl, heterocyclic, substituted aryl,
substituted heterocyclic, alkoxy, aryloxy, substituted alkoxy,
alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio. These
substituents may be attached to any carbon of an alkyl, alkenyl,
alkynyl or cycloalkyl group provided that the attachment
constitutes a stable chemical moiety.
[0035] The term "acyl" as used herein refers to a carbonyl
substituent, i.e., a C(O)(R) group where R is a straight- or
branched-chain hydrocarbon group including, without limitation,
alkyl, alkenyl, and alkynyl groups. In one embodiment the R groups
have 1 to about 8 carbon atoms, and in a further embodiment 1 to
about 6 carbon atoms. The term "substituted acyl" refers to an acyl
group which is substituted with 1 or more groups including halogen,
CN, OH, and NO.sub.2.
[0036] The term "aryl" as used herein refers to an aromatic system
which can include a single ring or multiple aromatic rings fused or
linked together where at least one part of the fused or linked
rings forms the conjugated aromatic system. The aryl groups
include, but are not limited to, phenyl, naphthyl, biphenyl,
anthryl, tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl,
fluorenyl, and carbazolyl. Desirably, the aryl group is an
optionally substituted phenyl group.
[0037] The term "substituted aryl" refers to an aryl group which is
substituted with one or more substituents including halogen, CN,
OH, NO.sub.2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy,
aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio,
which groups can be optionally substituted. Desirably, a
substituted aryl group is substituted with 1 to about 4
substituents.
[0038] The term "heteroaryl", as used herein, refers to an
optionally substituted, mono-, di-, tri-, or other multicyclic
aromatic ring system that includes at least one, and desirably from
1 to about 4 heteroatom ring members including sulfur, oxygen and
nitrogen. In one embodiment, a heteroaryl group can contain about 3
to about 50 carbon atoms, including all combinations and
subcombinations of ranges and specific numbers of carbon atoms
therein. In another embodiment, a heteroaryl group can contain
about 4 to about 10 carbons. Non-limiting examples of heteroaryl
groups include, for example, pyrrolyl, furyl, pyridyl,
1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl,
tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl,
thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl,
purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.
[0039] The term "substituted heteroaryl" refers to an heteroaryl
group which is substituted with one or more substituents including
halogen, CN, OH, NO.sub.2, amino, alkyl, cycloalkyl, alkenyl,
alkynyl, alkoxy.
[0040] The term "heterocyclic" as used herein refers to a stable 4-
to 7-membered monocyclic or multicyclic heterocyclic ring which is
saturated or partially unsaturated. The heterocyclic ring has in
its backbone carbon atoms and one or more heteroatoms including
nitrogen, oxygen, and sulfur atoms. Desirably, the heterocyclic
ring has 1 to about 4 heteroatoms in the backbone of the ring. When
the heterocyclic ring contains nitrogen or sulfur atoms in the
backbone of the ring, the nitrogen or sulfur atoms can be oxidized.
The term "heterocyclic" also refers to multicyclic rings in which a
heterocyclic ring is fused to an aryl ring. The heterocyclic ring
can be attached to the aryl ring through a heteroatom or carbon
atom provided the resultant heterocyclic ring structure is
chemically stable.
[0041] A variety of heterocyclic groups are known in the art and
include, without limitation, oxygen-containing rings,
nitrogen-containing rings, sulfur-containing rings, mixed
heteroatom-containing rings, fused heteroatom containing rings, and
combinations thereof. The heterocyclic groups are selected from,
but not limited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl,
dioxinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl,
piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
piperazinyl, azepinyl, triazinyl, pyrrolidinyl, azepinyl,
oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl,
dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl,
morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl,
thiepinyl, diazepinyl, benzofuranyl, thionapthene, indolyl,
benazazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl,
benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl,
benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl,
benzoxazinyl, xanthenyl, acridinyl, and purinyl rings.
[0042] The term "substituted heterocyclic" as used herein refers to
a heterocyclic group having one or more substituents including
halogen, CN, OH, NO.sub.2, amino, alkyl, cycloalkyl, alkenyl,
alkynyl, alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino,
and arylthio, which groups can be optionally substituted.
Desirably, a substituted heterocyclic group has 1 to 4
substituents.
[0043] The term "arylthio" as used herein refers to the S(aryl)
group, where the point of attachment is through the sulfur-atom and
the aryl group can be optionally substituted.
[0044] The term "alkoxy" as used herein refers to the O(alkyl)
group, where the point of attachment is through the oxygen-atom and
the alkyl group is optionally substituted.
[0045] The term "thioalkoxy" as used herein refers to the S(alkyl)
group, where the point of attachment is through the sulfur-atom and
the alkyl group is optionally substituted.
[0046] The term "aryloxy" as used herein refers to the O(aryl)
group, where the point of attachment is through the oxygen-atom and
the aryl group is optionally substituted.
[0047] The term "alkylcarbonyl" as used herein refers to the
C(O)(alkyl) group, where the point of attachment is through the
carbon-atom of the carbonyl moiety and the alkyl group is
optionally substituted.
[0048] The term "alkylcarboxy" as used herein refers to the
C(O)O(alkyl) group, where the point of attachment is through the
carbon-atom of the carboxy moiety and the alkyl group is optionally
substituted.
[0049] The term "alkylamino" as used herein refers to both
secondary and tertiary amines where the point of attachment is
through the nitrogen-atom and the alkyl groups are optionally
substituted. The alkyl groups can be the same or different.
[0050] The term "halogen" as used herein refers to Cl, Br, F, or I
groups.
[0051] The compounds described herein encompass tautomeric forms of
the structures provided herein characterized by the bioactivity of
the drawn structures. Further, the compounds described herein can
be used in the form of salts derived from pharmaceutically or
physiologically acceptable acids, bases, alkali metals and alkaline
earth metals.
[0052] Pharmaceutically acceptable salts can be formed from organic
and inorganic acids including, for example, acetic, propionic,
lactic, citric, tartaric, succinic, fumaric, maleic, malonic,
mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,
nitric, sulfuric, methanesulfonic, napthalenesulfonic,
benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly
known acceptable acids. Salts may also be formed from inorganic
bases, desirably alkali metal salts including, for example, sodium,
lithium, or potassium, and organic bases, such as ammonium salts,
mono-, di-, and trimethylammonium, mono-, di- and triethylammonium,
mono-, di- and tripropylammonium (iso and normal),
ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium,
benzylammonium, dibenzylammonium, piperidinium, morpholinium,
pyrrolidinium, piperazinium, 1-methylpiperidinium,
4-ethylmorpholinium, 1-iso-propylpyrrolidinium,
1,4-dimethylpiperazinium, 1-n-butyl piperidinium,
2-methylpiperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and
triethanolammonium, ethyl diethanolammonium,
n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium,
phenylmonoethanolammonium, and the like.
[0053] Physiologically acceptable alkali salts and alkaline earth
metal salts can include, without limitation, sodium, potassium,
calcium and magnesium salts in the form of esters, and
carbamates.
[0054] These salts, as well as other compounds described herein can
be in the form of esters, carbamates and other conventional
"pro-drug" forms, which, when administered in such form, convert to
the active moiety in vivo. In one embodiment, the prodrugs are
esters. See, e.g., B. Testa and J. Caldwell, "Prodrugs Revisited:
The "Ad Hoc" Approach as a Complement to Ligand Design", Medicinal
Research Reviews, 16(3):233-241, ed., John Wiley & Sons
(1996).
[0055] As described herein, the compounds described herein and/or
salts, prodrugs or tautomers thereof, are delivered in regimens
therapeutic or prophylactic purposes, as described herein.
[0056] The compounds discussed herein also encompass "metabolites"
which are unique products formed by processing the compounds
described herein by the cell or subject. Desirably, metabolites are
formed in vivo.
[0057] The compounds described herein are readily prepared by one
of skill in the art according to the following schemes from
commercially available starting materials or starting materials
which can be prepared using literature procedures. These schemes
show the preparation of representative compounds. Variations on
these methods, or other methods known in the art, can be readily
performed by one of skill in the art given the information provided
herein. ##STR9##
[0058] As illustrated in Scheme I, access to ketones 2 can be
achieved by reaction of an appropriately substituted benzoic acid
or its derivatives such as Weinreb amides 1 with a suitable organo
lithium or Grignard reagent. The reaction can be executed in an
aprotic solvent including but not limited to THF or diethyl ether
at a suitable temperature ranging from -78.degree. C. to room
temperature under a blanket of inert atmosphere such as nitrogen or
argon. To prevent the formation of carbinol side products, a
reversing quenching procedure (pouring the reaction mixture to a
diluted aqueous acidic solution such as hydrogen chloride solution)
is preferred. An alternative way to work up the reaction included
but not limited to an addition of trialkylsilyl chloride or
equivalent to the reaction before quenching the reaction mixture
with a diluted aqueous acidic solution. Cyclization of ketones 2 to
afford indanones 3 can be effected with a suitable Lewis acid such
as polyphosphoric acid (PPA) and aluminum chloride in an aprotic
solvent such as chlorobenzene, xylene, the Dowtherm.RTM. A reagent,
and nitrobenzene at the temperature ranging from room temperature
to refluxing temperature of the solvent used. Formation of 5-aryl
indanones 4, compounds described herein, can be achieved by a
number of coupling reactions including Suzuki and Stille protocols.
These reactions are commonly performed in the presence of a
transition metallic catalyst, e.g., palladium or nickel complex
often with phosphino ligands, e.g., triphenylphosphine (Ph.sub.3P),
1,1'-bis(diphenylphosphino)ferrocene (dppf), or
1,2-bis(diphenylphosphino)ethane (dppe). Under this catalytic
condition, an appropriately substituted aryl nucleophilic reagent,
e.g., aryl boronic acid, arylstannane, or aryl zinc compound, can
be coupled with 3 to produce the compounds described herein, 5-aryl
indanones 4. The commonly used bases in the reaction include but
not limited to sodium bicarbonate, sodium carbonate, potassium
phosphate, barium carbonate, cesium fluoride, and potassium
acetate. The most commonly used solvents in these reactions include
benzene, toluene, dimethylformamide (DMF), isopropanol, ethanol,
dimethoxyethane (DME), and ether. The coupling reaction is
generally executed under an inert atmosphere such as nitrogen or
argon at temperatures ranging from room temperature to 95.degree.
C. In the case when an appropriate aryl nucleophilic reagent is not
available, the 5-halogen of 3 can be converted to the borate or
stannane, which can be coupled with an appropriate aryl halide such
as aryl bromide or aryl iodide using any coupling reaction
described above to yield compounds 4. ##STR10##
[0059] Alternatively, indanones as well as their six-member ring
analogs, 3,4-dihydro-2H-naphthalen-1-ones 6, can be furnished from
appropriately substituted 3-phenylpropionic acids or
4-phenyl-butyric acids 5 as depicted in scheme II. Preferably,
acids 5 are activated by converted into their corresponding
carbonyl chloride or anhydrides by reacting with a suitable agent
such as thionyl chloride or oxalyl chloride. The activated
intermediates can be then in situ cyclized to form 6 using a
Friedel-Crafts acylation protocol by addition of an appropriate
Lewis acid such aluminum chloride or tin chloride in a suitable
solvent such as benzene, chlorobenzene, and nitrobenzene at the
temperature ranging from room temperature to refluxing temperature
of the solvent used. Formation of 5-aryl indanones or 6-aryl
3,4-dihydro-2H-naphthalen-1-ones 7, the compounds described herein,
can be readily effected using typical aforementioned coupling
procedures as illustrated in Scheme I. ##STR11##
[0060] Indanones or 3,4-dihydro-2H-naphthalen-1-ones 6 can also be
prepared via oxidation of appropriately substituted indans or
1,2,3,4-tetrahydro-naphthalenes using a suitable oxidant such as
chromium (VI) oxide or manganese (IV) oxide in a suitable solvent
such as water and acetic acid as depicted in scheme II. Conversion
of 6 to 7 can be readily effected via the aforementioned coupling
protocols.
[0061] Acyclic 1-(4-substituted-phenyl)-alkanones 10 can be
furnished from reaction of an appropriately substituted benzoic
acid or its suitable derivative such as Weinreb amide 9 with a
suitable organo lithium or Grignard reagent as illustrated in
scheme IV and this transformation can be executed aforementioned
for the preparation of ketones 2 in scheme I. Followed the same
coupling procedures as described above, the compounds described
herein 11, can be furnished by reacting ketones 10 with an
appropriate aryl nucleophilic reagent such as aryl boronic acid.
##STR12##
[0062] Also provided are pharmaceutical compositions containing one
or more compounds described herein and a pharmaceutically
acceptable carrier or excipient. Also provided are methods of
treatment which include administering to a mammal a
pharmaceutically effective amount of one or more compounds as
described as progesterone receptor modulators.
[0063] The compounds described herein may be combined with one or
more pharmaceutically acceptable carriers or excipients, for
example, solvents, diluents and the like. Suitably, the compounds
described herein are formulated for delivery to a subject by any
suitable route including, e.g., transdermal, mucosal (intranasal,
buccal, vaginal), oral, parenteral, among others. A variety of
suitable delivery devices can be utilized and include, without
limitation, tablets, caplets, capsules, gel tabs, dispersible
powders, granules, suspensions, injectable solutions, transdermal
patches, topical creams or gels, and vaginal rings, among
others.
[0064] One particularly desirable pharmaceutical composition, from
the standpoint of ease of preparation and administration, are solid
compositions, particularly tablets and hard-filled or liquid-filled
capsules. Oral administration of the compounds is most
desirable.
[0065] The compounds described herein may be administered orally as
well as by intravenous, intramuscular, or subcutaneous routes.
Solid carriers include starch, lactose, dicalcium phosphate,
microcrystalline cellulose, sucrose and kaolin. Liquid carriers
include sterile water, polyethylene glycols, non-ionic surfactants
and edible oils such as corn, peanut and sesame oils, as are
appropriate to the nature of the active ingredient and the
particular form of administration desired. Adjuvants customarily
employed in the preparation of pharmaceutical compositions may be
advantageously included, such as flavoring agents, coloring agents,
preserving agents, and antioxidants, for example, vitamin E,
ascorbic acid, butylatedhydroxytoluene (BHT) and
butylatedhydroxyanisole (BHA).
[0066] When formulated for oral delivery, the compounds described
herein can be in the form of a tablet, capsule, caplet, gel tab,
dispersible powders, granules, or suspensions. In one embodiment,
the compound can be combined with suspending agents, including
about 0.05 to about 5% of suspending agent, syrups containing, for
example, about 10 to about 50% of sugar, and/or elixirs containing,
for example, about 20 to about 50% ethanol, and the like.
[0067] The compounds described herein may also be administered
parenterally or intraperitoneally. Solutions or suspensions of the
compounds described herein as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a
surfactant such as hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid, polyethylene glycols and mixtures
thereof in oils. In one embodiment, the solutions or suspensions
containing the compounds described herein can contain about 0.05 to
about 5% suspending agent in an isotonic medium. Such
pharmaceutical preparations may contain, for example, about 25 to
about 90% of the compound in combination with the carrier.
Desirably, the pharmaceutical preparation contains about 5% and 60%
by weight of the compound.
[0068] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringe ability exits. It must be
stable under conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacterial and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol (e.g., glycerol,
propylene glycol and liquid polyethylene glycol), suitable mixtures
thereof, and vegetable oil.
[0069] The compounds described herein may also be administered via
a vaginal ring. Suitably, use of the vaginal ring is timed to cycle
to which the compound is being administered, including a 28-day
cycle. However, the vaginal ring can be inserted for longer or
shorter periods of time. See, U.S. Pat. Nos. 5,972,372; 6,126,958;
and 6,125,850, which are hereby incorporated by reference, for
formulations of the vaginal ring that can be used.
[0070] The compound can also be delivered via a transdermal patch.
Suitably, use of the patch is timed to the length of the cycle,
including a 28 day cycle. However, the patch can remain in place
for longer or shorter periods of time.
[0071] These compounds can be utilized in methods of contraception,
hormone replacement therapy, the treatment and/or prevention of
benign and malignant neoplastic disease including uterine
myometrial fibroids, endometriosis, benign prostatic hypertrophy,
carcinomas and adenocarcinomas of the endometrium, ovary, breast,
colon, prostate, pituitary, meningioma and other hormone-dependent
tumors, and the treatment of cycle-related symptoms, dysmenorrheal,
dysfunctional uterine bleeding, symptoms of premenstrual syndrome
and premenstrual dysphoric disorder, and for inducing amenorrhea.
Additional uses of the present progesterone receptor modulators
include the synchronization of estrus in livestock. In one
embodiment, the neoplastic disease is hormone-dependent.
[0072] The term "cycle-related symptoms" as used herein refers to
psychological and physical symptoms associated with a woman's
menstrual cycle arising in the luteal phase of the menstrual cycle.
It has been reported that most women report experiencing
cycle-related symptoms. The symptoms generally disappear after the
onset of menstruation, and the patient is free from symptoms during
the rest of the follicular phase. The cyclical nature of the
symptom variations is characteristic of cycle-related symptoms.
[0073] Cycle-related symptoms occur in about 95% of women who
experience some physical or mood changes with their menstrual
cycles. Only about one-third of those women experiences moderate to
severe cycle-related symptoms. Women vary in the number, type,
severity, and pattern of symptoms before menstruation. One thing
common to all the types of cyclic-related symptoms is the decrease
or elimination of the symptoms in the two weeks after menstruation
up to ovulation.
[0074] The term "cycle-related symptoms" refers to psychological
symptoms (for example, mood change, irritability, anxiety, lack of
concentration, or decrease in sexual desire) and physical symptoms
(for example, dysmenorrhea, breast tenderness, bloating, fatigue,
or food cravings) associated with a woman's menstrual cycle.
Cycle-related symptoms occur after ovulation but before menses and
usually terminate at the start of the menstrual period or shortly
thereafter. Cycle-related symptoms include, but are not limited to,
dysmenorrhea and moderate to severe cycle-related symptoms.
[0075] When utilized for these purposes, the compounds of formulas
I, II, or III can be administered in combination with other agents,
as well as in combination with each other. Such agents include,
without limitation, progestins, antiprogestins, estrogens, among
others. Progestins can include, without limitation, tanaproget,
levonorgestrel, norgestrel, desogestrel, 3-ketodesogestrel,
norethindrone, gestodene, norethindrone acetate, norgestimate,
osaterone, cyproterone acetate, trimegestone, dienogest,
drospirenone, nomegestrol, (17-deacetyl)norgestimate. Estrogens can
include, without limitation, ethinyl estradiol.
[0076] In one embodiment, a patient or subject being treated is a
mammalian subject and typically a female. Desirably, the subject is
a human. However, as used herein, a female can include non-human
mammals, e.g., cattle or livestock, horses, pigs, domestic animals,
etc.
[0077] Methods of inducing contraception, providing hormone
replacement therapy, or treating cycle-related symptoms are
provided, including administering to a mammal in need thereof a
pharmaceutically effective amount of a compound described herein.
In one embodiment, the compound of formula I utilized in the method
is of formula I, formula II, or formula III.
[0078] In another embodiment, methods of inducing contraception,
providing hormone replacement therapy, or treating cycle-related
symptoms are provided, including administering to a mammal in need
thereof a pharmaceutically effective amount of a compound of
formula I: ##STR13## wherein, R.sub.1 and R.sub.2 are,
independently, selected from among H, halogen, C.sub.1 to C.sub.6
alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl,
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; or
R.sub.1 and R.sub.2 are fused to form (a), (b), or (c): (a) a
carbon-based 3 to 6 membered saturated spirocyclic ring; (b) a
carbon-based 3 to 6 membered spirocyclic ring having in its
backbone one or more carbon-carbon double bonds; or (c) a
carbon-based 3 to 6 membered spirocyclic ring having in its
backbone 1 to 3 heteroatoms selected from among O, S, SO, SO.sub.2,
and NR.sup.C; wherein rings (a)-(c) are optionally substituted by 1
to 3 substituents selected from among F, Cl, and C.sub.1 to C.sub.3
alkyl; R.sub.3 is (i), (ii), or (iii): (i) an optionally
substituted aryl; (ii) a 5 or 6 membered heteroaryl ring containing
in its backbone 1 to 3 heteroatoms selected from among O, S, SO,
and SO.sub.2 and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; or (iii) a 5 or
6 membered heteroaryl ring containing in its backbone 1 or 3
NR.sup.C heteroatoms and substituted with 0 to 3 substituents
selected among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4
alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D;
R.sup.C is absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1
to C.sub.4 alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to
C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4
alkylamino; R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or
lower alkyl; R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are,
independently, H, F, or C.sub.1 to C.sub.3 alkyl; or a
pharmaceutically acceptable salt thereof.
[0079] In another embodiment, a method of treating or preventing
benign or malignant neoplastic disease is provided, including
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of formula I: ##STR14## wherein,
R.sub.1 and R.sub.2 are, independently, selected from among H,
halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3,
C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to
C.sub.8 cycloalkyl, aryl, substituted aryl, heteroaryl, and
substituted heteroaryl; R.sub.1 and R.sub.2 are fused to form (a),
(b), or (c): (a) a carbon-based 3 to 6 membered saturated
spirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone one or more carbon-carbon double bonds;
or (c) a carbon-based 3 to 6 membered spirocyclic ring having in
its backbone 1 to 3 heteroatoms selected from among O, S, SO,
SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are optionally
substituted by 1 to 3 substituents selected from among F, Cl, and
C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i), (ii), or (iii): (i) a
benzene ring of the structure: ##STR15## wherein, X is selected
from among halogen, CN, C.sub.1 to C.sub.4 alkyl, substituted
C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.6 alkenyl, substituted
C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, substituted
C.sub.2 to C.sub.6 alkynyl, C.sub.1 to C.sub.4 alkoxy, substituted
C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 thioalkoxy,
substituted C.sub.1 to C.sub.4 thioalkoxy, amino, C.sub.1 to
C.sub.4 alkylamino, substituted C.sub.1 to C.sub.4 alkylamino,
NO.sub.2, C.sub.1 to C.sub.3 perfluoroalkyl, 5 or 6 membered
heteroaryl ring containing in its backbone 1 to 3 heteroatoms,
COR.sup.C, OCOR.sup.C, or NR.sup.DCOR.sup.C; Y and Z are
independent substituents selected from among H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkyl, and
C.sub.1 to C.sub.4 thioalkoxy; (ii) a 5 or 6 membered heteroaryl
ring containing in its backbone 1 to 3 heteroatoms selected from
among O, S, SO, and SO.sub.2 and substituted with 0 to 3
substituents selected from among H, halogen, CN, NO.sub.2, OH,
amino, C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1
to C.sub.4 alkylamino, C.dbd.NOR.sup.C, COR.sup.D, and
NR.sup.CCOR.sup.D; or (iii) a 5 or 6 membered heteroaryl ring
containing in its backbone 1 or 3 NR.sup.C heteroatoms and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is absent, H, C.sub.1 to
C.sub.4 alkyl, substituted C.sub.1 to C.sub.4 alkyl, CN, or
COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl, C.sub.1 to
C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino; R.sub.4 is H,
halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.5,
R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, or C.sub.1
to C.sub.3 alkyl; or a pharmaceutically acceptable salt
thereof.
[0080] Also provided is a method of inducing contraception,
providing hormone replacement therapy, treating cycle-related
symptoms, or treating or preventing benign or malignant neoplastic
disease, including administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of formula II:
##STR16## wherein, R.sub.1 and R.sub.2 are, independently, selected
from among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; or R.sub.1 and R.sub.2 are
fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered
saturated spirocyclic ring; (b) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone one or more carbon-carbon
double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from among
F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i), (ii), or
(iii): (i) an optionally substituted benzene ring; (ii) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5 and R.sub.6 are, independently, H, F, or C.sub.1 to C.sub.3
alkyl; or a pharmaceutically acceptable salt thereof.
[0081] In one embodiment, when utilized in the method, the compound
is
1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbon-
itrile;
5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrro-
le-2-carbonitrile;
1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile;
4-acetyl-1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbon-
itrile; 5-(5-chlorothien-2-yl)-3,3-dimethylindan-1-one;
3,3-dimethyl-5-thien-3-yl-indan-1-one;
5-(3-acetylphenyl)indan-1-one;
5-(4-chlorophenyl)-3,3-dimethylindan-1-one;
4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile;
3-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile;
3,3-dimethyl-5-(4-methylphenyl)indan-1-one;
5-(4-methoxyphenyl)-3,3-dimethylindan-1-one;
5-(3-chlorophenyl)-3,3-dimethylindan-1-one;
3,3-dimethyl-5-(3-methylphenyl)indan-1-one;
5-(3-methoxyphenyl)-3,3-dimethylindan-1-one;
5-(3,5-dichlorophenyl)-3,3-dimethylindan-1-one;
5-(2-chlorophenyl)-3,3-dimethylindan-1-one;
5-(3,4-dichlorophenyl)-3,3-dimethylindan-1-one;
5-(2,3-dichlorophenyl)-3,3-dimethylindan-1-one;
5-(2,5-dichlorophenyl)-3,3-dimethylindan-1-one;
5-(2,4-dichlorophenyl)-3,3-dimethylindan-1-one;
3,3-dimethyl-5-phenylindan-1-one;
5-(3-chloro-4-fluorophenyl)-3,3-dimethylindan-1-one;
3,3-dimethyl-5-[3-(trifluoromethyl)phenyl]indan-1-one;
3,3-dimethyl-5-[4-(trifluoromethyl)phenyl]indan-1-one;
5-[4-(dimethylamino)phenyl]-3,3-dimethylindan-1-one;
5-[3-(dimethylamino)phenyl]-3,3-dimethylindan-1-one;
5-(3,4-difluorophenyl)-3,3-dimethylindan-1-one;
5-[3-(ethylsulfonyl)phenyl]-3,3-dimethylindan-1-one;
3-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-5-fluorobenzonitrile;
5-(4-acetylphenyl)-3,3-dimethylindan-1-one;
5-(3-acetylphenyl)-3,3-dimethylindan-1-one;
5-(2-acetylphenyl)-3,3-dimethylindan-1-one;
4-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile;
3-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile; and
2-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile.
[0082] Also provided is a method of providing hormone replacement
therapy or treating cycle-related symptoms, including administering
to a mammal in need thereof a pharmaceutically effective amount of
a compound of formula III: ##STR17## wherein, R.sub.2 is selected
from among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; R.sub.3 is aryl,
substituted aryl, heteroaryl, or substituted heteroaryl; R.sub.4 is
H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.9 is H,
F, or C.sub.1 to C.sub.3 alkyl; or a pharmaceutically acceptable
salt thereof.
[0083] Methods of inducing contraception or treating or preventing
benign or malignant neoplastic disease, are also provided and
include administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of formula III:
##STR18## wherein, R.sub.2 is selected from among H, halogen,
C.sub.1 to C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to
C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8
cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted
heteroaryl; R.sub.3 is heteroaryl or substituted heteroaryl;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.9 is H, F, or C.sub.1 to C.sub.3 alkyl; or a pharmaceutically
acceptable salt thereof.
[0084] In one embodiment, when utilized in the methods described
herein, the compound of formula III is selected from among
5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile;
1-methyl-5-(4-propionylphenyl)-1H-pyrrole-2-carbonitrile;
1-methyl-5-[4-(thien-2-yl-carbonyl)phenyl]-1H-pyrrole-2-carbonitrile;
5-(4-benzoylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile; and
5-[4-(2,2-dimethylpropanoyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile.
[0085] In another embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.1 and
R.sub.2 are, independently, H or C.sub.1 to C.sub.6 alkyl; R.sub.3
is a 5 membered heteroaryl ring containing in its backbone 1
NR.sup.C heteroatom and substituted with 0 to 3 substituents
selected from among H, CN, or C.sub.1 to C.sub.3 alkyl; R.sub.4,
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are H.
[0086] In a further embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is
1-methyl-2-cyanopyrrole, 1-methyl-2-cyano-4-acetylpyrrole or
2-chlorothiophene.
[0087] In yet another embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.1 is
heteroaryl or aryl.
[0088] In still a further embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is
4-cyanophenyl, 3-cyanophenyl, 3-acetylphenyl, 3-chlorophenyl,
3-chloro-4-fluorophenyl, 3-trifluoromethylphenyl, 3-fluorophenyl,
3,4-difluorophenyl, 3-methoxyphenyl, 3-methylphenyl,
4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl,
3,5-dichlorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl,
2,3-dichlorophenyl, 2,5-dichlorophenyl, 2,4-dichlorophenyl, phenyl,
4-trifluoromethylphenyl, 4-diaminophenyl, 3-diaminophenyl,
3-ethylsulfonylphenyl, 3-fluoro-5-cyanophenyl, 4-acetylphenyl,
2-acetylphenyl, or 2-cyanophenyl.
[0089] In another embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is of
the structure: ##STR19## wherein, U is O, S, or NR.sup.C; R.sup.6
is H, C.sub.1 to C.sub.3 alkyl, or COR.sup.D; R.sup.D is C.sub.1 to
C.sub.4 alkyl; X' is selected from among halogen, CN, NO.sub.2,
C.sub.1 to C.sub.3 alkyl, and C.sub.1 to C.sub.3 alkoxy; and Y' is
selected from among H and C.sub.1 to C.sub.4 alkyl.
[0090] In still another embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is of
the structure: ##STR20## X.sup.1 is halogen, CN, C.sub.1 to C.sub.3
alkoxy, or NO.sub.2.
[0091] In yet a further embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is a
benzene ring containing 0 to 3 substituents selected from among
halogen, CN, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to
C.sub.4 alkyl, C.sub.2 to C.sub.6 alkenyl, substituted C.sub.2 to
C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, substituted C.sub.2 to
C.sub.6 alkynyl, C.sub.1 to C.sub.3 alkoxy, substituted C.sub.1 to
C.sub.3 alkoxy, C.sub.1 to C.sub.3 thioalkoxy, substituted C.sub.1
to C.sub.3 thioalkoxy, amino, C.sub.1 to C.sub.3 alkylamino,
substituted C.sub.1 to C.sub.3 alkylamino, NO.sub.2, C.sub.1 to
C.sub.3 perfluoroalkyl, 5 or 6 membered heteroaryl ring containing
in its backbone 1 to 3 heteroatoms, COR.sup.C, OCOR.sup.C, and
NR.sup.DCOR.sup.C;
[0092] In another embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is a
benzene ring of the structure: ##STR21## wherein, X is selected
from among halogen, CN, C.sub.1 to C.sub.4 alkyl, substituted
C.sub.1 to C.sub.4 alkyl, C.sub.2 to C.sub.6 alkenyl, substituted
C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6 alkynyl, substituted
C.sub.2 to C.sub.6 alkynyl, C.sub.1 to C.sub.4 alkoxy, substituted
C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 thioalkoxy,
substituted C.sub.1 to C.sub.4 thioalkoxy, amino, C.sub.1 to
C.sub.4 alkylamino, substituted C.sub.1 to C.sub.4 alkylamino,
NO.sub.2, C.sub.1 to C.sub.3 perfluoroalkyl, 5 or 6 membered
heteroaryl ring containing in its backbone 1 to 3 heteroatoms,
COR.sup.C, OCOR.sup.C, or NR.sup.DCOR.sup.C; Y and Z are
independent substituents selected from among H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkyl, and
C.sub.1 to C.sub.4 thioalkoxy.
[0093] In yet a further embodiment, when utilized in the methods
described herein, the compounds include those wherein R.sub.3 is of
the structure: ##STR22## X is selected from among halogen, CN,
C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.3 alkyl, NO.sub.2,
C.sub.1 to C.sub.3 perfluoroalkyl, 5 membered heteroaryl ring
containing in its backbone 1 to 3 heteroatoms, and C.sub.1 to
C.sub.3 thioalkoxy; Y is selected from among H, halogen, CN,
NO.sub.2, C.sub.1 to C.sub.3 alkoxy, C.sub.1 to C.sub.4 alkyl, and
C.sub.1 to C.sub.3 thioalkoxy.
[0094] The effective dosage of a compound described herein may vary
depending on the particular compound employed, the mode of
administration and the severity of the condition being treated.
However, in general, satisfactory results are obtained when the
compounds are administered at a daily dosage of about 0.5 to about
500 mg/kg of animal body weight, about 1 to about 400 mg/kg, about
5 to about 300 mg/kg, about 10 to about 250 mg/kg, about 50 to
about 200 mg/kg, or about 100 to 150 mg/kg. For most large mammals,
the total daily dosage is from about 1 to 100 mg. In one
embodiment, the total daily dosage is from about 2 to 80 mg. This
dosage regimen may be adjusted to provide the optimal therapeutic
response. For example, several divided doses may be administered
daily or the dose may be proportionally reduced as indicated by the
exigencies of the therapeutic situation.
[0095] As previously noted, the compounds described herein may be
administered via a vaginal ring. Suitably, use of the vaginal ring
is timed to the 28 day cycle. In one embodiment, the ring is
inserted into the vagina, and it remains in place for 3 weeks.
During the fourth week, the vaginal ring is removed and menses
occurs. The following week a new ring is inserted to be worn
another 3 weeks until it is time for the next period. In another
embodiment, the vaginal ring is inserted weekly, and is replaced
for 3 consecutive weeks. Then, following 1 week without the ring, a
new ring is inserted to begin a new regimen. In yet another
embodiment, the vaginal ring is inserted for longer or shorter
periods of time.
[0096] Further, the previously mentioned patch is applied via a
suitable adhesive on the skin, where it remains in place for 1 week
and is replaced weekly for a total period of 3 weeks. During the
fourth week, no patch is applied and menses occurs. The following
week a new patch is applied to be worn to begin a new regimen. In
yet another embodiment, the patch remains in place for longer, or
shorter periods of time.
[0097] When used for contraception, the method typically includes
delivering a daily dosage unit containing a compound described
herein for 28 consecutive days to a female of child-bearing age.
Desirably, the method includes delivering the compound over a
period of 21 to 27 consecutive days followed by 1 to 7 consecutive
days in which no effective amount or no amount of the compound is
delivered. Optionally, the period of 1 to 7 days in which no
effective amount of the compound is delivered to the subject can
involve delivery of a second phase of daily dosage units of 1 to 7
days of a pharmaceutically acceptable placebo. Alternatively,
during this "placebo period", no placebo is administered.
[0098] In another embodiment, the method includes delivering a
compound described herein for 21 consecutive days followed by 7
days in which no effective amount of the compound is delivered.
Optionally, during these 7 days, a second phase of 7 daily dosage
units of an orally and pharmaceutically acceptable placebo can be
delivered. The compound may optionally be administered in
combination with a progestin, antiprogestin, estrogen, or
combination thereof.
[0099] In a further embodiment, the method includes delivering a
compound described herein for 23 consecutive days followed by 5
days in which no effective amount of the compound is delivered.
Optionally, during these 5 days, a second phase of 5 daily dosage
units of an orally and pharmaceutically acceptable placebo can be
delivered. The compound may optionally be administered in
combination with a progestin, antiprogestin, estrogen, or
combination thereof.
[0100] In yet another embodiment, the method includes delivering a
compound described herein for 25 consecutive days followed by 3
days in which no effective amount of the compound is delivered.
Optionally, during these 3 days, a second phase of 3 daily dosage
units of an orally and pharmaceutically acceptable placebo can be
delivered. The compound described herein may optionally be
administered in combination with a progestin, antiprogestin,
estrogen, or combination thereof.
[0101] In still a further embodiment, the method includes
delivering a compound described herein for 27 consecutive days
followed by 1 day in which no effective amount of the compound is
delivered. Optionally, a second phase of 1 daily dosage unit of an
orally and pharmaceutically acceptable placebo can be delivered.
The compound may optionally be administered in combination with a
progestin, antiprogestin, estrogen, or combination thereof.
[0102] In another embodiment, a method of contraception includes
administering to a female of child bearing age for 28 consecutive
days: (a) a first phase of from 14 to 24 daily dosage units of a
progestational agent equal in progestational activity to about 35
to about 100 .mu.g levonorgestrel; (b) a second phase of from 1 to
11 daily dosage units, at a daily dosage of from about 2 to 50 mg,
of a compound of formula I, formula II, formula III, or combination
thereof; and (c) optionally, a third phase of daily dosage units of
an orally and pharmaceutically acceptable placebo for the remaining
days of the 28 consecutive days in which no antiprogestin,
progestin or estrogen is administered; wherein the total daily
dosage units of the first, second and third phases equals 28.
[0103] In yet a further embodiment, a method of contraception
includes administering to a female of child bearing age for 28
consecutive days: (a) a first phase of from 14 to 24 daily dosage
units of a compound of formula I, formula II, formula III, or
combination thereof; (b) a second phase of from 1 to 11 daily
dosage units of an antiprogestin; and (c) optionally, a third phase
of daily dosage units of an orally and pharmaceutically acceptable
placebo for the remaining days of the 28 consecutive days in which
no antiprogestin, progestin or estrogen is administered; wherein
the total daily dosage units of the first, second and third phases
equals 28.
[0104] In yet another embodiment, a method of contraception is
provided which includes administering to a female of child bearing
age for 28 consecutive days: (a) a first phase of from 14 to 24
daily dosage units of a progestational agent equal in
progestational activity to about 35 to about 100 .mu.g
levonorgestrel; (b) a second phase of from 1 to 11 daily dosage
units, at a daily dosage of from about 2 to 50 mg, of a compound of
(i), (ii), or (iii): (i) a compound of formula I: ##STR23##
wherein, R.sub.1 and R.sub.2 are, independently, selected from
among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; provided that both R.sub.1
and R.sub.2 are not H; or R.sub.1 and R.sub.2 are fused to form
(a), (b), or (c): (a) a carbon-based 3 to 6 membered saturated
spirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone one or more carbon-carbon double bonds;
or (c) a carbon-based 3 to 6 membered spirocyclic ring having in
its backbone 1 to 3 heteroatoms selected from among O, S, SO,
SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are optionally
substituted by 1 to 3 substituents selected from among F, Cl, and
C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i) or (ii): (i) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, or
C.sub.1 to C.sub.3 alkyl; (ii) a compound of formula II: ##STR24##
wherein, R.sub.1 and R.sub.2 are, independently, selected from
among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; or R.sub.1 and R.sub.2 are
fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered
saturated spirocyclic ring; (b) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone one or more carbon-carbon
double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from among
F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i), (ii), or
(iii): (i) an optionally substituted benzene ring; (ii) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5 and R.sub.6 are, independently, H, F, or C.sub.1 to C.sub.3
alkyl; or (iii) a compound of formula III: ##STR25## wherein,
R.sub.2 is selected from among H, halogen, C.sub.1 to C.sub.6
alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl,
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; R.sub.3
is heteroaryl or substituted heteroaryl; R.sub.4 is H, halogen, CN,
OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1
to C.sub.3 alkyl; a pharmaceutically acceptable salt thereof; and
(c) optionally, a third phase of daily dosage units of an orally
and pharmaceutically acceptable placebo for the remaining days of
the 28 consecutive days in which no antiprogestin, progestin or
estrogen is administered; wherein the total daily dosage units of
the first, second and third phases equals 28.
[0105] In a further embodiment, a method of contraception is
provided which includes administering to a female of child bearing
age for 28 consecutive days: (a) a first phase of from 14 to 24
daily dosage units of a compound of formula (I), (ii), or (iii):
(i) a compound of formula I: ##STR26## wherein, R.sub.1 and R.sub.2
are, independently, selected from among H, halogen, C.sub.1 to
C.sub.6 alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6
alkenyl, C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl,
aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
provided that both R.sub.1 and R.sub.2 are not H; or R.sub.1 and
R.sub.2 are fused to form (a), (b), or (c): (a) a carbon-based 3 to
6 membered saturated spirocyclic ring; (b) a carbon-based 3 to 6
membered spirocyclic ring having in its backbone one or more
carbon-carbon double bonds; or (c) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone 1 to 3 heteroatoms selected
from among O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c)
are optionally substituted by 1 to 3 substituents selected from
among F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i) or (ii):
(i) a 5 or 6 membered heteroaryl ring containing in its backbone 1
to 3 heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, or
C.sub.1 to C.sub.3 alkyl; or (ii) a compound of formula II:
##STR27## wherein, R.sub.1 and R.sub.2 are, independently, selected
from among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; or R.sub.1 and R.sub.2 are
fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered
saturated spirocyclic ring; (b) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone one or more carbon-carbon
double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from among
F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i), (ii), or
(iii): (i) an optionally substituted benzene ring; (ii) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5 and R.sub.6 are, independently, H, F, or C.sub.1 to C.sub.3
alkyl; or (iii) a compound of formula III: ##STR28## wherein,
R.sub.2 is selected from among H, halogen, C.sub.1 to C.sub.6
alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl,
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; R.sub.3
is heteroaryl or substituted heteroaryl; R.sub.4 is H, halogen, CN,
OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1
to C.sub.3 alkyl; a pharmaceutically acceptable salt thereof, (b) a
second phase of from 1 to 11 daily dosage units, at a daily dosage
of from about 2 to 50 mg, of a progestational agent equal in
progestational activity to about 35 to about 100 .mu.g
levonorgestrel; and (c) optionally, a third phase of daily dosage
units of an orally and pharmaceutically acceptable placebo for the
remaining days of the 28 consecutive days in which no
antiprogestin, progestin or estrogen is administered; wherein the
total daily dosage units of the first, second and third phases
equals 28.
[0106] Also included are kits or packages of pharmaceutical
formulations designed for use in the regimens described herein.
Suitably, the kits contain one or more PR antagonist compounds as
described herein.
[0107] Advantageously, for use in the kits, the compound described
herein is formulated for the desired delivery vehicle and route.
For example, the compound can be formulated for oral delivery,
parenteral delivery, vaginal ring, transdermal delivery, or mucosal
delivery, as discussed in detail above. The kit is preferably a
pack (e.g. a blister pack) containing daily doses arranged in the
order in which they are to be taken.
[0108] In each of the regimens and kits described herein, it is
preferred that the daily dosage of each pharmaceutically active
component of the regimen remain fixed in each particular phase in
which it is administered. It is also understood that the daily dose
units described are to be administered in the order described, with
the first phase followed in order by the optional phases, including
any second and third phases. To help facilitate compliance with
each regimen, it is also preferred that the kits contain the
placebo described for the final days of the cycle. It is further
preferred that each package or kit contain a pharmaceutically
acceptable package having indicators for each day of the 28-day
cycle, such as a labeled blister package, dial dispenser, or other
packages known in the art.
[0109] These dosage regimens may be adjusted to provide the optimal
therapeutic response. For example, several divided doses of each
component may be administered daily or the dose may be
proportionally increased or reduced as indicated by the exigencies
of the therapeutic situation. In the descriptions herein, reference
to a daily dosage unit may also include divided units which are
administered over the course of each day of the cycle
contemplated.
[0110] In one embodiment, the kit is designed for daily oral
administration over a 28-day cycle, desirably for one oral
administration per day, and organized so as to indicate a single
oral formulation or combination of oral formulations to be taken on
each day of the 28-day cycle. Desirably each kit will include oral
tablets to be taken on each the days specified; desirably one oral
tablet will contain each of the combined daily dosages indicated.
For example, a kit can contain 21 to 27 daily dosage units of an
effective amount of the compound described herein and, optionally,
1 to 7 daily dosage units of a placebo and other appropriate
components including, e.g., instructions for use.
[0111] In another embodiment, the kit is designed for weekly or
monthly administration via a vaginal ring over a 28-day cycle.
Suitably, such a kit contains individual packaging for each of the
vaginal rings, i.e. one to three, required for a monthly cycle and
other appropriate components, including, e.g., instructions for
use.
[0112] In a further embodiment, the kit is designed for weekly or
monthly administration via a transdermal patch over a 28-day cycle.
Suitably, such a kit contains individual packaging for each of the
patches, i.e. one to three, required for a monthly cycle and other
appropriate components including, e.g., instructions for use.
[0113] In still another embodiment, the kit is designed for
parenteral delivery of a compound described herein. Such a kit is
typically designed for delivery at home and may include needles,
syringes, and other appropriate packaging and instructions for
use.
[0114] In yet another embodiment, the kit contains a compound
described herein in a gel or cream formulation. Optionally, the kit
can include appropriate packaging such as a tube or other
container, an applicator, and/or instructions for use.
[0115] In a further embodiment, the kit includes (a) a first phase
of from 14 to 21 daily dosage units of a progestational agent equal
in progestational activity to about 35 to about 150 .mu.g
levonorgestrel; (b) a second phase of from 1 to 11 daily dosage
units of a compound of formula I or II, each daily dosage unit
containing said compound at a daily dosage of from about 2 to 50
mg, wherein said compound is (i), (ii), or (iii): (i) a compound of
formula I: ##STR29## wherein, R.sub.1 and R.sub.2 are,
independently, selected from among H, halogen, C.sub.1 to C.sub.6
alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl,
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; provided
that both R.sub.1 and R.sub.2 are not H; or R.sub.1 and R.sub.2 are
fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered
saturated spirocyclic ring; (b) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone one or more carbon-carbon
double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from among
F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i) or (ii): (i) a
5 or 6 membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, or
C.sub.1 to C.sub.3 alkyl; (ii) a compound of formula II: ##STR30##
wherein, R.sub.1 and R.sub.2 are, independently, selected from
among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; or R.sub.1 and R.sub.2 are
fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered
saturated spirocyclic ring; (b) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone one or more carbon-carbon
double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from among
F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i), (ii), or
(iii): (i) an optionally substituted benzene ring; (ii) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5 and R.sub.6 are, independently, H, F, or C.sub.1 to C.sub.3
alkyl; or (iii) a compound of formula III: ##STR31## wherein,
R.sub.2 is selected from among H, halogen, C.sub.1 to C.sub.6
alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl,
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; R.sub.3
is heteroaryl or substituted heteroaryl; R.sub.4 is H, halogen, CN,
OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1
to C.sub.3 alkyl; or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable salt thereof; and (c) a third
phase of daily dosage units of an orally and pharmaceutically
acceptable placebo; wherein the total number of the daily dosage
units in the first phase, second phase and third phase equals
28.
[0116] In yet another embodiment, the kit includes (a) a first
phase of from 14 to 21 daily dosage units of a compound of formula
(I), (ii), or (iii): (i) a compound of formula I: ##STR32##
wherein, R.sub.1 and R.sub.2 are, independently, selected from
among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; provided that both R.sub.1
and R.sub.2 are not H; or R.sub.1 and R.sub.2 are fused to form
(a), (b), or (c): (a) a carbon-based 3 to 6 membered saturated
spirocyclic ring; (b) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone one or more carbon-carbon double bonds;
or (c) a carbon-based 3 to 6 membered spirocyclic ring having in
its backbone 1 to 3 heteroatoms selected from among O, S, SO,
SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are optionally
substituted by 1 to 3 substituents selected from among F, Cl, and
C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i) or (ii): (i) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are, independently, H, F, or
C.sub.1 to C.sub.3 alkyl; (ii) a compound of formula II: ##STR33##
wherein, R.sub.1 and R.sub.2 are, independently, selected from
among H, halogen, C.sub.1 to C.sub.6 alkyl, CF.sub.3,
CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl, C.sub.2 to C.sub.6
alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl, substituted aryl,
heteroaryl, and substituted heteroaryl; or R.sub.1 and R.sub.2 are
fused to form (a), (b), or (c): (a) a carbon-based 3 to 6 membered
saturated spirocyclic ring; (b) a carbon-based 3 to 6 membered
spirocyclic ring having in its backbone one or more carbon-carbon
double bonds; or (c) a carbon-based 3 to 6 membered spirocyclic
ring having in its backbone 1 to 3 heteroatoms selected from among
O, S, SO, SO.sub.2, and NR.sup.C; wherein rings (a)-(c) are
optionally substituted by 1 to 3 substituents selected from among
F, Cl, and C.sub.1 to C.sub.3 alkyl; R.sub.3 is (i), (ii), or
(iii): (i) an optionally substituted benzene ring; (ii) a 5 or 6
membered heteroaryl ring containing in its backbone 1 to 3
heteroatoms selected from among O, S, SO, and SO.sub.2 and
substituted with 0 to 3 substituents selected from among H,
halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4 alkyl, C.sub.1
to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino, C.dbd.NOR.sup.C,
COR.sup.D, and NR.sup.CCOR.sup.D; or (ii) a 5 or 6 membered
heteroaryl ring containing in its backbone 1 or 3 NR.sup.C
heteroatoms and substituted with 0 to 3 substituents selected from
among H, halogen, CN, NO.sub.2, OH, amino, C.sub.1 to C.sub.4
alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 alkylamino,
C.dbd.NOR.sup.C, COR.sup.D, and NR.sup.CCOR.sup.D; R.sup.C is
absent, H, C.sub.1 to C.sub.4 alkyl, substituted C.sub.1 to C.sub.4
alkyl, CN, or COR.sup.D; R.sup.D is H, C.sub.1 to C.sub.4 alkyl,
C.sub.1 to C.sub.4 alkoxy, or C.sub.1 to C.sub.4 alkylamino;
R.sub.4 is H, halogen, CN, OH, NO.sub.2, alkoxy, or lower alkyl;
R.sub.5 and R.sub.6 are, independently, H, F, or C.sub.1 to C.sub.3
alkyl; or (iii) a compound of formula III: ##STR34## wherein,
R.sub.2 is selected from among H, halogen, C.sub.1 to C.sub.6
alkyl, CF.sub.3, CF.sub.2CF.sub.3, C.sub.2 to C.sub.6 alkenyl,
C.sub.2 to C.sub.6 alkynyl, C.sub.3 to C.sub.8 cycloalkyl, aryl,
substituted aryl, heteroaryl, and substituted heteroaryl; R.sub.3
is heteroaryl or substituted heteroaryl; R.sub.4 is H, halogen, CN,
OH, NO.sub.2, alkoxy, or lower alkyl; R.sub.9 is H, F, or C.sub.1
to C.sub.3 alkyl; or a pharmaceutically acceptable salt thereof;
(b) a second phase of from 1 to 11 daily dosage units of a
progestational agent equal in progestational activity to about 35
to about 150 .mu.g levonorgestrel, each daily dosage unit
containing said progestational agent at a daily dosage of from
about 2 to 50 mg; and (c) a third phase of daily dosage units of an
orally and pharmaceutically acceptable placebo; wherein the total
number of the daily dosage units in the first phase, second phase
and third phase equals 28.
[0117] The following examples are illustrative only and are not
intended to be a limitation.
EXAMPLES
Example 1
5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile
[0118] To a stirred solution of 1-methyl-2-cyanopyrrole (1.6 g, 15
mmol) and triisopropyl borate (7.0 mL, 30 mmol) in tetrahydrofuran
(THF-45 mL) at 0.degree. C. was added lithium diisopropylamide
(LDA-2.0 M in heptane/THF/ethylbenzene, 13.3 mL, 26.6 mmol) in a
dropwise fashion over 45 minutes. The resulting solution was
stirred at 0.degree. C. for 1 hour. To the solution was added
1-(4-bromophenyl)-ethanone (1.0 g, 5 mmol) dissolved in glyme (45
mL), sodium carbonate (1.59 g, 15 mmol) dissolved in water (9 mL),
and tetrakis(triphenylphosphine) palladium (0) (0.28 g, 0.25 mmol).
The resulting solution was heated to reflux for 1.5 hours. The
solution was cooled to room temperature and partitioned between a
saturated aqueous ammonium chloride solution (50 mL) and ethyl
acetate (80 mL). The organic layer was separated, dried over
magnesium sulfate, filtered, and concentrated. The residue was
purified on a silica gel column (20% ethyl acetate in hexane) and
triturated with ether to give
5-(4-acetylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile as a yellow
solid (0.62 g, 55%). MS (ES) m/z 225.1; HRMS: calcd for
C.sub.14H.sub.12N.sub.2O+H.sup.+, 225.1022; found (ESI,
[M+H].sup.+), 225.1039.
Example 2
1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carboni-
trile
[0119] To a mixture of sodium chloride (1.23 g, 21.0 mmol) and
aluminum chloride (5.0 g, 38.2 mmol) at 130.degree. C. was added
1-(4-bromophenyl)-4-chlorobutan-1-one (1.0 g, 3.82 mmol) and the
resulting mixture was heated to 180.degree. C. for 20 minutes. The
mixture was allowed to cool to room temperature and poured to a
cold 1N aqueous HCl solution (300 mL). The mixture was extracted
several times with dichloromethane. The combined organic layers
were separated, dried over magnesium sulfate, filtered and
concentrated to give 5-bromo-3-methyl-indan-1-one (0.77 g, 89%).
The title compound,
1-methyl-5-(3-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbon-
itrile as an orange solid (0.65 g, 76%), was prepared from
5-bromo-3-methyl-indan-1-one and 1-methyl-2-cyanopyrrole according
to the same coupling procedure as described in example 1. MS (ES)
m/z 251.2; Anal. Calcd for C.sub.16H.sub.14N.sub.2O: C, 76.78; H,
5.64; N, 11.19. Found: C, 76.49; H, 5.49; N, 11.10. HRMS: calcd for
C.sub.16H.sub.14N.sub.2O+H.sup.+, 251.1179; found (ESI,
[M+H].sup.+), 251.1179.
Example 3
5-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-1-methyl-1H-pyrrole-2-car-
bonitrile
[0120] To a stirred solution of
1-(4-hydroxyphenyl)-3-methylbut-2-en-1-one (1.0 g, 5.67 mmol) in
dichlorobenzene (50 mL) was added aluminum chloride (1.97 g, 14.74
mmol). The mixture was heated to 150.degree. C. for 4 hours. After
cooled to room temperature, the reaction mixture was poured over
ice and extracted with dichloromethane (3.times.80 mL). The organic
layers were combined, dried over magnesium sulfate, filtered, and
concentrated. The residue was purified on a silica gel column (20%
ethyl acetate in hexane) to give 5-hydroxy-3,3-dimethylindan-1-one
as a tan solid (0.32 g, 32%). MS m/z 177.
[0121] A solution of 5-hydroxy-3,3-dimethylindan-1-one in anhydrous
pyridine at 0.degree. C. was treated with triflic anhydride under
an atmosphere of nitrogen. After completion of reaction indicated
by thin layer chromatography, the reaction solution was poured onto
a mixture of ice and 6N aqueous HCl solution and extracted with
diethyl ether. The organic layers were combined, washed with
saturated aqueous sodium bicarbonate solution, dried (MgSO.sub.4),
and concentrated to afford trifluoro-methanesulfonic acid
3,3-dimethyl-1-oxo-indan-5-yl ester that was used in the next step
without further purification.
[0122] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 1-methyl-2-cyanopyrrole according to the same coupling
procedure as described in example 1. MS (ES) m/z 265.1. HRMS: calcd
for C.sub.17H.sub.16N.sub.2O+H.sup.+, 265.13354; found (ESI,
[M+H].sup.+), 265.1332.
Example 4
1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile
[0123] The title compound was prepared from 5-bromo-1-indanone and
1-methyl-2-cyanopyrrole according to the coupling procedure as
described in example 1. MS (ESI) m/z 237; HRMS: calcd for
C.sub.15H.sub.12N.sub.2O+H.sup.+, 237.1022; found (ESI,
[M+H].sup.+), 237.1003; Anal. Calcd for C.sub.15H.sub.12N.sub.2O:
C, 76.25; H, 5.12; N, 11.86. Found: C, 75.99; H, 4.92; N,
11.80.
Example 5
4-acetyl-1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carboni-
trile
[0124] To a stirred solution of
1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile
(0.25 g, 1.0 mmol) in acetonitrile (25 mL) was added samarium
iodide (0.5 g, 1.2 mmol) and acetyl chloride (1.75 mL, 24.6 mmol).
The reaction mixture was heated in microwave to 120.degree. C. for
10 minutes. The mixture was treated with a 10% aqueous HCl solution
(50 mL) and extracted with ethyl acetate (3.times.50 mL). The
organic layers were combined, dried over magnesium sulfate,
filtered, and concentrated. The residue was purified on a silica
gel column (30% ethyl acetate in hexane) to give
4-acetyl-1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbon-
itrile as a tan solid (0.025 g, 8%). MS (ESI) m/z 279; HRMS: calcd
for C.sub.17H.sub.14N.sub.2O.sub.2+H.sup.+, 279.1128; found (ESI,
[M+H].sup.+), 279.1125.
Example 6
4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile
[0125] To a stirred solution of 5-bromo-1-indanone (0.40 g, 1.90
mmol) and 4-cyanophenyl boronic acid (0.36 g, 2.47 mmol) in glyme
(17 mL) was added a solution of sodium carbonate (0.60 g, 5.70
mmol) in water (3 mL) and tetrakis(triphenylphosphine) palladium
(0) (0.11 g, 0.10 mmol). The resulting solution was heated to
reflux for 2.5 hours. The solution was cooled to room temperature
and partitioned between a saturated aqueous ammonium chloride
solution (50 mL) and ethyl acetate (80 mL). The organic layer was
dried over magnesium sulfate, filtered, and concentrated. The
residue was purified on a silica gel column (20% ethyl acetate in
hexane) and triturated with ether to give
4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile as a white solid
(0.35 g, 79%). MS (ESI) m/z 234.0936; HRMS: calcd for
C.sub.16H.sub.11NO+H.sup.+, 234.09134; found (ESI, [M+H].sup.+),
234.0936.
Example 7
3-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile
[0126] The title compound was prepared from 5-bromo-1-indanone and
3-cyanophenyl boronic acid according to the coupling procedure as
described in example 6. MS m/z 234; HRMS: calcd for C.sub.16H,
NO+H.sup.+, 234.09134; found (ESI, [M+H].sup.+), 234.0905.
Example 8
5-(3-acetylphenyl)indan-1-one
[0127] The title compound was prepared from 3-acetylphenyl boronic
acid and 5-bromo-1-indanone according to the coupling procedure as
described in example 6. MS (ESI) m/z 251; HRMS: calcd for
C.sub.17H.sub.14O.sub.2+H.sup.+, 251.10666; found (ESI,
[M+H].sup.+), 251.1077.
Example 9
1-methyl-5-(4-propionylphenyl)-1H-pyrrole-2-carbonitrile
[0128] The title compound was prepared from
1-(4-bromophenyl)-propan-1-one and 1-methyl-2-cyanopyrrole
according to the coupling procedure as described in example 1. MS
(ES) m/z 239.2; HRMS: calcd for C.sub.15H.sub.14N.sub.2O+H.sup.+,
239.1179; found (ESI, [M+H].sup.+), 239.1193.
Example 10
1-methyl-5-[4-(thien-2-ylcarbonyl)phenyl]-1H-pyrrole-2-carbonitrile
[0129] To a stirred solution of 4-bromobenzoyl chloride (20.0 g,
91.1 mmol) in dichloromethane (300 mL) at -78.degree. C. was added
triethylamine (28.0 mL, 200.0 mmol), and O,N-dimethylhydroxylamine
hydrochloride (9.33 g, 95.6 mmol). The resulting solution was
allowed to warm to room temperature, stirred for 1.5 hours, and
then concentrated. The residue was triturated in acetone and the
resulting solid was dissolved in ethyl acetate washed with water
and brine. The organic layer was dried over magnesium sulfate,
filtered, and concentrated to give
4-bromo-N-methoxy-N-methylbenzamide (18.6 g, 84%). To a solution of
4-bromo-N-methoxy-N-methylbenzamide (3.0 g, 12.29 mmol) in THF (30
mL) at 0.degree. C. under nitrogen was added 2-thienyllithium (1.0
M in THF, 15 mL, 15 mmol) slowly over 10 minutes. The solution was
stirred at 0.degree. C. for 1 hour, poured into a saturated aqueous
ammonium chloride solution (150 mL), and extracted several times
with ethyl acetate. The combined organic layers were dried over
magnesium sulfate, filtered, and concentrated. The residue was
triturated with ether to give (4-bromophenyl)(thien-2-yl)methanone
as a brown solid (1.1 g, 34%). MS (ES) m/z 266.9.
[0130] The title compound was prepared from
(4-bromophenyl)(thien-2-yl)methanone and 1-methyl-2-cyanopyrrole
according to the coupling procedure as described in example 1. MS
(ES) m/z 293.1; HRMS: calcd for C.sub.17H.sub.12N.sub.2OS+H.sup.+,
293.0743; found (ESI, [M+H].sup.+), 293.0744.
Example 11
5-(4-benzoylphenyl)-1-methyl-1H-pyrrole-2-carbonitrile
[0131] The title compound was prepared from
(4-bromophenyl)-phenyl-methanone and 1-methyl-2-cyanopyrrole
according to the coupling procedure as described in example 1. MS
(ES) m/z 287.1; HRMS: calcd for C.sub.19H.sub.14N.sub.2O+H.sup.+,
287.11789; found (ESI, [M+H].sup.+), 287.1185.
Example 12
6-(3-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-one
[0132] Trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester was prepared from
6-hydroxy-3,4-dihydro-2H-naphthalen-1-one followed the triflation
procedure as described in the example 3. MS (ESI) m/z 295.
[0133] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-chlorophenyl
boronic acid according to the coupling procedure as described in
example 6. MS (ES) m/z 257.1.
Example 13
1-methyl-5-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrrole-2-carbonit-
rile
[0134] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and
1-methyl-2-cyanopyrrole according to the coupling procedure as
described in example 1. MS (ES) m/z 251.2; HRMS: calcd for
C.sub.16H.sub.14N.sub.2O+H.sup.+, 251.11789; found (ESI,
[M+H].sup.+), 251.1186.
Example 14
6-(3-chloro-4-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one
[0135] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and
3-chloro-4-fluorophenyl boronic acid according to the coupling
procedure as described in example 6. MS (ESD m/z 275.
Example 15
6-(4-chlorophenyl)-3,4-dihydronaphthalen-1(2H)-one
[0136] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 4-chlorophenyl
boronic acid according to the coupling procedure as described in
example 6. MS (ESI) m/z 257.
Example 16
6-[3-(trifluoromethyl)phenyl]-3,4-dihydronaphthalen-1(2H)-one
[0137] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and
3-trifluoromethylhenyl boronic acid according to the coupling
procedure as described in example 6. MS (ESI) m/z 291.
Example 17
6-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one
[0138] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-fluorophenyl
boronic acid according to the coupling procedure as described in
example 6. MS (ESI) m/z 241.
Example 18
6-(3,4-difluorophenyl)-3,4-dihydronaphthalen-1(2H)-one
[0139] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and
3,4-difluorophenyl boronic acid according to the coupling procedure
as described in example 6. MS (ESI) m/z 259.
Example 19
6-(3-methoxyphenyl)-3,4-dihydronaphthalen-1 (2H)-one
[0140] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methoxyphenyl
boronic acid according to the coupling procedure as described in
example 6. MS (ESI) m/z 253.
Example 20
6-(3-methylphenyl)-3,4-dihydronaphthalen-1(2H)-one
[0141] The title compound was prepared from
trifluoro-methanesulfonic acid
5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-methylphenyl
boronic acid according to the coupling procedure as described in
example 6. MS (ESI) m/z 237.
Example 21
5-(4-chlorophenyl)-3,3-dimethylindan-1-one
[0142] To a stirred solution of trifluoro-methanesulfonic acid
3,3-dimethyl-1-oxo-indan-5-yl ester (0.25 g, 0.81 mmol) in glyme (7
mL) was added 4-chlorophenyl boronic acid (0.19 g, 1.22 mmol), a
solution of sodium carbonate (0.26 g, 2.43 mmol) in water (1.5 mL),
and tetrakis(triphenylphosphine) palladium (0) (0.05 g, 0.04 mmol).
The resulting solution was heated to reflux for 2 hours. The
mixture was cooled to room temperature, concentrated, taken up in
ethyl acetate and filtered through a pad of the Celite.RTM.
reagent. The filtrate was concentrated and the residue was purified
by Gilson high performance liquid chromatography (HPLC-10 to 100
acetonitrile in water) to afford
5-(4-chlorophenyl)-3,3-dimethylindan-1-one as a white solid. (0.11
g, 50%). MS (ES) m/z 271.0; HRMS: calcd for
C.sub.17H.sub.15ClO+H.sup.+, 271.0884; found (ESI, [M+H].sup.+),
271.0877.
Example 22
5-(3,5-dimethylisoxazol-4-yl)-3,3-dimethylindan-1-one
[0143] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3,5-dimethylisoxazole-4-boronic acid according to the coupling
procedure described in example 21. MS m/z 256; HRMS: calcd for
C.sub.16H.sub.17NO.sub.2+H.sup.+, 256.13321; found (ESI,
[M+H].sup.+), 256.1343.
Example 23
5-(5-chlorothien-2-yl)-3,3-dimethylindan-1-one
[0144] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 5-chlorothien-2-yl boronic acid according to the procedure
described in example 21. MS m/z 277; HRMS: calcd for
C.sub.15H.sub.13ClOS+H.sup.+, 277.04484; found (ESI, [M+H].sup.+),
277.0444.
Example 24
3,3-dimethyl-5-thien-3-ylindan-1-one
[0145] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and thien-3-yl boronic acid according to the procedure described in
example 21. MS m/z 243; HRMS: calcd for C.sub.15H.sub.14OS+H.sup.+,
243.08381; found (ESI, [M+H].sup.+), 243.084.
Example 25
5-[4-(2,2-dimethylpropanoyl)phenyl]-1-methyl-1H-pyrrole-2-carbonitrile
[0146] The title compound was prepared from
1-(4-bromophenyl)-2,2-dimethylpropan-1-one and
1-methyl-2-cyanopyrrole according to the coupling procedure
described in example 1. MS m/z 267; HRMS: calcd for
C.sub.17H.sub.18N.sub.2O+H.sup.+, 267.14919; found (ESI,
[M+H].sup.+), 267.1494.
Example 26
3,3-dimethyl-5-(4-methylphenyl)indan-1-one
[0147] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 4-methylphenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 251.1; HRMS: calcd for
C.sub.18H.sub.18O+H.sup.+, 251.14304; found (ESI, [M+H].sup.+),
251.1431.
Example 27
5-(4-methoxyphenyl)-3,3-dimethylindan-1-one
[0148] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 4-methoxyphenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 267.1. HRMS: calcd for
C.sub.18H.sub.18O.sub.2+H.sup.+, 267.13796; found (ESI,
[M+H].sup.+), 267.1373.
Example 28
5-(3-chlorophenyl)-3,3-dimethylindan-1-one
[0149] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-chlorophenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 271.1; HRMS: calcd for
C.sub.17H.sub.15ClO+H.sup.+, 271.08842; found (ESI, [M+H].sup.+),
271.0881.
Example 29
3,3-dimethyl-5-(3-methylphenyl)indan-1-one
[0150] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-methylphenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 251.2; HRMS: calcd for
C.sub.18H.sub.18O+H.sup.+, 251.14304; found (ESI, [M+H].sup.+),
251.1428.
Example 30
5-(3-methoxyphenyl)-3,3-dimethylindan-1-one
[0151] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-methoxyphenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 267.2; HRMS: calcd for
C.sub.18H.sub.18O.sub.2+H.sup.+, 267.13796; found (ESI,
[M+H].sup.+), 267.1386.
Example 31
5-(3,5-dichlorophenyl)-3,3-dimethylindan-1-one
[0152] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3,5-dichlorophenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 305.1; HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2O+H.sup.+, 305.04944; found (ESI,
[M+H].sup.+), 305.0509.
Example 32
5-(2-chlorophenyl)-3,3-dimethylindan-1-one
[0153] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 2-chlorophenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 271.1; HRMS: calcd for
C.sub.17H.sub.15ClO+H.sup.+, 271.08842; found (ESI, [M+H].sup.+),
271.088.
Example 33
5-(3,4-dichlorophenyl)-3,3-dimethylindan-1-one
[0154] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3,4-dichlorophenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 305.1; HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2O+H.sup.+, 305.04944; found (ESI,
[M+H].sup.+), 305.0505.
Example 34
5-(2,3-dichlorophenyl)-3,3-dimethylindan-1-one
[0155] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 2,3-dichlorophenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 305.1; HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2O+H.sup.+, 305.04944; found (ESI,
[M+H].sup.+), 305.0504.
Example 35
5-(2,5-dichlorophenyl)-3,3-dimethylindan-1-one
[0156] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 2,5-dichlorophenyl boronic acid according to the procedure
described in example 21. MS m/z 305; HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2O+H.sup.+, 305.04944; found (ESI,
[M+H].sup.+), 305.0502.
Example 36
5-(2,4-dichlorophenyl)-3,3-dimethylindan-1-one
[0157] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 2,4-dichlorophenyl boronic acid according to the procedure
described in example 21. MS m/z 305; HRMS: calcd for
C.sub.17H.sub.14Cl.sub.2O+H.sup.+, 305.04944; found (ESI,
[M+H].sup.+), 305.0494.
Example 37
3,3-dimethyl-5-phenylindan-1-one
[0158] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and phenyl boronic acid according to the procedure described in
example 21. MS m/z 237; HRMS: calcd for C.sub.17H.sub.16O+H.sup.+,
237.12739; found (ESI, [M+H].sup.+), 237.1271.
Example 38
5-(3-chloro-4-fluorophenyl)-3,3-dimethylindan-1-one
[0159] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-chloro-4-fluorophenyl boronic acid according to the procedure
described in example 21. MS m/z 289; HRMS: calcd for
C.sub.17H.sub.14ClFO+H.sup.+, 289.07900; found (ESI, [M+H].sup.+),
289.0785.
Example 39
3,3-dimethyl-5-[3-(trifluoromethyl)phenyl]indan-1-one
[0160] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-trifluoromethylphenyl boronic acid according to the procedure
described in example 21. MS m/z 305; HRMS: calcd for
C.sub.18H.sub.15F.sub.3O+H.sup.+, 305.11478; found (ESI,
[M+H].sup.+), 305.1142.
Example 40
3,3-dimethyl-5-[4-(trifluoromethyl)phenyl]indan-1-one
[0161] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 4-(trifluoromethyl)phenyl boronic acid according to the
procedure described in example 21. MS m/z 305; HRMS: calcd for
C.sub.18H.sub.15F.sub.3O+H.sup.+, 305.11478; found (ESI,
[M+H].sup.+), 305.1145.
Example 41
5-[4-(dimethylamino)phenyl]-3,3-dimethylindan-1-one
[0162] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 4-(dimethylamino)phenyl boronic acid according to the procedure
described in example 21. MS m/z 280; HRMS: calcd for
C.sub.19H.sub.21NO+H.sup.+, 280.16959; found (ESI, [M+H].sup.+),
280.1691.
Example 42
5-[3-(dimethylamino)phenyl]-3,3-dimethylindan-1-one
[0163] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-(dimethylamino)phenyl boronic acid according to the procedure
described in example 21. MS m/z 280; HRMS: calcd for
C.sub.19H.sub.21NO+H.sup.+, 280.16959; found (ESI, [M+H].sup.+),
280.1689.
Example 43
5-(3,4-difluorophenyl)-3,3-dimethylindan-1-one
[0164] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3,4-difluorophenyl boronic acid according to the procedure
described in example 21. MS m/z 273; HRMS: calcd for
C.sub.17H.sub.14F.sub.2O+H.sup.+, 273.10855; found (ESI,
[M+H].sup.+), 273.1078.
Example 44
5-[3-(ethylsulfonyl)phenyl]-3,3-dimethylindan-1-one
[0165] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-(ethylsulfonyl)phenyl boronic acid according to the procedure
described in example 21. MS m/z 329; HRMS: calcd for
C.sub.19H.sub.20O.sub.3S+H.sup.+, 329.12059; found (ESI,
[M+H].sup.+), 329.1217.
Example 45
3-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)-5-fluorobenzonitrile
[0166] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-cyano-5-fluorophenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 280.1; HRMS: calcd for
C.sub.18H.sub.14FNO+H.sup.+, 280.11322; found (ESI, [M+H].sup.+),
280.1129.
Example 46
5-(4-acetylphenyl)-3,3-dimethylindan-1-one
[0167] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 4-acetylphenyl boronic acid according to the procedure
described in example 21. MS (ES) m/z 279.2; HRMS: calcd for
C.sub.19H.sub.18O.sub.2+H.sup.+, 279.13796; found (ESI,
[M+H].sup.+), 279.1395.
Example 47
5-(3-acetylphenyl)-3,3-dimethylindan-1-one
[0168] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-acetyl phenyl boronic acid according to the procedure
described in example 21. MS (ESD m/z 279; HRMS: calcd for
C.sub.19H.sub.18O.sub.2+H.sup.+, 279.13796; found (ESI,
[M+H].sup.+), 279.1374.
Example 48
5-(2-acetylphenyl)-3,3-dimethylindan-1-one
[0169] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 2-acetylphenyl boronic acid according to the procedure
described in example 21. MS (ESI) m/z 279; HRMS: calcd for
C.sub.19H.sub.18O.sub.2+H.sup.+, 279.13796; found (ESI,
[M+H].sup.+), 279.1383.
Example 49
4-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile
[0170] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 4-cyanophenyl boronic acid according to the procedure described
in example 21. MS (ESI) m/z 262; HRMS: calcd for
C.sub.18H.sub.15NO+H.sup.+, 262.12264; found (ESI, [M+H].sup.+),
262.1237.
Example 50
3-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile
[0171] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 3-cyanophenyl boronic acid according to the procedure described
in example 21. MS (ESI) m/z 262; HRMS: calcd for
C.sub.18H.sub.15NO+H.sup.+, 262.12264; found (ESI, [M+H].sup.+),
262.1219.
Example 51
2-(3,3-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile
[0172] The title compound was prepared from
trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester
and 2-cyanophenyl boronic acid according to the procedure described
in example 21. MS (ESI) m/z 262; HRMS: calcd for
C.sub.18H.sub.15NO+H.sup.+, 262.12264; found (ESI, [M+H].sup.+),
262.1234.
Example 52
Pharmacology
[0173] The compounds of this invention were tested in the relevant
assay as described below and their potency are in the range of 0.01
nM to 5 .mu.M in the in vitro assays and 0.001 to 300 mg/kg in the
in vivo assays. TABLE-US-00002 TABLE 1 Potency of representative
5-aryl-indan-1-one and analogs as PR modulators in progesterone
induced T47D alkaline phosphatase assay ##STR35## Example 3
##STR36## Example 13 ##STR37## Examples 9-11 ##STR38## Examples 21
to 38 Example Alk. Phos. Alk. Phos. No. R.sub.1 R.sub.2 R R.sub.9
IC.sub.50 (nM) EC.sub.50 (nM) 3 Me Me -- -- -- 10 9 -- H -- Et
115.2 -- 10 -- H -- Thien-2-yl 265.8 -- 11 -- H -- Ph 300 -- 13 H H
-- -- 27.5 -- 21 Me Me 4-Cl -- 199.5 -- 26 Me Me 4-Me -- 877.1 --
28 Me Me 3-Cl -- 66.3 -- 29 Me Me 3-Me -- 225.2 -- 32 Me Me 2-Cl --
737.3 -- 35 Me Me 2-Cl, 5-Cl -- 631.5 -- 36 Me Me 2-Cl, 4-Cl --
349.1 -- 37 Me Me H -- 300.4 -- 38 Me Me 3-Cl, 4-F -- 100.4 --
(1) T47D Cell Proliferation Assay
[0174] a) Objective: Determination of progestational and
antiprogestational potency by using a cell proliferation assay in
T47D cells. A compound's effect on DNA synthesis in T47D cells is
measured.
[0175] b) Methods
[0176] A. Reagents [0177] Growth medium: DMEM:F12 (1:1) (GIBCO,
BRL) supplemented with 10% (v/v) fetal bovine serum (not
heat-inactivated), 100 U/mL penicillin, 100 mg/mL streptomycin, and
2 mM of the GlutaMax.RTM. reagent (GIBCO, BRL). [0178] Treatment
medium: Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL)
phenol red-free supplemented with 0.5% charcoal stripped fetal
bovine serum, 100 U/mL penicillin, 200 mg/mL streptomycin, and 2 mM
of the GlutaMax.RTM. reagent (GIBCO, BRL).
[0179] B. Cell Culture [0180] Stock T47 D cells are maintained in
growth medium. For BrdU incorporation assay, cells are plated in
96-well plates (Falcon, Becton Dickinson Labware) at 10,000
cells/well in growth medium. After overnight incubation, the medium
is changed to treatment medium and cells are cultured for an
additional 24 hours before treatment. Stock compounds are dissolved
in appropriate vehicle (100% ethanol or 50% ethanol/50% DMSO),
subsequently diluted in treatment medium and added to the cells.
Progestin and antiprogestin reference compounds are run in full
dose-response curves. The final concentration of vehicle is 0.1%.
In control wells, cells receive vehicle only. Antiprogestins are
tested in the presence of 0.03 nM trimegestone, the reference
progestin agonist. Twenty-four hours after treatment, the medium is
discarded and cells are labeled with 10 mM BrdU (Amersham Life
Science, Arlington Heights, Ill.) in treatment medium for 4
hours.
[0181] C. Cell Proliferation Assay [0182] At the end of BrdU
labeling, the medium is removed and BrdU incorporation is measured
using a cell proliferation ELISA kit (#RPN 250, Amersham Life
Science) according to manufacturer's instructions. Briefly, cells
are fixed in an ethanol containing fixative for 30 min, followed by
incubation in a blocking buffer for 30 min to reduce background.
Peroxidase-labeled anti-BrdU antibody is added to the wells and
incubated for 60 minutes. The cells are rinsed three times with PBS
and incubated with 3,3'5,5'-tetramethylbenzidine (TMB) substrate
for 10-20 min depending upon the potency of tested compounds. Then
25 .mu.L of 1 M sulfuric acid is added to each well to stop color
reaction and optical density is read in a plate reader at 450 nm
within 5 minutes.
[0183] (c) Analysis of Results [0184] Square root-transformed data
are used for analysis of variance and nonlinear dose response curve
fitting for both agonist and antagonist modes. Huber weighting is
used to downweight the effects of outliers. EC.sub.50 or IC.sub.50
values are calculated from the retransformed values. JMP.RTM.
software (SAS Institute, Inc.) is used for both one-way analysis of
variance and non-linear dose response analyses in both single dose
and dose response studies.
[0185] (d) Reference Compounds:
[0186] Trimegestone and medroxyprogesterone acetate (MPA) were
reference progestins and RU486 is the reference antiprogestin. All
reference compounds were run in full dose-response curves and the
EC.sub.50 or IC.sub.50 values were calculated. TABLE-US-00003 TABLE
2 Estimated EC.sub.50, standard error (SE), and 95% confidence
intervals (CI) for individual studies EC.sub.50 95% CI Compound Exp
(nM) SE lower upper Trimegestone 1 0.017 0.003 0.007 0.040 2 0.014
0.001 0.011 0.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.001 0.013
0.027 2 0.017 0.001 0.011 0.024
[0187] TABLE-US-00004 TABLE 3 Estimated IC.sub.50, standard error,
and 95% confident interval for the antiprogestin, RU486 IC.sub.50
95% CI Compound Exp (nM) SE lower upper RU486 1 0.011 0.001 0.008
0.014 2 0.016 0.001 0.014 0.020 3 0.018 0.001 0.014 0.022
EC.sub.50: Concentration of a compound that gives half-maximal
increase in BrdU incorporation with SE; IC.sub.50: Concentration of
a compound that gives half-maximal decrease in 0.1 trimegestone
induced BrdU incorporation with SE (2) Rat Decidualization
Assay
[0188] (a) Objective: This procedure was used to evaluate the
effect of progestins and antiprogestins on rat uterine
decidualization and compare the relative potencies of various test
compounds.
[0189] (b) Methods
[0190] A. Reagents [0191] Test compounds were dissolved in 100%
ethanol and mixed with corn oil (vehicle). Stock solutions of the
test compounds in oil (the Mazola product) were then prepared by
heating (.about.80.degree. C.) the mixture to evaporate ethanol.
Test compounds were subsequently diluted with 100% corn oil or 10%
ethanol in corn oil prior to the treatment of animals. No
difference in decidual response was found when these two vehicles
were compared.
[0192] B. Animals (RACUC Protocol #5002) [0193] Ovariectomized
mature female Sprague-Dawley rats (.about.60-day old and 230 g)
were obtained from Taconic (Taconic Farms, N.Y.) following surgery.
Ovariectomy was performed at least 10 days prior to treatment to
reduce circulating sex steroids. Animals were housed under 12 hours
light/dark cycle and given standard rat chow and water ad
libitum.
[0194] C. Treatment [0195] Rats were weighed and randomly assigned
to groups of 4 or 5 before treatment. Test compounds in 0.2 mL
vehicle were administered by subcutaneous injection in the nape of
the neck or by gavage using 0.5 mL. The animals were treated once
daily for seven days. For testing antiprogestins, animals were
given the test compounds and a EC.sub.50 dose of progesterone (5.6
mg/kg) during the first three days of treatment. Following decidual
stimulation, animals continued to receive progesterone until
necropsy four days later.
[0196] D. Dosing [0197] Doses were prepared based upon mg/kg mean
group body weight. In all studies, a control group receiving
vehicle was included. Determination of dose-response curves was
carried out using doses with half log increases (e.g. 0.1, 0.3,
1.0, 3.0 mg/kg . . . ).
[0198] E. Decidual Induction [0199] Approximately 24 hours after
the third injection, decidualization was induced in one of the
uterine horns by scratching the antimesometrial luminal epithelium
with a blunt 21 G needle. The contralateral horn was not scratched
and served as an unstimulated control. Approximately 24 hours
following the final treatment, rats were sacrificed by CO.sub.2
asphyxiation and body weight measured. Uteri were removed and
trimmed of fat. Decidualized (D-horn) and control (C-horn) uterine
horns were weighed separately.
[0200] (c) Analysis of Results: [0201] The increase in weight of
the decidualized uterine horn was calculated by D-horn/C-horn and
logarithmic transformation was used to maximize normality and
homogeneity of variance. The Huber M-estimator was used to down
weight the outlying transformed observations for both dose-response
curve fitting and one-way analysis of variance. JMP.RTM. software
(SAS Institute, Inc.) was used for both one-way ANOVA and
non-linear dose-response analyses.
[0202] (d) Reference Compounds: All progestin reference compounds
were run in full dose-response curves and the EC.sub.50 for uterine
wet weight was calculated. TABLE-US-00005 TABLE 4 Estimated
EC.sub.50, standard error (SE), and 95% confidence intervals for
individual studies EC.sub.50 95% CI Compound Exp (mg/kg, s.c.) SE
lower upper Progesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41
8.76 3-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25
3 0.06 0.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12
0.02 0.09 0.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1
0.42 0.03 0.29 0.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61
[0203] TABLE-US-00006 TABLE 5 Estimated average EC.sub.50, standard
error, and 95% confidence intervals for dose-response curves of 3
reference compounds EC.sub.50 95% CI Compound (mg/kg, s.c.) SE
lower upper Progesterone 5.62 0.62 4.55 7.00 3-Ketodesogestrel 0.10
0.02 0.07 0.14 Levonorgestrel 0.10 0.01 0.08 0.12
[0204] TABLE-US-00007 TABLE 6 Estimated IC.sub.50, standard error,
and 95% confident interval for the antiprogestin, RU486 IC.sub.50
95% CI Compound Exp (mg/kg, p.o.) SE lower upper RU 486 1 0.21 0.07
0.05 0.96 2 0.14 0.02 0.08 0.27
[0205] Concentration: Compound concentration in assay
(default-mg/kg body weight)
[0206] Route of administration: Route the compound is administered
to the animals
[0207] Body weight: Mean total animal body weight (default-kg)
[0208] D-horn: Wet weight of decidualized uterine horn
(default-mg)
[0209] C-horn: Wet weight of control uterine horn (default-mg)
[0210] Decidual response: [(D-C)/C].times.100%
[0211] Progestational activity: Compounds that induce
decidualization significantly (p<0.05) compared to vehicle
control are considered active
[0212] Antiprogestational activity: Compounds that decrease
EC.sub.50 progesterone induced decidualization significantly
(p<0.05)
[0213] EC.sub.50 for uterine weight: Concentration of compound that
gives half-maximal increase in decidual response
(default-mg/kg)
[0214] IC.sub.50 for uterine weight: Concentration of compound that
gives half-maximal decrease in EC.sub.50 progesterone induced
decidual response (default-mg/kg)
(3) PRE-Luciferase Assay in CV-1 Cells
[0215] (a) Objective: To determine a compound's progestational or
antiprogestational potency based on its effect on PRE-luciferase
reporter activity in CV-1 cells co-transfected with human PR and
PRE-luciferase plasmids.
[0216] (b) Methods
[0217] A. Reagents [0218] Culture medium: [0219] Growth medium:
DMEM (BioWhittaker) containing 10% (v/v) fetal bovine serum (heat
inactivated), 0.1 mM MEM non-essential amino acids, 100 U/mL
penicillin, 100 mg/mL streptomycin, and 2 mM of the GlutaMax.RTM.
reagent (GIBCO, BRL). [0220] Experimental medium: DMEM
(BioWhittaker), phenol red-free, containing 10% (v/v)
charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEM
non-essential amino acids, 100 U/mL penicillin, 100 mg/mL
streptomycin, and 2 mM of the GlutaMax.RTM.(reagent (GIBCO,
BRL).
[0221] B. Cell Culture, Transfection, Treatment, and Luciferase
Assay [0222] Stock CV-1 cells were maintained in growth medium.
Co-transfection was done using 1.2.times.10.sup.7 cells, 5 mg pLEM
plasmid with hPR-B inserted at Sph1 and BamH1 sites, 10 mg pGL3
plasmid with two PREs upstream of the luciferase sequence, and 50
mg sonicated calf thymus DNA as carrier DNA in 250 mL.
Electroporation was carried out at 260 V and 1,000 mF in a Bio-Rad
Gene Pulsers II instrument. After electroporation, cells were
resuspended in growth medium and plated in 96-well plate at 40,000
cells/well in 200 .mu.L. Following overnight incubation, the medium
was changed to experimental medium. Cells were then treated with
reference or test compounds in experimental medium. Compounds were
tested for antiprogestational activity in the presence of 3 nM
progesterone. Twenty-four hours after treatment, the medium was
discarded, cells were washed three times with D-PBS (GIBCO, BRL).
Fifty mL of cell lysis buffer (Promega, Madison, Wis.) was added to
each well and the plates were shaken for 15 min in a Titer Plate
Shaker (Lab Line Instrument, Inc.). Luciferase activity was
measured using luciferase reagents from Promega.
[0223] (c) Analysis of Results [0224] Each treatment consists of at
least 4 replicates. Log transformed data were used for analysis of
variance and nonlinear dose response curve fitting for both agonist
and antagonist modes. Huber weighting was used to downweight the
effects of outliers. EC.sub.50 or IC.sub.50 values were calculated
from the retransformed values. JMP.RTM. software (SAS Institute,
Inc.) was used for both one-way analysis of variance and non-linear
response analyses.
[0225] (d) Reference Compounds
[0226] Progesterone and trimegestone were reference progestins and
RU486 was the reference antiprogestin. All reference compounds were
run in full dose-response curves and the EC.sub.50 or IC.sub.50
values were calculated. TABLE-US-00008 TABLE 7 Estimated EC.sub.50,
standard error (SE), and 95% confidence intervals (CI) for
reference progestins from three individual studies EC.sub.50 95% CI
Compound Exp (nM) SE lower upper Progesterone 1 0.616 0.026 0.509
0.746 2 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637
Trimegestone 1 0.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070
0.0094 3 0.0067 0.0003 0.0055 0.0082
[0227] TABLE-US-00009 TABLE 8 Estimated IC.sub.50, standard error
(SE), and 95% confident interval (CI) for the antiprogestin, RU486
from three individual studies IC.sub.50 95% CI Compound Exp (nM) SE
lower upper RU 486 1 0.028 0.002 0.019 0.042 2 0.037 0.002 0.029
0.048 3 0.019 0.001 0.013 0.027
Progestational activity: Compounds that increase PRE-luciferase
activity significantly (p<0.05) compared to vehicle control are
considered active. Antiprogestational activity: Compounds that
decrease 3 nM progesterone induced PRE-luciferase activity
significantly (p<0.05). EC.sub.50: Concentration of a compound
that gives half-maximal increase PRE-luciferase activity
(default-nM) with SE. IC.sub.50: Concentration of a compound that
gives half-maximal decrease in 3 nM progesterone induced
PRE-luciferase activity (default-nM) with SE. (4) T47D Cell
Alkaline Phosphatase Assay
[0228] (a) Purpose: To identify progestins or antiprogestins by
determining a compound's effect on alkaline phosphatase activity in
T47D cells.
[0229] (b) Methods
[0230] A. Reagents [0231] Culture medium: DMEM:F12 (1:1) (GIBCO,
BRL) supplemented with 5% (v/v) charcoal stripped fetal bovine
serum (not heat-inactivated), 100 U/mL penicillin, 100 mg/mL
streptomycin, and 2 mM of the GlutaMax.RTM. reagent (GIBCO, BRL).
[0232] Alkaline phosphatase assay buffer: [0233] I. 0.1 M Tris-HCl,
pH 9.8, containing 0.2% of the Triton X-100.RTM. reagent [0234] II.
0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenyl phosphate
(Sigma).
[0235] B. Cell Culture and Treatment [0236] Frozen T47D cells were
thawed in a 37.degree. C. water bath and diluted to 280,000
cells/mL in culture medium. To each well in a 96-well plate
(Falcon, Becton Dickinson Labware), 180 .mu.L of diluted cell
suspension was added. Twenty .mu.L of reference or test compounds
diluted in the culture medium was then added to each well. When
testing for progestin antagonist activity, reference antiprogestins
or test compounds were added in the presence of 1 nM progesterone.
The cells were incubated at 37.degree. C. in a 5%
CO.sub.2/humidified atmosphere for 24 hours. [0237] Note: For high
throughput screening, one concentration of each compound was tested
at 0.3 mg/mL. Based on an average molecular weight of 300 g/mol for
the compounds in the library, the concentration was approximately 1
mM. Subsequently, active compounds were tested in dose response
assays to determine EC.sub.50 or IC.sub.50.
[0238] C. Alkaline Phosphatase Enzyme Assay [0239] At the end of
treatment, the medium was removed from the plate. Fifty .mu.L of
assay buffer I was added to each well. The plates were shaken in a
titer plate shaker for 15 minutes. Then 150 .mu.L of assay buffer
II was added to each well. Optical density measurements were taken
at 5 min intervals for 30 min at a test wavelength of 405 nM.
[0240] (c) Analysis of Results [0241] Analysis of dose-response
data: For reference and test compounds, a dose response curve was
generated for dose (X-axis) vs. the rate of enzyme reaction (slope)
(Y-axis). Square root-transformed data were used for analysis of
variance and nonlinear dose response curve fitting for both agonist
and antagonist modes. Huber weighting was used to downweight the
effects of outliers. EC.sub.50 or IC.sub.50 values were calculated
from the retransformed values. JMP.RTM. software (SAS Institute,
Inc.) was used for both one-way analysis of variance and non-linear
dose response analyses in both single dose and dose response
studies.
[0242] (d) Reference Compounds:
[0243] Progesterone and trimegestone were reference progestins and
RU486 was the reference antiprogestin. All reference compounds were
run in full dose response curves and the EC.sub.50 or IC.sub.50
values were calculated. TABLE-US-00010 TABLE 9 Estimated EC.sub.50,
standard error (SE), and 95% confidence intervals (CI) for
reference progestins from three independent experiments EC.sub.50
95% CI Compound Exp (nM) SE lower upper Progesterone 1 0.839 0.030
0.706 0.996 2 0.639 0.006 0.611 0.669 3 1.286 0.029 1.158 1.429
Trimegestone 1 0.084 0.002 0.076 0.091 2 0.076 0.001 0.072 0.080 3
0.160 0.004 0.141 0.181
[0244] TABLE-US-00011 TABLE 10 Estimated IC.sub.50 standard error,
and 95% confident interval for the reference antiprogestin RU486
from three independent experiments IC.sub.50 95% CI Compound Exp
(nM) SE lower upper RU 486 1 0.103 0.002 0.092 0.115 2 0.120 0.001
0.115 0.126 3 0.094 0.007 0.066 0.134
[0245] All publications cited in this specification are
incorporated herein by reference. While the invention has been
described with reference to particular embodiments, it will be
appreciated that modifications can be made without departing from
the spirit of the invention. Such modifications are intended to
fall within the scope of the appended claims.
* * * * *