2,1-BENZISOTHIAZOLINE 2,2-DIOXIDES

2,1-BENZISOTHIAZOLINE 2,2-DIOXYDES

English Abstract

A progesterone receptor antagonist of formula (1) wherein R1, and R2 are each,
independently, hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, arylalkyl, heteroarylalkyl, and alkynyl; or R1 and R2 are taken
together to form a ring and together contain -CH2(CH2)nCH2-, -CH2CH2CMe2CH2CH2-
, -O(CH2)pCH2-, O(CH2)qO-, -CH2CH2OCH2CH2-, -CH2CH2NR7CH2CH2-; or R1 and R2
are a double bond, said double bond having two methyl groups bonded to the
terminal end, having a cycloalkyl group bonded to the terminal end, having an
oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end; R5 is a trisubstituted phenyl ring having structure (z), or R5
is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected from the group consisting of O, S, SO2 and NR6 or pharmaceutically
acceptable salt thereof.

French Abstract

La présente invention concerne un antagoniste du récepteur de progestérone de formule (1) dans laquelle R¿1?, et R¿2? représentent individuellement hydrogène, alky, alkyle substitué, hydroxy, alcoxy, alcoxy substitué, aryle, aryle substitué, hétéroaryle, hétéroaryle substitué, arylalkyle, hétéroarylalkyle, et alcynyle; ou R¿1? et R¿2? pris ensemble contiennent -CH¿2?(CH¿2?)¿n?CH¿2?-, -CH¿2?CH¿2?CMe¿2?CH¿2?-CH¿2?-, -O(CH¿2?)¿p?CH¿2?-, O(CH¿2?)¿q?O-, -CH¿2?CH¿2?OCH¿2?CH¿2?-, -CH¿2?CH¿2?NR¿7?CH¿2?CH¿2?-; ou R¿1? et R¿2? représentent une double liaison, cette double liaison ayant deux groupes méthyle liés à l'extrémité terminale, un groupe cycloalkyle lié à l'extrémité terminale, un oxygène lié à l'extrémité terminale, ou un cycloéther lié à l'extrémité terminale; R?5¿ représente un cycle phénylique trisubstitué de structure (2), ou R?5¿ représente un cycle hétéroaryle à 5 ou 6 éléments contenant 1, 2, ou 3 hétéroatomes sélectionnés dans le groupe constitué par O, S, SO¿2? et NR?6¿, ou un sel de celui-ci acceptable sur le plan pharmaceutique.

Claims

-21-
WHAT IS CLAIMED IS:
1. A compound formula I having the structure
<IMG>
wherein
R1, and R2 are each, independently, hydrogen, alky, substituted alkyl,
hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary,
arylalkyl, heteroarylalkyl, and alkynyl; or
R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-
,
-CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-,
-CH2CH2NR7CH2CH2-; or
R1 and R2 are a double bond, said double bond having two methyl groups bonded
to
the terminal end, having a cycloalkyl group bonded to the terminal end, having
an oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl,
substituted or,
COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aminoalkyl, or
substituted aminoalkyl;

-22-
R4 is hydrogen, halogen, -CN, -NH2; alkyl, substituted alkyl, alkoxy, alkoxy,
aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure,
<IMG>
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl,
substituted aminoalkyl, -NO2, perffuoroalkyl, 5 or 6 membered
heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B,
-OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons
being optionally substituted with one or two substituents independently
selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl,
alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.

-23-
2. The compound according to claim 1, wherein
wherein
R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-;
n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a trisubstituted phenyl ring having the structure,
<IMG>
X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl,
S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NO2,
perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3
heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, and NR6 with said ring carbons being
optionally substituted with one or two substituents independently selected
from
the group consisting of hydrogen, halogen, CN, NO2 , alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
3. The compound according to claim 2, wherein
R5 is a disubstituted phenyl ring having the structure,

-24-
<IMG>
X is halogen, -CN, or -NO2;
Y is hydrogen, halogen, -CN, -NO2, alkoxy, alkyl, or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing a heteroatom selected
from the
group consisting of O, S, and NR6 with said ring carbons being optionally
substituted with one or two substituents independently selected from the group
consisting of hydrogen, halogen, CN, or NO2;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring
double bond;
or pharmaceutically acceptable salt thereof.
4. A compound of Claim 3 wherein R5 is selected from the group of
<IMG>
5. The compound of claim 1, which is 5-(3-chlorophenyl)-
spiro[2,1-benzisothiazole-3(1H),1'-cyclohexane] 2,2-dioxide or a
pharmaceutically
acceptable salt thereof.

-25-
6. A method of providing progestational therapy to a mammal in need thereof
which comprises administering a progestationally effective amount of compound
formula 1 having the structure
<IMG>
wherein
R1, and R2 are each, independently, hydrogen, alley, substituted alkyl,
hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary,
arylalkyl, heteroarylalkyl, and alkynyl; or
R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-,
-CH2CH2CMeCH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-,
-CH2CH2NR7CH2CH2-; or
R1 and R2 are a double bond, said double bond having two methyl groups bonded
to
the terminal end, having a cycloalkyl group bonded to the terminal end, having
an oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl,
substituted or,
COR A;
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aminoalkyl, or
substituted aminoalkyl;

-26-
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy,
aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure,
<IMG>
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl,
substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered
heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B,
-OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons
being optionally substituted with one or two substituents independently
selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl,
alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof to said mammal.

-27-
7. A method of treating or inhibiting breast, uterine, ovarian, endometrial,
or
prostate cancer which comprises administering a compound formula 1 having the
structure
<IMG>
wherein
R1, and R2 are each, independently, hydrogen, alky, substituted alkyl,
hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary,
arylalkyl, heteroarylalkyl, and alkynyl; or
R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-,
-CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-,
-CH2CH2NR7CH2CH2-; or
R1 and R2 are a double bond, said double bond having two methyl groups bonded
to
the terminal end, having a cycloalkyl group bonded to the terminal end, having
an oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl,
substituted or,
COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aminoalkyl, or
substituted aminoalkyl;

-28-
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy,
aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure,
<IMG>
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl,
substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered
heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B,
-OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons
being optionally substituted with one or two substituents independently
selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl,
alkoxy, aminoalkyl, CORD, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, to said mammal.

-29-
8. A method of providing contraception in a mammal in need thereof, which
comprises administering an effective amount compound formula 1 having the
structure
<IMG>
wherein
R1, and R2 are each, independently, hydrogen, alky, substituted alkyl,
hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary,
arylalkyl, heteroarylalkyl, and alkynyl; or
R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-,
-CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-,
-CH2CH2NR,CH2CH2-; or
R1 and R2 are a double bond, said double bond having two methyl groups bonded
to
the terminal end, having a cycloalkyl group bonded to the terminal end, having
an oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl,
substituted or,
COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aminoalkyl, or
substituted aminoalkyl;

-30-
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy,
aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure,
<IMG>
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2 alkyl, aminoalkyl,
substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered
heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B,
-OCOR B, or -NR7COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons
being optionally substituted with one or two substituents independently
selected from the group consisting of hydrogen, halogen, CN, NO2, alkyl,
alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, to said mammal.

-31-
9. A pharmaceutical composition, which comprises a compound formula 1 having
the structure
<IMG>
wherein
R1, and R2 are each, independently, hydrogen, alky, substituted alkyl,
hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary,
arylalkyl, heteroarylalkyl, and alkynyl; or
R1 and R2 are taken together form a ring and together contain -CH2(CH2)n CH2-,
-CH2CH2CMe2CH2CH2-, -O(CH2)p CH2-, O(CH2)q O-, -CH2CH2OCH2CH2-,
-CH2CH2NR7CH2CH2-; or
R1 and R2 are a double bond, said double bond having two methyl groups bonded
to
the terminal end, having a cycloalkyl group bonded to the terminal end, having
an oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end;
R7 is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NH2, alkyl, substituted alkyl, alkenyl, alkynyl,
substituted or,
COR A;
R A is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aminoalkyl, or
substituted aminoalkyl;

-32-
R4 is hydrogen, halogen, -CN, -NH2, alkyl, substituted alkyl, alkoxy, alkoxy,
aminoalkyl, or substituted aminoalkyl;
R5 is a trisubstituted phenyl ring having the structure,
<IMG>
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
thioalkyl, substituted thioalkyl, S(O)alkyl, S(O)2alkyl, aminoalkyl,
substituted aminoalkyl, -NO2, perfluoroalkyl, 5 or 6 membered
heterocyclic ring containing 1 to 3 heteroatoms, thioalkoxy, -COR B,
-OCOR B, or -NR C COR B;
R B is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R C is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioalkyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, SO, SO2 and NR6 with said ring carbons
being optionally substituted with one or two substituents independently
selected from the group consisting of hydrogen, halogen, CN, NO2 , alkyl,
alkoxy, aminoalkyl, COR D, and NR E COR D;
R D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R E is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

Description

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WO 00/66574 PCT/US00/11823
2,1-BENZISOTHIAZOLINE 2,2-DIOXIDES
Background of the Invention
Intracellular receptors (IR) form a class of structurally related gene
regulators
known as "ligand dependent transcription factors" (R. M. Evans, Science 240,
889,
1988). The steroid receptor family is a subset of the IR family, including
progesterone
receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid
receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone, but
synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel,
have
been made which also serve as ligands. Once a ligand is present in the fluid
surrounding a cell, it passes through the membrane via passive diffusion, and
binds to
the IR to create a receptor/ligand complex. This complex binds to specific
gene
promoters present in the cell's DNA. Once bound to the DNA the complex
modulates
the production of mRNA and protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone
is termed an agonist, whilst a compound which inhibits the effect of the
hormone is an
antagonist.
PR agonists (natural and synthetic) are known to play an important role in the
health of women. PR agonists are used in birth control formulations, typically
in the
presence of an ER agonist. ER agonists are used to treat the symptoms of
menopause,
but have been associated with a proliferative effect on the uterus which can
lead to an
increased risk of uterine cancers. Co-administration of a PR agonist reduces
or ablates
2~ that risk.
PR antagonists may also be used in contraception. In this context they may be
administered alone (Ulmann et al, Ann. N. Y. Acad Sci. 261, 248, 1995), in
combination with a PR agonist (Kekkonen et al, Fertility and Sterility 60,
610, 1993)
or in combination with a partial ER antagonist such as tamoxifen (WO 95-
9619997 Al
960704).

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WO 00/66574 PCT/US00/11823
-2-
PR antagonists may also be useful for the treatment of hormone dependent
breast cancers (Horwitz et al, Horm Cancer, 283, pub: Birkhaeuser, Boston,
Mass.,
ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also
be
useful for the treatment of non-malignant chronic conditions such as fibroids
(Murphy
et al, J. Clin. Endo. Metab. 76, 513, 1993) and endometriosis (Kettel et al,
Fertility
and Sterility 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post
menopausal patients in combination with a partial ER antagonist such as
tamoxifen
(US 5719136).
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).
Jones et al (US 5,688,810) is the PR antagonist dihydroquinoline A.
Me
a
A
Jones et al described the enol ether B (US 5,693,646) as a PR ligand.
F
Me
H Me
B

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WO 00/66574 PCT/US00/11823
-3-
Jones et al described compound C (US 5,696,127) as a PR ligand.
F
Me
a
C
Zhi et al described lactones D, E and F as PR antagonists (J. Med. Chem. 41,
291, 1998).
0
~ O O Me I ~ O Me I ~ Me
i ~ ~ / ~ ~ i
Me ~ ~ Me ~ ~ Me
H Me H Me O O H Me
D E F
Zhi et al described the ether G as a PR antagonist (J. Med Chem. 41, 291,
1998).
~O Me
i
Me
Me
G
Combs et al disclosed the amide H as a ligand for the PR (J. Med. Chem. 38,
4880, 1995).

CA 02371758 2001-10-29
WO 00/66574 PCT/US00/11823
-4-
/ F
I
~N.N ~ gr
O
H
Penman et al described the vitamin D analog I as a PR ligand (Tetrahedron.
Lett. 35, 2295, 1994).
I
Hamann et al described the PR antagonist J (Ann. N. Y. Acad. Sci. 761, 383,
1995).
OMe
Br I ~HZC ~ Me
OAc Me Me
J
Chen et al described the PR antagonist K (Chen et al, POI-37, 16'~ Int. Cong.
Het. Chem., Montana, 1997).

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WO 00/66574 PCT/US00/11823
-5-
CI
N
H
K
Kurihari et al described the PR ligand L (J. Antibiotics 50, 360, 1997).
OAc
O
O ~ \ OH
L
There are several examples of 2,1-benzisothiazoline 2,2-dioxides ('sultams')
in
the chemical and patent literature which contain no reference to progesterone
activity,
and do not carry the correct substitution pattern for PR modulator activity.
Chiarino et al described the preparation of the parent 2,1-benzisothiazoline
2,2-
dioxide, i.e., M (and derivatives, e.g., N), that was used in the present
invention (J.
Heterocycl. Chem. 23(6), 1645-9, 1986).
SO ~N
N 2 ~ S02
H ~ N
H
M N
Skorcz et al described a series of 5-(2-morpholinyl)-2,1-benzisothiazolines,
e.g., O, which are useful as central nervous depressants (U.S. 3,635,964).

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WO 00/66574 PCT/US00/11823
-6-
CN
O /
SOZ
N
O
Kasnireddy et al disclosed a series of cyclic sulfonamides, e.g., P and Q,
useful for
controlling undesired vegetation (WO 9533746).
CF3
_ /
N
O ~
N O O N- 'O
F / I F
N S02 ~ ~ N S02
H H
CI CI
P Q
Detailed Description of the Invention
This invention provides progesterone receptor antagonists of Formula 1 having
the structure
R~ R2
R5 \
~~ ~S 02
~~N
R4 v
R3
1

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WO 00/66574 PCT/US00/11823
wherein
R,, and Rzare each, independently, hydrogen, alley, substituted alkyl,
hydroxy, alkoxy,
substituted alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroary,
arylalkyl, heteroarylalkyl, and alkynyl; or
R, and Rz are taken together form a ring and together contain -CHz(CHz)nCHz- ,
-CHZCHZCMezCHzCHz-, -O(CHz)pCHz-, O(CHz)q0-, -CHZCHZOCHZCHz-,
-CHZCHZNR~CHZCHz-; or
R, and Rz are a double bond, said double bond having two methyl groups bonded
to
the terminal end, having a cycloalkyl group bonded to the terminal end, having
an oxygen bonded to the terminal end, or having a cycloether bonded to the
terminal end;
R~ is hydrogen or alkyl of 1-6 carbon atoms;
n = 1-5;
p = 1-4;
q = 1-4;
R3 is hydrogen, hydroxyl, NHz, alkyl, substituted alkyl, alkenyl, alkynyl,
substituted or,
COR";
RA is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
aminoallcyl, or
substituted aminoalkyl;
R4 is hydrogen, halogen, -CN, -NHz, alkyl, substituted alkyl, alkoxy, alkoxy,
aminoalkyl, or substituted aminoallcyl;
RS is a trisubstituted phenyl ring having the structure,
Y~'~~ Z
I
X
X is halogen, OH, -CN, alkyl, substituted alkyl, alkoxy, substituted alkoxy,
thioalkyl,
substituted thioalkyl, S(O)alkyl, S(O)zalkyl, aminoalkyl, substituted
aminoalkyl,

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WO 00/66574 PCT/US00/11823
_g_
-NOz, perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3
heteroatoms, thioalkoxy, -CORB, -OCORB, or -NR~CORB;
RB is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoalkyl;
R~ is hydrogen, alkyl, or substituted alkyl;
Y and Z are each, independently, hydrogen, halogen, -CN, -NOz, alkoxy, alkyl,
or thioallcyl; or
RS is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, SO, SOz and NR6 with said ring carbons
being optionally substituted with one or two substituents independently
selected from the group consisting of hydrogen, halogen, CN, NOz alkyl,
alkoxy, aminoalkyl, CORD, and NRECORD;
RD is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy,
substituted alkoxy, aminoalkyl, or substituted aminoallcyl;
RE is hydrogen, alkyl, or substituted alkyl;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof, which are usefiil for
contraception, in the
treatment of fibroids, endometriosis, breast, uterine, ovarian and prostate
cancer, and
post menopausal hormone replacement therapy
Preferred compounds of this invention are those having the structure:
R~ R2
R5 \
~S 02
R4 N
R3
1
wherein
R, and Rz are taken together form a ring and together contain -CHz(CHz)"CHz- ;
n = 2-3;

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R3 is hydrogen;
R4 is hydrogen;
RS is a trisubstituted phenyl ring having the structure,
Y\=~~ z
s x
X is halogen, OH, -CN, alkyl, alkoxy, thioalkyl, substituted thioalkyl,
S(O)alkyl, S(O)2alkyl, aminoalkyl, substituted aminoalkyl, -NOz,
perffuoroalkyl, 5 or 6 membered heterocyclic ring containing 1 to 3
heteroatoms, or thioalkoxy;
Y and Z are each, independently, hydrogen, halogen, -CN, -NO2, alkoxy, alkyl,
or thioallcyl; or
R5 is a five or six membered heteroaryl ring containing 1, 2, or 3 heteroatoms
selected
from the group consisting of O, S, and NR6 with said ring carbons being
optionally substituted with one or two substituents independently selected
from
the group consisting of hydrogen, halogen, CN, NOZ , alkyl, or alkoxy;
R6 is hydrogen, alkyl, alkoxycarbonyl, or is absent when the nitrogen of NR6
is
bonded to a ring double bond;
or pharmaceutically acceptable salt thereof.
More preferred compounds of this invention are those having the structure
R~ R2
R5 \
~~ N S02
Ra v
R3
1
wherein
R, and RZ are taken together form a ring and together contain -CHZ(CHZ)nCH2- ;

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n = 2-3;
R3 is hydrogen;
R4 is hydrogen;
R5 is a disubstituted phenyl ring having the structure,
X
Y
X is halogen, -CN, or -NOz ;
Y is hydrogen, halogen, -CN, -NOz, alkoxy, alkyl, or thioalkyl; or
RS is a five or six membered heteroaryl ring containing a heteroatom selected
from the
group consisting of O, S, and NR6 with said ring carbons being optionally
substituted with one or two substituents independently selected from the group
consisting of hydrogen, halogen, CN, or NOz ;
R6 is hydrogen, or is absent when the nitrogen of NR6 is bonded to a ring
double bond;
or pharmaceutically acceptable salt thereof.
The compounds of this invention may contain an asymmetric carbon atom and
some of the compounds of this invention may contain one or more asymmetric
centers
and may thus give rise to optical isomers and diastereoisomers. While shown
without
respect to stereochemistry in Formula 1, the present invention includes such
optical
isomers and diastereoisomers; as well as the racemic and resolved,
enantiomerically
pure R and S stereoisomers; as well as other mixtures of the R and S
stereoisomers
and pharmaceutically acceptable salts thereof.
The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having 1-6 carbon atoms; "alkenyl"
includes
both straight- and branched-chain alkyl group of 2-6 carbon atoms containing
at least
one carbon-carbon double bond; "alkynyl" group includes both straight- and

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branched-chain alkyl group of 2-6 carbon atoms with at least one carbon-carbon
triple
bond.
The terms "substituted alkyl", "substituted alkenyl", and "substituted
alkynyl"
refer to alkyl, alkenyl, and alkynyl as containing one or more substituents
from the
group including halogen, CN, OH, NOz, amino, aryl, heterocyclic, substituted
aryl,
substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy,
alkylcarbonyl,
allcylcarboxy, alkylamino, arylthio. These substituents may be attached to any
carbon
of alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a
stable
chemical moiety.
The term "aryl" is used herein to refer to an aromatic system of 6-14 carbon
atoms, which may be a single ring or multiple aromatic rings fused or linked
together
as such that at least one part of the fused or linked rings forms the
conjugated aromatic
system. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl,
tetrohydronaphthyl, phenanthryl groups.
The term "substituted aryl" refers to aryl substituted by one or more
substituents from the group including halogen, CN, OH, NOz, amino, alkyl,
cycloallcyl,
alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl,
alkylcarboxy,
alkylamino, or arylthio.
The term "heterocyclic" is used herein to describe a stable 4-14 membered
monocyclic or multicyclic heterocyclic ring which is saturated, partially
unsaturated, or
unsaturated, and which consists of carbon atoms and from one to four
heteroatoms
selected from the group including N, O, and S atoms. The N and S atoms may be
oxidized, as an N-oxide, sulfoxide, or sulfone. The heterocyclic ring also
includes any
multicyclic ring in which any of above defined heterocyclic rings is fused to
an aryl
ring. The heterocyclic ring may be attached at any heteroatom or carbon atom
provided the resultant structure is chemically stable. Such heterocyclic
groups include,
for example, tetrahydrofuran, piperidinyl, piperazinyl, 2-oxopiperidinyl,
azepinyl,
pyrrolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
oxazolyl,
isoxazolyl, morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl,
benzothienyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.

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T'he term "substituted heterocyclic" is used herein to describe a heterocyclic
having one or more substituents selected from the group which includes
halogen, CN,
OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted
alkenyl,
alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,
alkylamino,
or arylthio.
The term "thioallcyl" is used herein to refer to the SR group, where R is
alkyl
or substituted alkyl.
The term "alkoxy" is used herein to refer to the OR group, where R is alkyl or
substituted alkyl.
The term "aryloxy" is used herein to refer to the OR group, where R is aryl or
substituted aryl.
The term "alkylcarbonyl" is used herein to refer to the RCO group, where R is
alkyl or substituted alkyl.
The term "alkylcarboxy" is used herein to refer to the COOR group, where R is
alkyl or substituted alkyl. This term is also referred to as alkoxycarbonyl.
The term "aminoallcyl" refers to both secondary and tertiary amines wherein
the
alkyl or substituted alkyl groups may be either same or different and the
point of
attachment is on the nitrogen atom
The term "halogen"is defined as Cl, Br, F, and I.
Pharmaceutically acceptable salts can be formed from organic and inorganic
acids. for example, acetic, propionic, lactic, citric, tartaric, succinic,
fumaric, malefic,
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, preferably alkali metal salts, for example, sodium,
lithium, or
potassium, and organic bases, such as ammonium, mono-, di-, and
trimethylammonium, mono-, di- and triethylammonium, mono-, di- and tripropyl-
ammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium,
cyclohexylammonium, benzylammonium, dibenzylammonium, piperidinium, morpho-
linium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-
ethylmorpholinium, 1-iso-

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propylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl piperidinium, 2-
methyl-
piperidinium, 1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium,
ethyl
diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methyl-
ammonium, phenylmonoethanolammonium, and the like.
The compounds of this invention were be prepared 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 of this invention.
SO2CI SO2NH2 / / I ,SO2
S02
/ I / I ~ W I N W N
CI ~ CI H PG
4 5 6 7
,) ~~) I -.~, _-.
R f ''
R~ R2 Br ~ R2 R~ R~
/ / Ar / R2 Ar / R2
I N SO2 ~ \ I N SO2 \ I N SO2 I ,SO2
H
PG PG PG
1 ~ B 9 10 11
Scheme 1
According to Scheme 1, commercially available sulfonyl chloride 4 is converted
via the sulfonamide 5 to the 2,1-benzisothiazoline 2,2-dioxide 6 as described
in the
literature (Chiarino et al, J. Heterocycl. Chem. 23(6), 1645-9, 1986). The
nitrogen
atom of sultam 6 is then protected by a suitable protecting group, e.g.,
trimethyl silyl
ethyl.
The protected sultam 7 next is treated with a strong organo-metallic base
(e.g.,
butyl lithium, lithium diisopropylamide, potassium hexamethyldisilylazide) in
an inert
solvent (e.g., THF, diethyl ether) under nitrogen at reduced temperature (ca. -
20 °C)
(Kende et al, Synth. Commun. 12, 1, 1982). The resulting di-anion then is
treated with
excess electrophile such as an alkyl halide, preferably the iodide. If R, and
Rz are to be
joined such as the product contains a spirocycle at position 3, then the
electrophile
should be bifunctional, i.e., a diiodide. Subsequent bromination of the sultam
8

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proceeds regioselectively at room temperature with bromine in acetic acid (an
organic
co-solvent such as dichloromethane may be added as required) in the presence
of
sodium acetate, to give the aryl bromide 9. Judicious choice of reaction
conditions may
facilitate simultaneous removal of the protecting group at this step.
The bromide 9 then is reacted with a palladium salt (e.g.,
tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g., THF,
dimethoxyethane, ethanol, toluene) under an inert atmosphere (argon,
nitrogen). The
mixture then is treated with an arylboronic acid or arylboronic acid ester and
a base
(sodium carbonate, triethylamine, potassium phosphate) in water or fluoride
source
(cesium fluoride) under anhydrous conditions at elevated temperature to give
the
biphenyl sultam 10. Finally, the protecting group is removed under appropriate
conditions and the final product 11 is isolated and purified by standard
means.
If R, and Rz are different then the intermediate is prepared by reacting the
dianion of 7 with one equivalent of the electrophile R,-X (X = leaving group,
e.g.,
iodide). The resultant mono-alkylated compound may be then isolated and re-
subjected
to the reaction conditions using Rz-X, or alternatively used in situ for the
second
allcylation with RZ-X. Alternatively, if the desired product is to contain RZ
= H, then
the isolated mono-alkylated intermediate is taken though the subsequent steps.
Br ~ R~,. 'Rz Ar ~ R~,. 'Rz
N SOz ~ N SOz
i
PG PG
9 10
Scheme 2
Other methodologies also are available for coupling the aryl group, Ar, to the
sultam platform: for example, reaction of the bromide 9 with an aryl stannane,
aryl
zinc, or aryl magnesium halide in the presence of a palladium or nickel
catalyst
(Scheme 2). The required aryl-metallic species are formed via standard
techniques.
Furthermore, the bromide 9 may be converted to an aryl boronic acid via
standard
procedures (treatment with n-butyllithium followed by addition of trimethyl
borate and

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subsequent boronic ester hydrolysis) that will then undergo the range of
previously
described coupling procedures with a suitable aryl bromide.
The antiprogestational activity of the compounds of this invention was
demonstrated in an in vitro standard pharmacological test procedure which
evaluated
the antiprogestational potency of a representative compound of this invention
by
measuring its effect on PRE-luciferase reporter activity in CV-1 cells co-
transfected
with human PR and PRE-luciferase plasmids. The procedure used and results
obtained
are described in Example 2 below.
The results obtained in this standard pharmacological test procedure
demonstrate that the compounds of this invention are progestational
antagonists, and
are therefore useful as oral contraceptives (male and female), in hormone
replacement
therapy (particularly when combined with an estrogen), in the treatment of
endometriosis, luteal phase defects, benign breast and prostatic diseases and
prostatic,
breast, ovarian, uterine and endometrial cancers.
The compounds of this invention can be used alone as a sole therapeutic agent
or can be used in combination with other agents, such as other estrogens,
progestins,
or androgens.
The compounds of this invention can be formulated neat or with a
pharmaceutical carrier for administration, the proportion of which is
determined by the
solubility and chemical nature of the compound, chosen route of administration
and
standard pharmacological practice. The pharmaceutical carrier may be solid or
liquid.
A solid carrier can include one or more substances which may also act as
flavoring agents, lubricants, solubilizers, suspending agents, fillers,
glidants,
compression aids, binders or tablet-disintegrating agents; it can also be an
encapsulating material. In powders, the carrier is a finely divided solid
which is in
admixture with the finely divided active ingredient. In tablets, the active
ingredient is
mixed with a carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The powders and
tablets
preferably contain up to 99% of the active ingredient. Suitable solid carriers
include,
for example, calcium phosphate, magnesium stearate, talc, sugars, lactose,
dextrin,
starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange resins.

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Liquid carriers are used in preparing solutions, suspensions, emulsions,
syrups,
elixirs and pressurized compositions. The active ingredient can be dissolved
or
suspended in a pharmaceutically acceptable liquid carrier such as water, an
organic
solvent, a mixture of both or pharmaceutically acceptable oils or fats. The
liquid
carrier can contain other suitable pharmaceutical additives such as
solubilizers,
emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending
agents,
thickening agents, colors, viscosity regulators, stabilizers or osmo-
regulators. Suitable
examples of liquid carriers for oral and parenteral administration include
water
(partially containing additives as above, e.g. cellulose derivatives,
preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric alcohols and
polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils
(e.g.
fractionated coconut oil and arachis oil). For parenteral administration, the
carrier can
also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile
liquid
carriers are useful in sterile liquid form compositions for parenteral
administration.
The liquid carrier for pressurized compositions can be halogenated hydrocarbon
or
other pharmaceutically acceptable propellant.
Liquid pharmaceutical compositions which are sterile solutions or suspensions
can be utilized by, for example, intramuscular, intraperitoneal or
subcutaneous
injection. Sterile solutions can also be administered intravenously. The
compounds of
this invention can also be administered orally either in liquid or solid
composition form.
The compounds of this invention may be administered rectally or vaginally in
the form of a conventional suppository. For administration by intranasal or
intrabronchial inhalation or insufflation, the compounds of this invention may
be
formulated into an aqueous or partially aqueous solution, which can then be
utilized in
the form of an aerosol. T'he compounds of this invention may also be
administered
transdermally through the use of a transdermal patch containing the active
compound
and a carrier that is inert to the active compound, is non toxic to the skin,
and allows
delivery of the agent for systemic absorption into the blood stream via the
skin. The
carrier may take any number of forms such as creams and ointments, pastes,
gels, and
occlusive devices. The creams and ointments may be viscous liquid or semisolid
emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of
absorptive powders dispersed in petroleum or hydrophilic petroleum containing
the
active ingredient may also be suitable. A variety of occlusive devices may be
used to
release the active ingredient into the blood stream such as a semipermeable
membrane
covering a reservoir containing the active ingredient with or without a
carrier, or a

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matrix containing the active ingredient. Other occlusive devices are known in
the
literature.
The dosage requirements vary with the particular compositions employed, the
route of administration, the severity of the symptoms presented and the
particular
subject being treated. Based on the results obtained in the standard
pharmacological
test procedures, projected daily dosages of active compound would be 0.02
~g/kg -
750 ~g/kg. Treatment will generally be initiated with small dosages less than
the
optimum dose of the compound. Thereafter the dosage is increased until the
optimum
effect under the circumstances is reached; precise dosages for oral,
parenteral, nasal, or
intrabronchial administration will be determined by the administering
physician based
on experience with the individual subject treated. Preferably, the
pharmaceutical
composition is in unit dosage form, e.g. as tablets or capsules. In such form,
the
composition is sub-divided in unit dose containing appropriate quantities of
the active
ingredient; the unit dosage forms can be packaged compositions, for example,
packaged powders, vials, ampoules, pre filled syringes or sachets containing
liquids.
The unit dosage form can be, for example, a capsule or tablet itself, or it
can be the
appropriate number of any such compositions in package form
The following provides the preparation of a representative compound of this
invention.
Example 1
5-(3-chlorophenyl~piro[2.1-benzisothiazole-3(1H).1'-cyclohexane] 2,2-dioxide
To 1,3-dihydro-2,1-benzisothiazoline 2,2-dioxide (Chiarino et al, J.
Heterocycl. Chem. 23(6), 1645-9, 1986) (0.74 g, 4.4 mmol) in anhydrous
dichloromethane (minimum amount) at room temperature was added sequentially
N,N-
diisopropylethylamine (0.76 mL, 4.4 mmol) and 2-(trimethylsilyl)ethoxymethyl
chloride (0.77 mL, 4.4 mmol). After 30 min, the reaction was poured into water
(50
mL), the layers were separated, and the aqueous phase was extracted with ethyl
acetate (2 x 50 mL). The organic layers were combined, washed with brine (30
mL),
dried over magnesium sulfate, filtered and concentrated in vacuo to give 1, 3-
dihydro-
1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (1.3 g, 99%) as
an off
white solid. 'H NMR (CDC13, 300MHz) 8 0.02 (s, 9 H), 0.97 (dd, 2 H, J= 8.3,
8.2

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Hz), 3. 73 (dd, 2 H, J = 8.2, 8.3 Hz), 4.40 (s, 2 H), 5.08 (s, 2 H), 7.05 (d,
1 H, J = 7.4
Hz), 7.07 (dd, 1 H), 7.26 (d, 1 H, J = 7.4 Hz), 7.35 ('t', 1 H, J = 7.6, 7.6
Hz). MS
((+) ApCI m/z 317 [M+NH4]+.
To 1,3-dihydro-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide
~(1.3
g, 4.3 mmol) in anhydrous tetrahydrofuran (13 mL) at room temperature was
added
1,5-diiodopentane (1.29 mL, 8.6 mmol). The mixture was cooled to -78 °C
and
lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofiu-an, 17.3 mL,
17 mmol)
was added. After 15 min, the reaction mixture was poured into water (50 mL),
the
layers were separated, and the aqueous phase was extracted with ethyl acetate
(3 x 50
mL). The organic layers were combined, washed with brine (30 mL), dried over
magnesium sulfate, filtered and concentrated in vacuo. Purification by flash
column
chromatography (5% ethyl acetate/hexane) on silica gel gave 1,3-dihydro-3-
spirocyclohexyl-1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide
(0.8 g,
51%) as an off white solid. 'H NMR (CDCl3, 300 MHz) S 0.00 (s, 9 H), 0.95 (dd,
2
H, J = 8.3, 8.2 Hz), 1.18-2.36 (m, 10 H), 3.72 (dd, 2 H, J = 8.2, 8. 3 Hz), 5.
06 (s, 2
H), 7.03 ('t', 1 H, J= 7.8 Hz), 7.06 (dd, 1 H, J= 1, 7.6 Hz), 7.18 (dd, 1 H,
J= l.l,
7.6 Hz), 7.28 (dt, 1 H, J= 1.3, 7.7 Hz). MS (EI) mlz 367 [M]+.
To a stirred solution of 1,3-dihydro-3-spirocyclohexyl-1-(2'-
trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.8 g, 2.2 mmol) in
glacial acetic
acid (5 mL) at room temperature was added dropwise a solution of bromine (0.11
mL,
2.2 mmol) in glacial acetic acid (2.2 mL) After stirring for 10 min, anhydrous
sodium
acetate (0.18 g, 2.2 mmol) was added and the solution was concentrated in
vacuo.
The residue was dissolved in ethyl ether (50 mL) and washed sequentially with
water
(50 mL), aqueous saturated sodium bicarbonate solution (50 mL), water (50 mL)
and
brine (30 mL). The organic layer was dried over magnesium sulfate, filtered
and
concentrated in vacuo. Purification by flash column chromatography (20% ethyl
acetate/hexane) on silica gel gave a complex mixture of products (0.56 g) with
identical TLC characteristics as a white foam. The mixture was used without
further
purification.

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A solution of the mixture containing 5-bromo-1,3-dihydro-3-spirocyclohexyl-
1-(2'-trimethylsilylethyl)-2,1-benzisothiazoline 2,2-dioxide (0.56 g, 1.25
mmol) and
tetrakis(triphenylphosphine)palladium(0) (100 mg) in toluene (25 mL) was
stirred
under a flow of nitrogen for 25 min. To the solution was added sequentially
solutions
of 3-chlorophenylboronic acid (0.4 g, 2.5 mmol) in absolute ethanol (5 mL) and
potassium carbonate (0.35 g, 2.5 mmol) in water (5 mL). The mixture was heated
to
80 °C for 16 h and allowed to cool. The reaction mixture was poured
into aqueous
saturated sodium bicarbonate solution (50 mL) and the layers were separated.
The
aqueous phase was extracted with ethyl acetate (3 x 50 mL). The organic layers
were
combined, washed with water (50 mL) and brine (30 mL) and dried over magnesium
sulfate. The solution was filtered, concentrated in vacuo, and the residue was
purified
by flash column chromatography on silica gel (2% ethyl acetate/toluene) and
then by
HPLC to give the title compound (65 mg) as a low melting yellow foam. HPLC
conditions: Zorbax PRO, C18, 10u, 15A, 50 x 250 mm; mobile phase composition
and gradient program, 70% water/ 30% AcCN; flow rate, 100 mL/min; injection
volume, 120 mg/3 mL MeOH; detection wavelength, 280 nm, 500 PSI; temperature,
amb. 'H NMR (DMSO-db, 300 MHz), 8 1.47-2.19 (m, 10 H), 6.87 (d, 1 H , J = 8.2
Hz), 7.38 ('d', 1 H, J = 8.1 Hz), 7.46 ('t', 1 H, J = 7.9, 7.7 Hz), 7.56 (dd,
1 H, J =
1.7, 8.2 Hz), 7.62 ('d', 1 H, J = 7.7 Hz), 7.71, ('d', 1 H, J = 1.7 Hz), 7.75
(bs, 1H),
10.55 (bs, 1 H). MS (EI) m/z 347 [M]+. Anal. Calcd for CISH,sCINOaS: C, 62.15;
H,
5.22: N, 4.03. Found: C, 59.84; H, 5.30; N, 3.57.
Example 2 - Biological Activity
The antiprogestational activity of the compound of Example 1 was
demonstrated in a conventional pharmacological test.
Rea~ants
Growth medium: DMEM (BioWhittaker) containing 10% (v/v) fetal
bovine serum (heat inactivated), 0.1 mM MEM non-essential amino acids,
100U/ml penicillin, 100mg/ml streptomycin, and 2 mM GlutaMax (GIBCO,
BRL).

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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, 100U/ml penicillin, 100mg/ml streptomycin, and
2
mM GlutaMax (GIBCO, BRL).
Test Procedure
Stock CV-1 cells were maintained in growth medium. Co-transfection
was done using 1.2x10' cells, 5 mg pLEM plasmid with hPR-B inserted at Sphl
and
BamHl sites, 10 mg pGL3 plasmid with two PREs upstream of the luciferase
sequence, and 50 mg sonicated calf thymus DNA as Garner DNA in 250 ml.
Electroporation was carned out at 260 V and 1,000 mF in a Biorad Gene Pulser
II.
After electroporation, cells were resuspended in growth medium and plated in
96-well
plate at 40,000 cells/well in 200 ml. 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 were discarded, cells were washed three times with D-PBS (GIBCO, BRL).
Fifty ml of cell lysis buffer (Promega, Madison, WI) 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.
When evaluated in the above-described test procedure, the compound of
Example 1 had an ICSO of 900 nM. The ICSO is the concentration of test
compound
that gives half maximal decrease in 3 nM progesterone induced PRE-luciferase
activity.
All publications cited in this specification are incorporated herein by
reference herein. While the invention has been described with reference to a
particularly preferred embodiment, 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.

Representative Drawing