U.S. patent application number 11/624808 was filed with the patent office on 2007-06-21 for cyclohexyl derivatives as selective estrogen receptor modulators.
Invention is credited to Nareshkumar F. Jain, Mark J. Mecielag, William V. Murray, Raymond A. Ng, Zhihua Sui.
Application Number | 20070142379 11/624808 |
Document ID | / |
Family ID | 33551508 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070142379 |
Kind Code |
A1 |
Jain; Nareshkumar F. ; et
al. |
June 21, 2007 |
CYCLOHEXYL DERIVATIVES AS SELECTIVE ESTROGEN RECEPTOR
MODULATORS
Abstract
The present invention is directed to novel cyclohexyl
derivatives, pharmaceutical compositions containing them and their
use in the treatment of disorders and diseases mediated by an
estrogen receptor.
Inventors: |
Jain; Nareshkumar F.;
(Raritan, NJ) ; Mecielag; Mark J.; (Raritan,
NJ) ; Murray; William V.; (Raritan, NJ) ; Ng;
Raymond A.; (Raritan, NJ) ; Sui; Zhihua;
(Raritan, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
33551508 |
Appl. No.: |
11/624808 |
Filed: |
January 19, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10858435 |
Jun 1, 2004 |
7183445 |
|
|
11624808 |
Jan 19, 2007 |
|
|
|
60474783 |
May 31, 2003 |
|
|
|
Current U.S.
Class: |
514/238.2 ;
514/317; 514/408; 514/543; 544/171; 546/235; 548/571; 560/55 |
Current CPC
Class: |
C07C 29/60 20130101;
C07C 69/757 20130101; C07C 43/23 20130101; C07C 41/30 20130101;
C07C 43/215 20130101; C07C 2601/16 20170501; A61P 43/00 20180101;
A61P 15/02 20180101; C07D 295/088 20130101; C07C 29/12 20130101;
A61P 35/00 20180101; C07C 37/055 20130101; A61P 19/10 20180101;
C07C 41/22 20130101; A61P 19/08 20180101; C07C 2602/08 20170501;
A61P 25/28 20180101; A61P 3/06 20180101; A61P 19/02 20180101; C07C
45/69 20130101; C07C 41/20 20130101; C07C 41/26 20130101; A61P 9/10
20180101; C07C 2602/10 20170501; C07C 39/23 20130101; C07C 2601/14
20170501; A61P 9/00 20180101; C07C 217/18 20130101; C07D 209/04
20130101; A61P 15/00 20180101; A61P 5/30 20180101; C07C 39/17
20130101; C07C 41/18 20130101; C07C 45/69 20130101; C07C 49/683
20130101; C07C 45/69 20130101; C07C 47/47 20130101; C07C 37/055
20130101; C07C 39/23 20130101; C07C 41/30 20130101; C07C 43/215
20130101; C07C 41/22 20130101; C07C 43/225 20130101; C07C 41/26
20130101; C07C 43/23 20130101; C07C 41/18 20130101; C07C 43/23
20130101; C07C 41/20 20130101; C07C 43/23 20130101; C07C 29/12
20130101; C07C 33/38 20130101; C07C 29/60 20130101; C07C 33/38
20130101 |
Class at
Publication: |
514/238.2 ;
514/317; 514/543; 514/408; 546/235; 544/171; 548/571; 560/055 |
International
Class: |
A61K 31/5375 20060101
A61K031/5375; A61K 31/445 20060101 A61K031/445; A61K 31/40 20060101
A61K031/40; C07C 69/76 20060101 C07C069/76; C07D 265/30 20060101
C07D265/30; C07D 211/32 20060101 C07D211/32; C07D 207/04 20060101
C07D207/04 |
Claims
1. A compound of the formula (I) ##STR77## wherein represents a
single or a double bond; R.sup.1a is selected from the group
consisting of hydrogen and lower alkyl; R.sup.1 is selected from
the group consisting of alkyl, hydroxy substituted alkyl, alkenyl,
hydroxy substituted alkenyl, alkynyl, hydroxy substituted alkynyl,
alkoxyalkyl, alkoxy-carbonyl, alkyl-carbonyl, aryl-carbonyl,
heteroaryl-carbonyl, heterocycloalkyl-carbonyl,
alkyl-carbonyl-alkyl, NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-alkoxy-alkyl; R.sup.A and R.sup.B are each
independently selected from the group consisting of hydrogen and
alkyl; alternatively R.sup.A and R.sup.B are taken together with
the N atom to which they are bound to form a heteroaryl or
heterocycloalkyl group; R.sup.2 is selected from the group
consisting of hydrogen, carboxy, alkyl, hydroxy substituted alkyl,
alkenyl, hydroxy substituted alkenyl, alkynyl, hydroxy substituted
alkynyl, alkoxyalkyl, alkoxy-carbonyl, alkyl-carbonyl,
aryl-carbonyl, heteroaryl-carbonyl, heterocycloalkyl-carbonyl,
alkyl-carbonyl-alkyl, NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-alkoxy-alkyl; alternatively R.sup.1 and R.sup.2 are
taken together with the atoms to which they are bound to form a
five to eight membered saturated ring structure of the formula
##STR78## wherein n is an integer from 1 to 4; wherein R.sup.C and
R.sup.D are independently selected from hydrogen, hydroxy, alkyl,
alkenyl, alkynyl or alkoxy; alternatively R.sup.C and R.sup.D are
taken together with the carbon atom to which they are bound to form
an oxo group; alternatively still, R.sup.1 and R.sup.2 are taken
together with the atoms to which they are bound to form a
heteroatom containing saturated ring structure of the formula
##STR79## wherein m is an integer from 1 to 3; R.sup.3 is selected
from the group consisting of hydrogen and alkyl; ##STR80## is
selected from the group consisting of aryl, aralkyl and heteroaryl;
wherein the heteroaryl group is bound to the core structure through
a carbon atom; and wherein the aryl, aralkyl or heteroaryl group is
optionally substituted with one or more substitutents independently
selected from hydroxy, alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-alkoxy; ##STR81## is selected from the group
consisting of aryl, aralkyl and heteroaryl; wherein the heteroaryl
group is bound to the core structure through a carbon atom; and
wherein the aryl, aralkyl or heteroaryl group is optionally
substituted with one or more substitutents independently selected
from hydroxy, alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-alkoxy; provided that when is a double bond,
R.sup.1a is hydrogen, R.sup.2 is hydrogen, R.sup.3 is hydrogen, and
##STR82## are the same and selected from the group consisting of
phenyl or substituted phenyl, wherein the substituents on the
phenyl are one to two selected from alkoxy, then R.sup.1 is other
than hydroxy substituted lower alkyl or alkoxycarbonyl; provided
further that when is a double bond, R.sup.1a is hydrogen or lower
alkyl, ##STR83## is phenyl, then R.sup.1 is selected from the group
consisting of NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-alkoxy-alkyl; provided further that when is a
single bond, R.sup.1a is hydrogen, R.sup.2 is hydrogen or lower
alkyl, R.sup.3 is hydrogen, and ##STR84## are the same and are
phenyl, then R.sup.1 is other than lower alkyl, hydroxy substituted
lower alkyl, alkylcarbonyl or alkoxycarbonyl; provided further that
when is a single bond, R.sup.1 is lower alkyl, R.sup.1a is
hydrogen, R.sup.2 is hydrogen, R.sup.3 is hydrogen and ##STR85## is
other than benzimidazolyl; provided further that when is a single
or double bond, R.sup.1a is lower alkyl, R.sup.3 is hydrogen,
R.sup.1 and R.sup.2 are taken together with the atoms to which they
are bound to form cyclohexyl or 3-hydroxyphenyl and ##STR86## is
other than 4-(NR.sup.AR.sup.B-lower alkoxy)-phenyl, wherein R.sup.A
and R.sup.B are each independently selected from hydrogen or lower
alkyl or R.sup.A and R.sup.B are taken together with the N atom to
which they are bound to form piperidinyl; provided further than
when is a single or double bond, R.sup.1a is hydrogen, R.sup.3 is
hydrogen and R.sup.1 and R.sup.2 are taken together with the atoms
to which they are bound to form ##STR87## then ##STR88## are not
the same and phenyl; provided further that when is a double bond,
R.sup.1a is lower alkyl, R.sup.3 is hydrogen and R.sup.1 and
R.sup.2 are taken together with the atoms to which they are bound
to form a five membered saturated ring structure of the formula
##STR89## wherein R.sup.C is selected from hydroxy or alkoxy, then
##STR90## are other than phenyl or substituted phenyl, wherein the
substituents on the phenyl are one or more independently selected
from hydroxy, alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-alkoxy; or a pharmaceutically acceptable salt
thereof.
2. A compound as in claim 1 wherein represents a single or a double
bond; R.sup.1a is selected from the group consisting of hydrogen
and lower alkyl; R.sup.1 is selected from the group consisting of
lower alkyl, hydroxy substituted lower alkyl, lower alkenyl,
hydroxy substituted lower alkenyl, lower alkoxy-lower alkyl, lower
alkoxy-carbonyl, lower alkyl-carbonyl, phenyl-carbonyl, lower
alkyl-carbonyl-lower alkyl, NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-lower alkoxy-lower alkyl; R.sup.A and R.sup.B are
each independently selected from the group consisting of hydrogen
and lower alkyl; alternatively R.sup.A and R.sup.B are taken
together with the N atom to which they are bound to form a five to
six membered heteroaryl or a five to six membered heterocycloalkyl
group; R.sup.2 is selected from the group consisting of hydrogen,
carboxy, lower alkyl, hydroxy substituted lower alkyl, lower
alkenyl, hydroxy substituted lower alkenyl, lower alkoxy-lower
alkyl, lower alkoxy-carbonyl, lower alkyl-carbonyl,
phenyl-carbonyl, lower alkyl-carbonyl-lower alkyl,
NR.sup.AR.sup.B-carbonyl and NR.sup.AR.sup.B-lower alkoxy-lower
alkyl; alternatively, R.sup.1 and R.sup.2 are taken together with
the atom to which they are bound to form a saturated ring structure
of the formula; ##STR91## wherein n is an integer from 1 to 4;
R.sup.C and R.sup.D are independently selected from the group
consisting of hydrogen, hydroxy, lower alkyl, lower alkynyl and
lower alkoxy; alternatively R.sup.C and R.sup.D are taken together
with the carbon atom to which they are bound to form an oxo group;
alternatively still, R.sup.1 and R.sup.2 are taken together with
the atom to which they are bound to form a heteroatom containing
saturated ring structure of the formula ##STR92## wherein m is an
integer from 1 to 2; R.sup.3 is selected from the group consisting
of hydrogen and lower alkyl; ##STR93## is selected from the group
consisting of aryl and heteroaryl; wherein the heteroaryl group is
bound to the core structure through a carbon atom; and wherein the
aryl or heteroaryl group is optionally substituted with one to two
substitutents independently selected from hydroxy, lower alkoxy,
aralkyl, aralkyloxy or NR.sup.AR.sup.B-lower alkoxy; ##STR94## is
selected from the group consisting of aryl and heteroaryl; wherein
the heteroaryl group is bound to the core structure through a
carbon atom; and wherein the aryl or heteroaryl group is optionally
substituted with one to two substitutents independently selected
from hydroxy, lower alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-lower alkoxy; provided that when is a double bond,
R.sup.1a is hydrogen, R.sup.2 is hydrogen, R.sup.3 is hydrogen, and
##STR95## are the same and selected from the group consisting of
phenyl or substituted phenyl, wherein the substituents on the
phenyl are one to two selected from lower alkoxy, then R.sup.1 is
other than hydroxy substituted lower alkyl or lower
alkoxy-carbonyl; provided further that when is a double bond,
R.sup.1a is hydrogen or lower alkyl, ##STR96## is phenyl, then
R.sup.1 is selected from the group consisting of
NR.sup.AR.sup.B-carbonyl and NR.sup.AR.sup.B-lower alkoxy-lower
alkyl; provided further that when is a single bond, R.sup.1a is
hydrogen, R.sup.2 is hydrogen or lower alkyl, R.sup.3 is hydrogen,
and ##STR97## are the same and are phenyl, then R.sup.1 is other
than lower alkyl, hydroxy substituted lower alkyl, lower
alkyl-carbonyl or lower alkoxy-carbonyl; provided further that when
is a single bond, R.sup.1 is lower alkyl, R.sup.1a is hydrogen,
R.sup.2 is hydrogen, R.sup.3 is hydrogen and ##STR98## is other
than benzimidazolyl; provided further that when is a single or
double bond, R.sup.1a is lower alkyl, R.sup.3 is hydrogen, R.sup.1
and R.sup.2 are taken together with the atoms to which they are
bound to form cyclohexyl or 3-hydroxyphenyl and ##STR99## is other
than 4-(NR.sup.AR.sup.B-lower alkoxy)-phenyl, wherein R.sup.A and
R.sup.B are each independently selected from hydrogen or lower
alkyl or R.sup.A and R.sup.B are taken together with the N atom to
which they are bound to form piperidinyl; provided further than
when is a single or double bond, R.sup.1a is hydrogen, R.sup.3 is
hydrogen and R.sup.1 and R.sup.2 are taken together with the atoms
to which they are bound to form ##STR100## then ##STR101## are not
the same and phenyl; provided further that when is a double bond,
R.sup.1a is lower alkyl, R.sup.3 is hydrogen and R.sup.1 and
R.sup.2 are taken together with the atoms to which they are bound
to form a five membered saturated ring structure of the formula
##STR102## wherein R.sup.C is selected from hydroxy or lower
alkoxy, then ##STR103## are other phenyl or substituted phenyl,
wherein the substituents on the phenyl are one or more
independently selected from hydroxy, lower alkoxy, aralkyl,
aralkyloxy or NR.sup.AR.sup.B-lower alkoxy; or a pharmaceutically
acceptable salt thereof.
3. A compound as in claim 2 wherein represents a single or a double
bond; R.sup.1a is selected from the group consisting of hydrogen
and lower alkyl; R.sup.1 is selected from the group consisting of
lower alkyl, hydroxy substituted lower alkyl, hydroxy substituted
lower alkenyl, lower alkoxy-lower alkyl, lower alkoxy-carbonyl,
lower alkyl-carbonyl-lower alkyl and NR.sup.AR.sup.B-lower
alkoxy-lower alkyl and NR.sup.AR.sup.B-carbonyl; wherein R.sup.A
and R.sup.B are independently selected from hydrogen and lower
alkyl; alternatively R.sup.A and R.sup.B are taken together with
the nitrogen atom to which they are bound to form a five to six
membered heteroaryl or a five to six membered heterocycloalkyl;
R.sup.2 is selected from the group consisting of hydrogen, carboxy,
lower alkyl, hydroxy substituted lower alkyl, lower alkyl-carbonyl,
lower alkoxy-lower alkyl, lower alkyl-carbonyl-lower alkyl and
NR.sup.AR.sup.B-lower alkoxy-lower alkyl; R.sup.3 is selected from
the group consisting of hydrogen and lower alkyl; ##STR104## is
selected from the group consisting of aryl; wherein the aryl group
is optionally substituted with a substituent selected from hydroxy,
lower alkoxy and aralkyloxy; ##STR105## is selected from the group
consisting of aryl; wherein the aryl group is optionally
substituted with one to two substituents independently selected
from hydroxy, lower alkoxy, aralkyl and NR.sup.AR.sup.B-lower
alkoxy; provided that when is a double bond, R.sup.1a is hydrogen,
R.sup.2 is hydrogen, R.sup.3 is hydrogen, and ##STR106## are the
same and selected from the group consisting of phenyl or
substituted phenyl, wherein the substituent on the phenyl is
selected from lower alkoxy, then R.sup.1 is other than hydroxy
substituted lower alkyl or lower alkoxy-carbonyl; provided further
that when is a double bond, R.sup.1a is hydrogen or lower alkyl,
##STR107## is phenyl, then R.sup.1 is selected from the group
consisting of NR.sup.AR.sup.B-carbonyl and NR.sup.AR.sup.B-lower
alkoxy-lower alkyl; provided further that when is a single bond,
R.sup.1a is hydrogen, R.sup.2 is hydrogen or lower alkyl, R.sup.3
is hydrogen, and ##STR108## are the same and are phenyl, then
R.sup.1 is other than lower alkyl, hydroxy substituted lower alkyl,
lower alkyl-carbonyl or lower alkoxy-carbonyl; or a
pharmaceutically acceptable salt thereof.
4. A compound as in claim 3 wherein represents a single or a double
bond; R.sup.1a is selected from the group consisting of hydrogen
and methyl. R.sup.1 is selected from the group consisting of
methyl, hydroxymethyl, 1-hydroxy-propyn-2-yl, 1-hydroxy-n-propyl,
methoxymethyl, methoxycarbonyl, methylcarbonylmethyl,
dimethylamino-ethoxy-methyl, morpholinyl-ethoxy-methyl,
morpholinylcarbonyl and diethylaminocarbonyl; R.sup.2 is selected
from the group consisting of hydrogen, carboxy, methyl,
hydroxymethyl, methoxycarbonyl, methoxymethyl, methylcarbonylmethyl
and dimethylamino-ethoxy-methyl; R.sup.3 is selected from the group
consisting of hydrogen and ethyl; ##STR109## is selected from the
group consisting of phenyl, 4-hydroxyphenyl, 4-methoxyphenyl and
4-benzyloxy-phenyl; ##STR110## is selected from the group
consisting of phenyl, 4-hydroxyphenyl, 4-methoxyphenyl,
4-dimethylaminoethoxy-phenyl, 4-hydroxy-3-benzyl-phenyl and
4-(piperidinyl-ethoxy)-phenyl; provided that when is a double bond,
R.sup.1a is hydrogen, R.sup.2 is hydrogen, R.sup.3 is hydrogen, and
##STR111## are the same and selected from the group consisting of
phenyl and 4-methoxyphenyl, then R.sup.1 is other than
hydroxymethyl, 1-hydroxy-n-propyl or methoxycarbonyl; provided
further that when is a double bond, R.sup.1a is hydrogen or methyl,
##STR112## is phenyl, then R.sup.1 is selected from the group
consisting of dimethylamino-ethoxy-methyl,
morpholinyl-ethoxy-methyl, morpholinylcarbonyl and
diethylaminocarbonyl; provided further that when is a single bond,
R.sup.1a is hydrogen, R.sup.2 is hydrogen or methyl, R.sup.3 is
hydrogen, and ##STR113## are the same and are phenyl, then R.sup.1
is other than methyl, hydroxymethyl, 1-hydroxy-n-propyl or
methoxycarbonyl; or a pharmaceutically acceptable salt thereof.
5. A compound as in claim 2 wherein represents a single or a double
bond; R.sup.1a is selected from the group consisting of hydrogen
and lower alkyl; R.sup.1 and R.sup.2 are taken together with the
atoms to which they are bound to form a saturated ring structure of
the formula ##STR114## wherein n is an integer from 1 to 4; R.sup.C
and R.sup.D are independently selected from the group consisting of
hydrogen, hydroxy and lower alkynyl; alternatively R.sup.C and
R.sup.D are taken together with the carbon atom to which they are
bound to form an oxo group; alternatively, R.sup.1 and R.sup.2 are
taken together with the atoms to which they are bound to form a
heteroatom containing saturated ring structure of the formula
##STR115## wherein m is an integer from 1 to 2; R.sup.3 is
hydrogen; ##STR116## is aryl; wherein the aryl group is optionally
substituted with a substituent selected from hydroxy or lower
alkoxy; ##STR117## is aryl; wherein the aryl is optionally
substituted with a substituent selected from lower alkoxy; provided
than when is a single or double bond, R.sup.1a is hydrogen, R.sup.3
is hydrogen and R.sup.1 and R.sup.2 are taken together with the
atoms to which they are bound to form ##STR118## then ##STR119##
are not the same and phenyl; provided further that when is a double
bond, R.sup.1a is lower alkyl, R.sup.3 is hydrogen and R.sup.1 and
R.sup.2 are taken together with the atoms to which they are bound
to form ##STR120## then ##STR121## is other than phenyl or
substituted phenyl wherein the substituent selected from hydroxy or
lower alkoxy and ##STR122## is other than phenyl or substituted
phenyl, wherein the substituent on the phenyl is lower alkoxy; or a
pharmaceutically acceptable salt thereof.
6. A compound as in claim 5 wherein represents a single or a double
bond; R.sup.1a is selected from the group consisting of hydrogen
and methyl; R.sup.1 and R.sup.2 are taken together with the atom to
which they are bound to form a ring structure selected from the
group consisting of 3-hydroxy-3-ethynyl-cyclopentyl,
3-hydroxy-cyclopentyl, 3-oxo-cyclopentyl, 3-hydroxy-cyclohexyl,
3-oxo-cyclohexyl, 3-oxo-cyclooctyl and dihydro-fur-4-yl; R.sup.3 is
hydrogen; ##STR123## is selected from the group consisting of
phenyl, 4-hydroxyphenyl and 4-methoxyphenyl; ##STR124## is selected
from the group consisting of phenyl and 4-methoxyphenyl; provided
than when is a single or double bond, R.sup.1a is hydrogen, R.sup.3
is hydrogen and R.sup.1 and R.sup.2 are taken together with the
atoms to which they are bound to form ##STR125## then ##STR126##
are not the same and phenyl; provided further that when is a double
bond, R.sup.1a is methyl and R.sup.3 is hydrogen, then R.sup.1 and
R.sup.2 are taken together with the atoms to which they are bound
to form a ring structure other than ##STR127## or a
pharmaceutically acceptable salt thereof.
7-10. (canceled)
11. A compound of formula (III) ##STR128## wherein represents a
single or a double bond; X is selected from the group consisting of
C(O) and CH.sub.2; R.sup.4 is selected from the group consisting of
hydrogen and lower alkyl; R.sup.5 is selected from the group
consisting of alkyl; R.sup.6 is selected from the group consisting
of -(aralkyl)-Q-(alkyl)-NR.sup.AR.sup.B; Q is selected from the
group consisting of O and S; R.sup.A and R.sup.B are each
independently selected from the group consisting of hydrogen and
alkyl; alternatively R.sup.A and R.sup.B are taken together with
the N atom to which they are bound to form a heteroaryl or
heterocycloalkyl group; or a pharmaceutically acceptable salt
thereof.
12. A compound as in claim 11 wherein represents a single or a
double bond; X is selected from the group consisting of C(O) and
CH.sub.2; R.sup.4 is selected from the group consisting of hydrogen
and lower alkyl; R.sup.5 is selected from the group consisting of
lower alkyl; R.sup.6 is selected from the group consisting of
-(benzyl)-Q-(lower alkyl)-NR.sup.AR.sup.B; Q is selected from the
group consisting of O and S; R.sup.A and R.sup.B are each
independently selected from the group consisting of hydrogen and
lower alkyl; alternatively R.sup.A and R.sup.B are taken together
with the N atom to which they are bound to form a five to six
membered heteroaryl or a five to six membered heterocycloalkyl
group; or a pharmaceutically acceptable salt thereof.
13. A compound as in claim 12 wherein represents a single or a
double bond; X is C(O); R.sup.4 is selected from the group
consisting of lower alkyl; R.sup.5 is selected from the group
consisting of lower alkyl; R.sup.6 is selected from the group
consisting of -(benzyl)-O-(lower alkyl)-NR.sup.AR.sup.B wherein
R.sup.A and R.sup.B are each independently selected from lower
alkyl; alternatively R.sup.A and R.sup.B are taken together with
the N atom to which they are bound to form a five to six membered
heteroaryl or five to six membered heterocycloalkyl group; or a
pharmaceutically acceptable salt thereof.
14. A compound as in claim 13 wherein represents a single or a
double bond; X is C(O); R.sup.4 is ethyl; R.sup.5 is methyl;
R.sup.6 is selected from the group consisting of
4-(dimethylamino-ethoxy)-benzyl, 4-(morpholinyl-ethoxy)-benzyl,
4-(piperidinyl-ethoxy)-benzyl and 4-(pyrrolidinyl-ethoxy)-benzyl;
or a pharmaceutically acceptable salt thereof.
15. A compound selected from the group consisting of
3-(4-benzyloxy-benzyl)-2-methyl-4-oxo-cyclohex-2-enecarboxylic acid
ethyl ester;
4-{4-hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl-
]-cyclohex-1-enyl}-phenol; or a pharmaceutically acceptable salt
thereof.
16. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1.
17. A pharmaceutical composition made by mixing a compound of claim
1 and a pharmaceutically acceptable carrier.
18. A process for making a pharmaceutical composition comprising
mixing a compound of claim 1 and a pharmaceutically acceptable
carrier.
19. A method of treating a disorder mediated by an estrogen
receptor, in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of the compound of
claim 1.
20. The method of claim 19, wherein the disorder mediated by an
estrogen receptor is selected from the group consisting of hot
flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia,
loss of cognitive function, degenerative brain diseases,
cardiovascular diseases, cerebrovascular diseases, cancer of the
breast tissue, hyperplasia of the breast tissue, cancer of the
endometrium, hyperplasia of the endometrium, cancer of the cervix,
hyperplasia of the cervix, cancer of the prostate, hyperplasia of
the prostate, endometriosis, uterine fibroids, osteoarthritis and
contraception.
21. The method of claim 19, wherein the disorder mediated by an
estrogen receptor is selected from the group consisting of
osteoporosis, hot flashes, vaginal dryness, breast cancer and
endometriosis.
22. A method of treating a disorder mediated by an estrogen
receptor in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of the composition
of claim 16.
23. A method of contraception comprising co-therapy with a
therapeutically effective amount of a compound as in claim 1 and a
progestogen or a progestogen antagonist.
24-31. (canceled)
32. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 11.
33. A pharmaceutical composition made by mixing a compound of claim
11 and a pharmaceutically acceptable carrier.
34. A process for making a pharmaceutical composition comprising
mixing a compound of claim 11 and a pharmaceutically acceptable
carrier.
35. A method of treating a disorder mediated by an estrogen
receptor, in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of the compound of
claim 11.
36. The method of claim 35, wherein the disorder mediated by an
estrogen receptor is selected from the group consisting of hot
flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia,
loss of cognitive function, degenerative brain diseases,
cardiovascular diseases, cerebrovascular diseases, cancer of the
breast tissue, hyperplasia of the breast tissue, cancer of the
endometrium, hyperplasia of the endometrium, cancer of the cervix,
hyperplasia of the cervix, cancer of the prostate, hyperplasia of
the prostate, endometriosis, uterine fibroids, osteoarthritis and
contraception.
37. The method of claim 35, wherein the disorder mediated by an
estrogen receptor is selected from the group consisting of
osteoporosis, hot flashes, vaginal dryness, breast cancer and
endometriosis.
38. A method of treating a disorder mediated by an estrogen
receptor in a subject in need thereof comprising administering to
the subject a therapeutically effective amount of the composition
of claim 32.
39. A method of contraception comprising co-therapy with a
therapeutically effective amount of a compound as in claim 11 and a
progestogen or a progestogen antagonist.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to novel cyclohexyl
derivatives, pharmaceutical compositions containing them and their
use in the treatment or prevention of disorders and diseases
mediated by an estrogen receptor such as hot flashes, vaginal
dryness, osteopenia, osteoporosis, hyperlipidemia, loss of
cognitive function, degenerative brain diseases, cardiovascular,
cerebrovascular diseases, hormone sensitive cancers and hyperplasia
(in tissues including breast, endometrium, and cervix in women and
prostate in men), endometriosis, uterine fibroids, osteoarthritis;
and as contraceptive agents either alone or in combination with a
progestogen or progestogen antagonist. The compounds of the
invention are selective estrogen receptor modulators.
BACKGROUND OF THE INVENTION
[0002] Estrogens are a group of female hormones essential for the
reproductive process and for the development of the uterus,
breasts, and other physical changes associated with puberty.
Estrogens have an effect on various tissues throughout a woman's
body, not only those involved in the reproductive process, such as
the uterus, breasts, and external genitalia, but also tissues in
the central nervous system, bones, the liver, skin, and the urinary
tract. The ovaries produce most of the estrogens in women's
body.
[0003] Menopause is defined as the permanent cessation of menses
due to loss of ovarian follicular function and the almost
termination of estrogen production. The midlife transition of
menopause is characterized by a decrease in estrogen that provokes
both short-term and long-term symptoms with the vasomotor,
urogenital, cardiovascular, skeletal and central nervous systems,
such as hot flushes, urogenital atrophy, increased risk of
cardiovascular disease, osteoporosis, cognitive and psychological
impairment, including an increased risk of cognitive disorders and
Alzheimer's disease (AD).
[0004] Seventy-five percent of all women experience some occurrence
of vasomotor symptoms associated with the onset of menopause such
as body sweating and hot flushes. These complaints may begin
several years before menopause and in some women may continue for
more than 10 years either relatively constant, or as instant
attacks without a definable, provoking cause.
[0005] Urogenital symptoms associated with the onset of menopause
involving the vagina include a sensation of dryness, burning,
itching, pain during intercourse, superficial bleeding and
discharge, along with atrophy, stenosis. Symptoms involving the
urinary tract include a burning sensation during urination,
frequent urgency, recurrent urinary tract infections, and urinary
incontinence. These symptoms have been reported to occur in up to
50% of all women near the time of menopause and are more frequent a
few years after menopause. If left un-treated, the problems can
become permanent.
[0006] Heart attack and stroke are major causes of morbidity and
mortality among senior women. Female morbidity from these diseases
increases rapidly after menopause. Women who undergo premature
menopause are at greater coronary risk than menstruating women of
similar age. The presence of serum estrogen has a positive effect
on serum lipids. The hormone promotes vasodilation of blood
vessels, and enhances the formation of new blood vessels. Thus the
decrease in serum estrogen levels in postmenopausal women results
in adverse cardiovascular effect. Additionally, it is theorized
that differences in the ability of blood to coagulate may account
for the observed difference in the occurrence of heart disease
before and after menopause.
[0007] The skeleton is under a continuous process of bone
degeneration and regeneration in a carefully regulated interaction
among the bone cells. These cells are directly affected by
estrogen. Estrogen deficiency results in a loss of bone structure,
and decrease of bone strength. Rapid loss of bone mass during the
year immediately following menopause leads postmenopausal
osteoporosis and increased risk of fracture.
[0008] Estrogen deficiency is also one of the causes for the
degenerative changes in the central nervous system and may lead to
Alzheimer's disease and decline of cognition. Recent evidence
suggests an association between estrogen, menopause, and cognition.
More particularly, it has been reported that estrogen replacement
therapy and the use of estrogen in women may prevent the
development of AD, and improve cognitive function.
[0009] Hormone replacement therapy (HRT)--more specifically
estrogen replacement therapy (ERT)--is commonly prescribed to
address the medical problems associated with menopause, and also to
help hinder osteoporosis and primary cardiovascular complications
(such as coronary artery disease) in both a preventive and
therapeutical manner. As such, HRT is considered a medical therapy
for prolonging the average life span of postmenopausal women and
providing a better quality of life.
[0010] ERT effectively relieves the climacteric symptoms and
urogenital symptoms and has shown significant benefits in the
prevention and treatment of heart disease in postmenopausal women.
Clinical reports have shown that ERT lowered heart attack rates and
mortality rates in populations that received ERT versus similar
populations not on ERT. ERT initiated soon after menopause may also
help maintain bone mass for several years. Controlled
investigations have shown that treatment with ERT has a positive
effect even in older women up to age of 75 years.
[0011] However, there are numerous undesirable effects associated
with ERT that reduce patient compliance. Venous thromboembolism,
gallbladder disease, resumption of menses, mastodynia, and a
possible increased risk of developing uterine and/or breast cancer
are the risks associated with ERT. Up to 30% of women who were
prescribed with ERT do not fill the prescription, and the
discontinuation rate is between 38% and 70%, with safety concerns,
and adverse effects (bloating and break-through bleeding) the most
important reasons for discontinuation.
[0012] A new class of pharmacological agents known as Selective
Estrogen Receptor Modulators or SERMs have been designed and
developed as alternatives for HRT. Raloxifene, a nonsteroidal
benzothiophere SERM is marketed in the US and Europe for the
prevention and treatment of osteoporosis under the trademark of
Evista.RTM.. Raloxifene has been shown to reduce bone loss and
prevent fracture without adversely stimulating endometrial and
mammary tissue, though raloxifene is somewhat less efficacious than
ERT for protecting against bone loss. Raloxifene is unique and
differs significantly from ERT in that it does not stimulate the
endometrium and has the potential for preventing breast cancer.
Raloxifene has also demonstrated beneficial estrogen agonist
effects on cardiovascular risk factors, more specifically through a
rapid and sustained decrease in total and low-density lipoprotein
cholesterol levels in patients treated with raloxifene. In
addition, raloxifene has been shown to reduce plasma concentration
of homocysteine, an independent risk factor for atherosclerosis and
thromboembolic disease.
[0013] However, raloxifene has been reported to exacerbate symptoms
associated with menopause such as hot flushes and vaginal dryness,
and does not improve cognitive function in senior patients.
Patients taking raloxifene have reported higher rates of hot
flashes compared with either placebo or ERT users and more leg
cramps than placebo users, although women who took ERT had a higher
incidence of vaginal bleeding and breast discomfort than raloxifene
or placebo users.
[0014] As yet, neither raloxifene nor any of the other currently
available SERM compounds has been shown to have the ability to
provide all the benefits of currently available ERT such as
controlling postmenopausal syndrome and preventing AD, without
causing adverse side effects such as increasing risk of endometrial
and breast cancer and bleeding. Thus there exists a need for
compounds which are selective estrogen receptor modulators and
which provide all of the benefits of ERT while also addressing the
vasomotor, urogenital and cognitive disorders or conditions
associated with the decrease in systemic estrogen associated with
menopause.
SUMMARY OF THE INVENTION
[0015] The present invention is directed to a compound of the
general formula (I) ##STR1##
[0016] wherein
[0017] represents a single or a double bond;
[0018] R.sup.1a is selected from the group consisting of hydrogen
and lower alkyl;
[0019] R.sup.1 is selected from the group consisting of alkyl,
hydroxy substituted alkyl, alkenyl, hydroxy substituted alkenyl,
alkynyl, hydroxy substituted alkynyl, alkoxyalkyl, alkoxy-carbonyl,
alkyl-carbonyl, aryl-carbonyl, heteroaryl-carbonyl,
heterocycloalkyl-carbonyl, alkyl-carbonyl-alkyl,
NR.sup.AR.sup.B-carbonyl and NR.sup.AR.sup.B-alkoxy-alkyl;
[0020] R.sup.A and R.sup.B are each independently selected from the
group consisting of hydrogen and alkyl; alternatively R.sup.A and
R.sup.B are taken together with the N atom to which they are bound
to form a heteroaryl or heterocycloalkyl group;
[0021] R.sup.2 is selected from the group consisting of hydrogen,
carboxy, alkyl, hydroxy substituted alkyl, alkenyl, hydroxy
substituted alkenyl, alkynyl, hydroxy substituted alkynyl,
alkoxyalkyl, alkoxy-carbonyl, alkyl-carbonyl, aryl-carbonyl,
heteroaryl-carbonyl, heterocycloalkyl-carbonyl,
alkyl-carbonyl-alkyl, NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-alkoxy-alkyl;
[0022] alternatively R.sup.1 and R.sup.2 are taken together with
the atoms to which they are bound to form a five to eight membered
saturated ring structure of the formula ##STR2##
[0023] wherein n is an integer from 1 to 4;
[0024] wherein R.sup.C and R.sup.D are independently selected from
hydrogen, hydroxy, alkyl, alkenyl, alkynyl or alkoxy; alternatively
R.sup.C and R.sup.D are taken together with the carbon atom to
which they are bound to form an oxo group;
[0025] alternatively still, R.sup.1 and R.sup.2 are taken together
with the atoms to which they are bound to form a heteroatom
containing saturated ring structure of the formula ##STR3##
[0026] wherein m is an integer from 1 to 3;
[0027] R.sup.3 is selected from the group consisting of hydrogen
and alkyl; ##STR4## is selected from the group consisting of aryl,
aralkyl and heteroaryl; wherein the heteroaryl group is bound to
the core structure through a carbon atom; and wherein the aryl,
aralkyl or heteroaryl group is optionally substituted with one or
more substitutents independently selected from hydroxy, alkoxy,
aralkyl, aralkyloxy or NR.sup.AR.sup.B-alkoxy; ##STR5## is selected
from the group consisting of aryl, aralkyl and heteroaryl; wherein
the heteroaryl group is bound to the core structure through a
carbon atom; and wherein the aryl, aralkyl or heteroaryl group is
optionally substituted with one or more substitutents independently
selected from hydroxy, alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-alkoxy;
[0028] provided that when is a double bond, R.sup.1a is hydrogen,
R.sup.2 is hydrogen, R.sup.3 is hydrogen, and ##STR6## are the same
and selected from the group consisting of phenyl or substituted
phenyl, wherein the substituents on the phenyl are one to two
selected from alkoxy, then R.sup.1 is other than hydroxy
substituted lower alkyl or alkoxycarbonyl;
[0029] provided further that when is a double bond, R.sup.1a is
hydrogen or lower alkyl, ##STR7## is phenyl, then R.sup.1 is
selected from the group consisting of NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-alkoxy-alkyl;
[0030] provided further that when is a single bond, R.sup.1a is
hydrogen, R.sup.2 is hydrogen or lower alkyl, R.sup.3 is hydrogen,
and ##STR8## are the same and are phenyl, then R.sup.1 is other
than lower alkyl, hydroxy substituted lower alkyl, alkylcarbonyl or
alkoxycarbonyl;
[0031] provided further that when is a single bond, R.sup.1 is
lower alkyl, R.sup.1a is hydrogen, R.sup.2 is hydrogen, R.sup.3 is
hydrogen and ##STR9## is other than benzimidazolyl;
[0032] provided further that when is a single or double bond,
R.sup.1a is lower alkyl, R.sup.3 is hydrogen, R.sup.1 and R.sup.2
are taken together with the atoms to which they are bound to form
cyclohexyl or 3-hydroxyphenyl and ##STR10## is 4-hydroxyphenyl,
then ##STR11## is other than 4-(NR.sup.AR.sup.B-lower
alkoxy)-phenyl, wherein R.sup.A and R.sup.B are each independently
selected from hydrogen or lower alkyl or R.sup.A and R.sup.B are
taken together with the N atom to which they are bound to form
piperidinyl;
[0033] provided further than when is a single or double bond,
R.sup.1a is hydrogen, R.sup.3 is hydrogen and R.sup.1 and R.sup.2
are taken together with the atoms to which they are bound to form
##STR12## then ##STR13## are not the same and phenyl;
[0034] provided further that when is a double bond, R.sup.1a is
lower alkyl, R.sup.3 is hydrogen and R.sup.1 and R.sup.2 are taken
together with the atoms to which they are bound to form a five
membered saturated ring structure of the formula ##STR14##
[0035] wherein R.sup.C is selected from hydroxy or alkoxy, then
##STR15## are other than phenyl or substituted phenyl, wherein the
substituents on the phenyl are one or more independently selected
from hydroxy, alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-alkoxy;
[0036] or a pharmaceutically acceptable salt thereof.
[0037] The present invention is further directed to compounds of
formula (II) ##STR16##
[0038] wherein
[0039] X is selected from the group consisting C(O) and
CH.sub.2;
[0040] R.sup.4 is selected from the group consisting of hydrogen
and lower alkyl;
[0041] R.sup.5 is selected from the group consisting of alkyl;
[0042] R.sup.6 is selected from the group consisting of
-(aralkyl)-Q-(alkyl)-NR.sup.AR.sup.B;
[0043] Q is selected from the group consisting of O and S;
[0044] R.sup.A and R.sup.B are each independently selected from the
group consisting of hydrogen and alkyl; alternatively R.sup.A and
R.sup.B are taken together with the N atom to which they are bound
to form a heteroaryl or heterocycloalkyl group; ##STR17## is
selected from the group consisting of aryl, aralkyl, heteroaryl and
heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group
is bound to the core structure through a carbon atom; and wherein
the aryl, aralkyl, heteroaryl or heterocycloalkyl group is
optionally substituted with one or more substitutents independently
selected from halogen, hydroxy, alkoxy, aralkyloxy or
NR.sup.AR.sup.B-alkoxy;
[0045] or a pharmaceutically acceptable salt thereof.
[0046] The present invention is further directed to a compound of
formula (III) ##STR18##
[0047] represents a single or a double bond;
[0048] X is selected from the group consisting of C(O) and
CH.sub.2;
[0049] R.sup.4 is selected from the group consisting of hydrogen
and lower alkyl;
[0050] R.sup.5 is selected from the group consisting of alkyl;
[0051] R.sup.6 is selected from the group consisting of
-(aralkyl)-Q-(alkyl)-NR.sup.AR.sup.B;
[0052] Q is selected from the group consisting of O and S;
[0053] R.sup.A and R.sup.B are each independently selected from the
group consisting of hydrogen and alkyl; alternatively R.sup.A and
R.sup.B are taken together with the N atom to which they are bound
to form a heteroaryl or heterocycloalkyl group;
[0054] or a pharmaceutically acceptable salt thereof.
[0055] The present invention is further directed to a compound
selected from the group consisting of
3-(4-benzyloxy-benzyl)-2-methyl-4-oxo-cyclohex-2-enecarboxylic acid
ethyl ester
4-{4-hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]--
cyclohex-1-enyl}-phenol and pharmaceutically acceptable salts
thereof.
[0056] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and
any of the compounds described above. An illustration of the
invention is a pharmaceutical composition made by mixing any of the
compounds described above and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing any of the compounds
described above and a pharmaceutically acceptable carrier.
[0057] Exemplifying the invention are methods of treating a
disorder mediated by one or more estrogen receptors in a subject in
need thereof comprising administering to the subject a
therapeutically effective amount of any of the compounds or
pharmaceutical compositions described above.
[0058] Illustrating the invention is a method of contraception
comprising administering to a subject in need thereof co-therapy
with a therapeutically effective amount of a compound of formula
(I) with a progestogen or progestogen antagonist.
[0059] Another example of the invention is the use of any of the
compounds described herein in the preparation of a medicament for
treating: (a) hot flashes, (b) vaginal dryness, (c) osteopenia, (d)
osteoporosis, (e) hyperlipidemia, (f) loss of cognitive function,
(g) a degenerative brain disorder, (h) cardiovascular disease, (i)
cerebrovascular disease (j) breast cancer, (k) endometrial cancer,
(l) cervical cancer, (m) prostate cancer, (n) benign prostatic
hyperplasia, (o) endometriosis, (p) uterine fibroids, (q)
osteoarthritis and for (r) contraception in a subject in need
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0060] The present invention is directed to compounds of formula
(I), (II) and (III) ##STR19##
[0061] wherein R.sup.1, R.sup.1a, R.sup.2, R.sup.3, ##STR20## , X,
R.sup.4, R.sup.5, R.sup.6 and ##STR21## are as herein defined. The
compounds of the present invention are modulators of an estrogen
receptor, useful for the treatment and prevention of disorders
associated with estrogen depletion, including, but not limited to
hot flashes, vaginal dryness, osteopenia, osteoporosis,
hyperlipidemia, loss of cognitive function, degenerative brain
diseases, cardiovascular and cerebrovascular diseases); for the
treatment of hormone sensitive cancers and hyperplasia (in tissues
including breast, endometrium, and cervix in women and prostate in
men); for the treatment and prevention of endometriosis, uterine
fibroids, and osteoarthritis; and as contraceptive agents either
alone or in combination with a progestogen or progestogen
antagonist.
[0062] In an embodiment of the present invention is a single bond.
In another embodiment of the present invention is a double
bond.
[0063] In an embodiment of the present invention R.sup.1a is
selected from the group consisting of hydrogen and lower alkyl.
Preferably R.sup.1a is selected from the group consisting of
hydrogen and methyl.
[0064] In an embodiment of the present invention R.sup.1 is
selected from the group consisting of lower alkyl, hydroxy
substituted lower alkyl, lower alkenyl, hydroxy substituted lower
alkenyl, lower alkoxy-lower alkyl, lower alkoxy-carbonyl, lower
alkyl-carbonyl, phenyl-carbonyl, lower alkyl-carbonyl-lower alkyl,
NR.sup.AR.sup.B-carbonyl and NR.sup.AR.sup.B-lower alkoxy-lower
alkyl. In another embodiment of the present invention R.sup.1 is
selected from the group consisting of lower alkyl, hydroxy
substituted lower alkyl, hydroxy substituted lower alkenyl, lower
alkoxy-lower alkyl, lower alkoxy-carbonyl, lower
alkyl-carbonyl-lower alkyl and NR.sup.AR.sup.B-lower alkoxy-lower
alkyl and NR.sup.AR.sup.B-carbonyl. Preferably, R.sup.1 is selected
from the group consisting of methyl, hydroxymethyl,
1-hydroxy-propyn-2-yl, 1-hydroxy-n-propyl, methoxymethyl,
methoxycarbonyl, methylcarbonylmethyl, dimethylamino-ethoxy-methyl,
morpholinyl-ethoxy-methyl, morpholinylcarbonyl and
diethylaminocarbonyl.
[0065] In an embodiment of the present invention, R.sup.A and
R.sup.B are each independently selected from the group consisting
of hydrogen and lower alkyl; alternatively R.sup.A and R.sup.B are
taken together with the N atom to which they are bound to form a
five to six membered heteroaryl or a five to six membered
heterocycloalkyl group. Preferably, R.sup.A and R.sup.B are
independently selected from the group consisting of hydrogen and
methyl or are taken together with the nitrogen atom to which they
are bound to form morpholinyl.
[0066] In an embodiment of the present invention, R.sup.2 is
selected from the group consisting of hydrogen, carboxy, lower
alkyl, hydroxy substituted lower alkyl, lower alkenyl, hydroxy
substituted lower alkenyl, lower alkoxy-lower alkyl, lower
alkoxy-carbonyl, lower alkyl-carbonyl, phenyl-carbonyl, lower
alkyl-carbonyl-lower alkyl, NR.sup.AR.sup.B-carbonyl and
NR.sup.AR.sup.B-lower alkoxy-lower alkyl. In another embodiment of
the present invention, R.sup.2 is selected from the group
consisting of hydrogen, carboxy, lower alkyl, hydroxy substituted
lower alkyl, lower alkyl-carbonyl, lower alkoxy-lower alkyl, lower
alkyl-carbonyl-lower alkyl and NR.sup.AR.sup.B-lower alkoxy-lower
alkyl. Preferably, R.sup.2 is selected from the group consisting of
hydrogen, carboxy, methyl, hydroxymethyl, methoxycarbonyl,
methoxymethyl, methylcarbonylmethyl and
dimethylamino-ethoxy-methyl.
[0067] In an embodiment of the present invention R.sup.1 and
R.sup.2 are taken together with the atom to which they are bound to
form a saturated ring structure of the formula; ##STR22##
[0068] wherein n is an integer from 1 to 4.
[0069] In another embodiment of the present invention R.sup.1 and
R.sup.2 are taken together with the atom to which they are bound to
form a heteroatom containing saturated ring structure of the
formula ##STR23##
[0070] wherein m is an integer from 1 to 2.
[0071] Preferably, R.sup.1 and R.sup.2 are taken together with the
atom to which they are bound to form a ring structure selected from
the group consisting of 3-hydroxy-3-ethynyl-cyclopentyl,
3-hydroxy-cyclopentyl, 3-oxo-cyclopentyl, 3-hydroxy-cyclohexyl,
3-oxo-cyclohexyl, 3-oxo-cyclooctyl and dihydro-fur-4-yl; wherein
the R.sup.1+R.sup.2 ring is bound to the core structure through the
1,2-positions, numbering clockwise.
[0072] In an embodiment of the present invention R.sup.C and
R.sup.D are independently selected from the group consisting of
hydrogen, hydroxy, lower alkyl, lower alkynyl and lower alkoxy;
alternatively R.sup.C and R.sup.D are taken together with the
carbon atom to which they are bound to form an oxo group. In
another embodiment of the present invention, R.sup.C and R.sup.D
are independently selected from the group consisting of hydrogen,
hydroxy and lower alkynyl; alternatively R.sup.C and R.sup.D are
taken together with the carbon atom to which they are bound to form
an oxo group.
[0073] In an embodiment of the present invention, R.sup.3 is
selected from the group consisting of hydrogen and lower alkyl.
Preferably, R.sup.3 is selected from the group consisting of
hydrogen and ethyl.
[0074] In an embodiment of the present invention, ##STR24## is
selected from the group consisting of aryl and heteroaryl; wherein
the heteroaryl group is bound to the core structure through a
carbon atom; and wherein the aryl or heteroaryl group is optionally
substituted with one to two substitutents independently selected
from hydroxy, lower alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-lower alkoxy. In another embodiment of the present
invention, ##STR25## is selected from the group consisting of aryl;
wherein the aryl group is optionally substituted with a substituent
selected from hydroxy, lower alkoxy and aralkyloxy. Preferably,
##STR26## is selected from the group consisting of phenyl,
4-hydroxyphenyl, 4-methoxyphenyl and 4-benzyloxy-phenyl.
[0075] In another embodiment of the present invention, ##STR27## is
aryl; wherein the aryl group is optionally substituted with a
substituent selected from hydroxy or lower alkoxy. Preferably
##STR28## is selected from the group consisting of phenyl,
4-hydroxyphenyl and 4-methoxyphenyl.
[0076] In an embodiment of the present invention ##STR29## is
selected from the group consisting of aryl and heteroaryl; wherein
the heteroaryl group is bound to the core structure through a
carbon atom; and wherein the aryl or heteroaryl group is optionally
substituted with one to two substitutents independently selected
from hydroxy, lower alkoxy, aralkyl, aralkyloxy or
NR.sup.AR.sup.B-lower alkoxy. In another embodiment of the present
invention, ##STR30## is selected from the group consisting of aryl;
wherein the aryl group is optionally substituted with one to two
substituents independently selected from hydroxy, lower alkoxy,
aralkyl and NR.sup.AR.sup.B-lower alkoxy. Preferably, ##STR31## is
selected from the group consisting of phenyl, 4-hydroxyphenyl,
4-methoxyphenyl, 4-dimethylaminoethoxy-phenyl,
4-hydroxy-3-benzyl-phenyl and 4-(piperidinyl-ethoxy)-phenyl.
[0077] In another embodiment of the present invention, ##STR32## is
aryl; wherein the aryl is optionally substituted with a substituent
selected from lower alkoxy. Preferably, ##STR33## is selected from
the group consisting of phenyl and 4-methoxyphenyl.
[0078] In an embodiment of the present invention, X is selected
from the group consisting C(O) and CH.sub.2. Preferably, X is
C(O).
[0079] In an embodiment of the present invention, R.sup.4 is
selected from the group consisting of hydrogen and lower alkyl. In
another embodiment of the present invention, R.sup.4 is selected
from the group consisting of lower alkyl. Preferably, R.sup.4 is
ethyl.
[0080] In an embodiment of the present invention, R.sup.5 is
selected from the group consisting of lower alkyl. Preferably,
R.sup.5 is methyl.
[0081] In an embodiment of the present invention, R.sup.6 is
selected from the group consisting of -(benzyl)-Q-(lower
alkyl)-NR.sup.AR.sup.B. In another embodiment of the present
invention, R.sup.6 is selected from the group consisting of
-(benzyl)-O-(lower alkyl)-NR.sup.AR.sup.B. Preferably, R.sup.6 is
selected from the group consisting of
4-(dimethylamino-ethoxy)-benzyl, 4-(morpholinyl-ethoxy)-benzyl,
4-(piperidinyl-ethoxy)-benzyl and
4-(pyrrolidinyl-ethoxy)-benzyl.
[0082] In an embodiment of the present invention, Q is selected
from the group consisting of O and S. Preferably, Q is O.
[0083] In an embodiment of the present invention, R.sup.A and
R.sup.B are each independently selected from the group consisting
of hydrogen and lower alkyl; alternatively R.sup.A and R.sup.B are
taken together with the N atom to which they are bound to form a
five to six membered heteroaryl or a five to six membered
heterocycloalkyl group. In another embodiment of the present
invention, wherein R.sup.A and R.sup.B are each independently
selected from lower alkyl; alternatively R.sup.A and R.sup.B are
taken together with the N atom to which they are bound to form a
five to six membered heteroaryl or five to six membered
heterocycloalkyl group. Preferably, R.sup.A and R.sup.B are each
methyl or are taken together with the N atom to which they are
bound to form a morpholinyl, piperidinyl or pyrrolidinyl group.
[0084] In an embodiment of the present invention, ##STR34## is
selected from the group consisting of aryl, aralkyl and heteroaryl;
wherein the heteroaryl group is bound to the core structure through
a carbon atom; and wherein the aryl, aralkyl or heteroaryl group is
optionally substituted with one to two substitutents independently
selected from halogen, hydroxy, alkoxy, aralkyloxy or
NR.sup.AR.sup.B-alkoxy. In another embodiment of the present
invention, ##STR35## is selected from the group consisting of aryl
and heteroaryl; wherein the heteroaryl group is bound to the core
structure through a carbon atom; and wherein the aryl or heteroaryl
group is optionally substituted with a substituent selected from
halogen, hydroxy or lower alkoxy. Preferably, ##STR36## is selected
from the group consisting of 4-fluorophenyl, 4-hydroxyphenyl,
4-methoxyphenyl and 5-indolyl.
[0085] In an embodiment of the present invention is a compound
selected from the group consisting of
3-(4-benzyloxy-benzyl)-2-methyl-4-oxo-cyclohex-2-enecarboxylic acid
ethyl ester and
4-{4-hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benz-
yl]-cyclohex-1-enyl}-phenol.
[0086] In yet another embodiment of the present invention is a
compound of formula (I) selected from group as listed in Table 1.
In yet another embodiment of the present invention is a compound of
formula (I) selected from group as listed in Table 2. In yet
another embodiment of the present invention is a compound of
formula (I) selected from group as listed in Table 3.
[0087] In an embodiment of the present invention is a compound of
formula (II) selected from group as listed in Table 4. In another
embodiment of the present invention is a compound of formula (III)
selected from group as listed in Table 5.
[0088] Representative compounds of the present invention are as
listed in Tables 1, 2, 3, 4 and 5. Unless otherwise noted, in the
Tables below, in the column headed with the symbol the notation 2
shall indicate a double bond, whereas the notation 1, shall
indicate a single bond. TABLE-US-00001 TABLE 1 ##STR37## ID No
R.sup.1a R.sup.1 R.sup.2 R.sup.3 ##STR38## ##STR39## 1 methyl
hydroxy- H H 4-hydroxy 4-hydroxy-phenyl methyl phenyl 2 H dimethyl-
hydroxy H 4-hydroxy phenyl amino- methyl phenyl ethoxy- methyl 3
methyl hydroxy- H H 4-hydroxy 4-dimethylamino- methyl phenyl
ethyloxy-phenyl 4 H hydroxy- methyl ethyl 4-hydroxy
4-methoxy-phenyl methyl phenyl 5 H methoxy- hydroxy 4- phenyl
methyl methyl benzyloxy phenyl 6 methyl hydroxy- H H 4-hydroxy
4-dimethylamino- methyl phenyl ethyloxy-phenyl 7 methyl hydroxy- H
H 4-hydroxy 4-hydroxy-phenyl methyl phenyl
[0089] TABLE-US-00002 TABLE 2 ##STR40## ID No R.sup.1a R.sup.1
R.sup.2 R.sup.3 ##STR41## ##STR42## 8 H methoxymethyl methoxymethyl
H 4-benzyloxy- phenyl phenyl 9 H methylcarbonyl methylcarbonyl H
4-benzyloxy- phenyl methyl methyl phenyl 10 H morpholinyl- carbonyl
H phenyl phenyl carbonyl 11 H diethylamino- methoxy- H phenyl
phenyl carbonyl carbonyl 12 methyl 1-hydroxy-n- H H 4-methoxy-
4-methoxy- propyl phenyl phenyl 13 H hydroxymethyl hydroxymethyl H
4-benzyloxy- H phenyl 14 H morpholinyl- methoxy- H phenyl phenyl
carbonyl carbonyl 15 H dimethylamino- hydroxymethyl H 4-hydroxy-
phenyl ethoxy-methyl phenyl 16 H hydroxymethyl dimethylamino- H
4-hydroxy- phenyl ethoxy-methyl phenyl 17 methyl --CH(OH)--CCH H H
4-methoxy- 4-methoxy- phenyl phenyl 18 H hydroxymethyl
hydroxymethyl H phenyl phenyl (*) 19 H morpholinyl hydroxymethyl H
4-methoxy- 4-methoxy- ethoxymethyl phenyl phenyl 20 H hydroxymethyl
methyl ethyl 4-methoxy- 4-hydroxy- phenyl phenyl 21 H methoxymethyl
hydroxymethyl H 4-hydroxy- phenyl phenyl 22 H methoxy- methoxy- H
phenyl phenyl carbonyl carbonyl 23 H hydroxymethyl H H phenyl
phenyl 24 H methyl methyl H 4-hydroxy- phenyl phenyl 25 methyl
hydroxymethyl H H 4-hydroxy- H phenyl 26 H hydroxymethyl
hydroxymethyl H 4-methoxy- 4-methoxy- phenyl phenyl 27 methyl
hydroxymethyl H H 4-hydroxy- 4-hydroxy- phenyl phenyl 28 H
dimethylamino- hydroxymethyl H 4-benzyloxy- phenyl ethoxy-methyl
phenyl 29 methyl hydroxymethyl H H 4-methoxy- 4-methoxy- phenyl
phenyl 30 methyl hydroxymethyl H H 4-methoxy- 4-hydroxy-3- phenyl
benzyl-phenyl 31 H methyl methyl H 4-benzyloxy- phenyl phenyl 32 H
hydroxymethyl hydroxymethyl H 4-hydroxy- phenyl phenyl 33 H
hydroxymethyl hydroxymethyl H phenyl phenyl (#) 34 H hydroxymethyl
methyl H phenyl phenyl 35 H diethylamino- carboxy H phenyl phenyl
carbonyl 36 methyl hydroxymethyl methyl H phenyl phenyl 75 H
hydroxymethyl methyl ethyl 4-hydroxy- 4-(piperidinyl- phenyl
ethoxy)- phenyl (*) Indicates that the R.sup.1 and R.sup.2 groups
are in a cis orientation relative to each other; (#) Indicates that
the R.sup.1 and R.sup.2 groups are in a trans orientation relative
to each other.
[0090] TABLE-US-00003 TABLE 3 ##STR43## ID No ##STR44## R.sup.1a
##STR45## ##STR46## ##STR47## 48 2 H 3-hydroxy-3- 4-methoxy-
4-methoxy- (##) ethynyl-cyclopentyl phenyl phenyl 49 2 H 3-hydroxy-
4-methoxy- H cyclopentyl phenyl 50 2 methyl 3-hydroxy- 4-methoxy- H
cyclopentyl phenyl 51 2 H 3-oxo-cyclopentyl H 4-hydroxy- phenyl 52
2 H dihydrofur-4-yl phenyl phenyl 53 2 H 3-oxo-cyclooctyl phenyl
phenyl 54 2 H 3-oxo-cyclopentyl 4-methoxy- 4-methoxy- phenyl phenyl
55 2 H 3-hydroxy- phenyl H cyclopentyl 56 2 H 3-oxo-cyclohexyl
phenyl phenyl 57 2 H 3-hydroxy- 4-methoxy- 4-methoxy- (##)
cyclopentyl phenyl phenyl 58 2 H 3-hydroxy- phenyl phenyl (##)
cyclohexyl 59 2 H 3-hydroxy-3- 4-methoxy- 4-methoxy- (**)
ethynyl-cyclopentyl phenyl phenyl 60 2 H 3-hydroxy- phenyl phenyl
(**) cyclohexyl 61 2 H 3-hydroxy- 4-methoxy- 4-methoxy- (**)
cyclopentyl phenyl phenyl 62 2 methyl 3-oxo-cyclopentyl 4-hydroxy-
H phenyl 63 1 H 3-hydroxy- phenyl phenyl cyclohexyl 64 2 H
3-oxo-cyclopentyl 4-hydroxy- H phenyl 65 1 H 3-hydroxy- 4-hydroxy-
hydroxy cyclopentyl phenyl 66 2 H 3-hydroxy- 4-hydroxy- H
cyclopentyl phenyl 67 2 H 3-oxo-cyclopentyl phenyl phenyl (**)
Indicates that in the substituent group wherein R.sup.1 and R.sup.2
are taken together with the carbon atoms to which they are bound to
form a ring structure, the relative stereochemistry between the
carbon atoms numbered 2 and 3 is cis. (##) Indicates that in the
substituent group wherein R.sup.1 and R.sup.2 are taken together
with the carbon atoms to which they are bound to form a ring
structure, the relative stereochemistry between the carbon atoms
numbered 2 and 3 is trans.
[0091] TABLE-US-00004 TABLE 4 ##STR48## ID No R.sup.6 ##STR49## 37
4-(dimethylamino-ethoxy)-benzyl 5-indolyl 38
4-(piperidinyl-ethoxy)-benzyl 4-hydroxy phenyl 39
4-(piperidinyl-ethoxy)-benzyl 4-methoxy phenyl 40
4-(dimethylamino-n-propoxy)-benzyl 5-indolyl 41
4-(morpholinyl-ethoxy)-benzyl 5-indolyl 42
4-(pyrrolidinyl-ethoxy)-benzyl 4-hydroxy phenyl 43
4-(piperidinyl-ethoxy)-benzyl 5-indolyl 44
4-(dimethylamino-ethoxy)-benzyl 4-hydroxy phenyl 45
4-(piperidinyl-ethoxy)-benzyl 4-fluoro phenyl 47
4-(pyrrolidinyl-ethoxy)-benzyl 5-indolyl
[0092] TABLE-US-00005 TABLE 5 ##STR50## ID No ##STR51## R.sup.6 68
1 4-(morpholinyl-ethoxy)-benzyl 69 1
4-(dimethylamino-ethoxy)-benzyl 70 1 4-(pyrrolidinyl-ethoxy)-benzyl
71 2 4-(piperidinyl-ethoxy)-benzyl 72 1
4-(dimethylamino-n-propoxy)-benzyl
[0093] Additional compounds of the present invention, prepared as
intermediates in the preparation of the compounds of formula (I),
formula (II) or formula (III), include: ##STR52##
[0094] wherein the compound #74, the hydroxymethyl, methyl and
piperidinyl-ethoxy-benzyl substituents on the cyclohexene core are
all in the cis conformation.
[0095] As used herein, "halogen" shall mean chlorine, bromine,
fluorine and iodine.
[0096] As used herein, the term "alkyl" whether used alone or as
part of a substituent group, include straight and branched chains,
preferably, a chain containing one to eight carbon atoms. For
example, alkyl radicals include, but are not limited to methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,
pentyl and the like. Unless otherwise noted, "lower" when used with
alkyl means a carbon chain composition of 1-4 carbon atoms.
[0097] As used herein, unless otherwise noted, the term "alkenyl"
whether used alone or as part of a substituent group, shall include
straight and branched chains containing at least one unsaturated
double bond. For example, vinyl, propenyl or allyl, butenyl,
buten-2-yl, buten-3-yl, 2-methyl-buten-2-yl, and the like.
Preferably, the alkenyl group containing two to eight carbon atoms.
Unless otherwise noted, "lower" when used with alkenyl means a
carbon chain composition of 2-4 carbon atoms.
[0098] As used herein, unless otherwise noted, the term "alkynyl"
whether used alone or as part of a substituent group, shall include
straight and branched chains containing at least one unsaturated
triple bond. For example, ethynyl, propynyl, butyn-2-yl, and the
like. Preferably, the alkynyl group containing two to eight carbon
atoms. Unless otherwise noted, "lower" when used with alkynyl means
a carbon chain composition of 2-4 carbon atoms.
[0099] As used herein, unless otherwise noted, "alkoxy" shall
denote an oxygen ether radical of the above described straight or
branched chain alkyl groups. For example, methoxy, ethoxy,
n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless
otherwise noted, "lower" when used with alkoxy means an alkoxy
group comprising 1-4 carbon atoms.
[0100] As used herein, unless otherwise noted, "aryl" shall refer
to unsubstituted carbocylic aromatic groups such as phenyl,
naphthyl, and the like.
[0101] As used herein, unless otherwise noted, "aralkyl" shall mean
any lower alkyl group substituted with an aryl group such as
phenyl, naphthyl and the like. For example, benzyl, phenylethyl,
phenylpropyl, naphthylmethyl, and the like.
[0102] As used herein, unless otherwise noted, the term
"aralkyloxy" shall mean an aralkyl-O-- group, wherein the aralkyl
is as defined above and wherein the aralkyloxy group is bound
through the O atom. Suitable examples include, but are not limited
to benzyloxy, phenyl-ethoxy, and the like.
[0103] As used herein, unless otherwise noted, the term
"cycloalkyl" shall mean any stable 3-8 membered monocyclic,
saturated ring system, for example cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0104] As used herein, unless otherwise noted, "heteroaryl" shall
denote any five or six membered monocyclic aromatic ring structure
containing at least one heteroatom selected from the group
consisting of O, N and S, optionally containing one to three
additional heteroatoms independently selected from the group
consisting of O, N and S; or a nine or ten membered bicyclic
aromatic ring structure containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heteroaryl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
[0105] Examples of suitable heteroaryl groups include, but are not
limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl,
purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl,
indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl,
benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl,
quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the
like.
[0106] As used herein, the term "heterocycloalkyl" shall denote any
five to seven membered monocyclic, saturated or partially
unsaturated ring structure containing at least one heteroatom
selected from the group consisting of O, N and S, optionally
containing one to three additional heteroatoms independently
selected from the group consisting of O, N and S; or a nine to ten
membered saturated, partially unsaturated or partially aromatic
bicyclic ring system containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heterocycloalkyl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
[0107] Examples of suitable heteroaryl groups include, but are not
limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,
imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,
morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,
indolinyl, chromenyl, 3,4-methylenedioxyphenyl,
2,3-dihydrobenzofuryl, dihydrofuryl, and the like. Preferred
heterocycloalkyl groups include dihydrofuryl, morpholinyl,
piperidinyl, and pyrrolidinyl.
[0108] When a particular group is "substituted" (e.g., Ph, aryl,
heteroaryl, heteroaryl), that group may have one or more
substituents, preferably from one to five substituents, more
preferably from one to three substituents, most preferably from one
to two substituents, independently selected from the list of
substituents.
[0109] With reference to substituents, the term "independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0110] Unless otherwise noted, when naming the substituent group
wherein R.sup.1 and R.sup.2 are taken together with the carbon
atoms to which they are bound to form a ring structure, said
substituent group--the rightmost ring structure of the bicyclic
structure of compounds of formula (Iaa) or (Iab) ##STR53##
[0111] shall be named such that the bridging carbon atoms are
numbered 1 and 2 and any R.sup.C and/or R.sup.D substituents are
bound at the carbon atom numbered 3. Remaining carbon and/or oxygen
atoms within the substituent group wherein R.sup.1 and R.sup.2 are
taken together with the carbon atoms to which they are bound to
form a ring structure, will be numbered in order, counting
clockwise.
[0112] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
[0113]
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula ##STR54##
[0114] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows: TABLE-US-00006 Bu.sub.3SnH =
Tributyl Tin Hydride DCM = Dichloromethane DIBAL-H = Diisobutyl
aluminum hydride DIPEA = Di-isopropylethylamine DMEM = Dulbecco's
Modified Eagle Medium (Gibco) DMF = N,N-Dimethylformamide DMSO =
Dimethylsulfoxide DTT = Dithiothreitol Et.sub.2O = Diethyl Ether
EtOH = Ethanol HEPES = 4-(2-Hydroxyethyl)-1-Piperizine Ethane
Sulfonic Acid HPLC = High Pressure Liquid Chromatography KHMDS =
Potassium Bis(trimethylsilyl)amide KOtBu = Potassium t-butoxide LAH
= Lithium aluminum hydride LDA = Lithium diisopropylamide LHMDS =
Lithium Bis(trimethylsilyl)amide MeOH = Methanol nBuLi = n-Butyl
lithium NMR = Nuclear Magnetic Resonance PBS = Phosphate Buffered
Saline Pd(dppf)Cl.sub.2 =
dichloro[1,1'-bis(diphenyl-phosphino)-ferrocene] palladium (II)
Pd.sub.2Cl.sub.2(PPh.sub.3).sub.2 = Palladium
Bis(triphenylphosphine)chloride Pd(PPh.sub.3).sub.4 =
tetrakistriphenylphosphine palladium (0) TBS =
t-Butyldimethylsilane TBSCl = t-Butyldimethylchlorosilane tBuOH =
t-butanol TEA = Triethylamine THF = Tetrahydrofuran TIPS =
Triisopropylsilane CORRECT??? TLC = Thin Layer Chromatography TMSCl
= Trimethylsilyl chloride TsCl = Tosyl chloride
[0115] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0116] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated. Wherein the
present invention directed to co-therapy comprising administration
of one or more compound(s) of formula (I), compound(s) of formula
(II) and/or compound(s) of formula (III) and a progestogen or
progestogen antagonist, "therapeutically effective amount" shall
mean that amount of the combination of agents taken together so
that the combined effect elicits the desired biological or
medicinal response. For example, the therapeutically effective
amount of co-therapy comprising administration of a compound of
formula (I) and progestogen would be the amount of the compound of
formula (I) and the amount of the progestogen that when taken
together or sequentially have a combined effect that is
therapeutically effective. Further, it will be recognized by one
skilled in the art that in the case of co-therapy with a
therapeutically effective amount, as in the example above, the
amount of the compound of formula (I) and/or the amount of the
progestogen or progestogen antagonist individually may or may not
be therapeutically effective.
[0117] As used herein, the term "co-therapy" shall mean treatment
of a subject in need thereof by administering one or more compounds
of formula (I), compounds of formula (II) and/or compounds of
formula (III) with a progestogen or progestogen antagonist, wherein
the compound(s) of formula (I), compound(s) of formula (II), or
compound(s) of formula (III) and the progestogen or progestogen
antagonist are administered by any suitable means, simultaneously,
sequentially, separately or in a single pharmaceutical formulation.
Where the compound(s) of formula (I), compound(s) of formula (II),
compound(s) of formula (III) and the progestogen or progestogen
antagonist are administered in separate dosage forms, the number of
dosages administered per day for each compound may be the same or
different. The compound(s) of formula (I), compound(s) of formula
(II), compound(s) of formula (III) and the progestogen or
progestogen antagonist may be administered via the same or
different routes of administration. Examples of suitable methods of
administration include, but are not limited to, oral, intravenous
(iv), intramuscular (im), subcutaneous (sc), transdermal, and
rectal. Compounds may also be administered directly to the nervous
system including, but not limited to, intracerebral,
intraventricular, intracerebroventricular, intrathecal,
intracisternal, intraspinal and/or peri-spinal routes of
administration by delivery via intracranial or intravertebral
needles and/or catheters with or without pump devices. The
compound(s) of formula I, compound(s) of formula (II), compound(s)
of formula (III) and the progestogen or progestogen antagonist may
be administered according to simultaneous or alternating regimens,
at the same or different times during the course of the therapy,
concurrently in divided or single forms.
[0118] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0119] As used herein, the term "disease or disorder modulated by
an estrogen receptor" shall mean any disease or disorder which is
mediated by the estrogen .alpha., any disease or disorder which is
mediated by the estrogen .beta. receptor or any disease or disorder
which is mediated by both the estrogen .alpha. and estrogen .beta.
receptors. For example, hot flashes, vaginal dryness, osteopenia,
osteoporosis, hyperlipidemia, loss of cognitive function, a
degenerative brain disorder, cardiovascular disease,
cerebrovascular disease breast cancer, endometrial cancer, cervical
cancer, prostate cancer, benign prostatic hyperplasia (BPH),
endometriosis, uterine fibroids, osteoarthritis and
contraception.
[0120] As used herein, the term "degenerative brain disease" shall
include cognitive disorder, dementia, regardless of underlying
cause and Alzheimer's disease.
[0121] As used herein, the term "cardiovascular disease" shall
include elevated blood lipid levels, coronary arthrosclerosis and
coronary heart disease.
[0122] As used herein, the term "cerebrovascular disease" shall
include abnormal regional cerebral blood flow and ischemic brain
damage.
[0123] Compounds of formula (I) wherein R.sup.1 and R.sup.2 are not
taken together with the atoms to which they are bound to form a
ring structure and wherein R1 is selected from the group consisting
of hydroxy-methyl and NR.sup.AR.sup.B-alkoxy-methyl may be prepared
according to the process outlined in Scheme 1. ##STR55##
[0124] Accordingly, a suitably substituted compound of formula
(IV), a known compound or compound prepared by known methods is
reacted with a suitably substituted compound of formula (V),
wherein Y is hydrogen, lower alkyl (such as methyl, ethyl) or lower
alkoxy (such as methoxy, ethoxy), a known compound or compound
prepared by known methods, in the presence of a Lewis acid such as
BF.sub.3.Etherate, tin tetrachloride, titanium tetrachloride,
magnesium bromide, and the like, preferably at a temperature in the
range of about -78 to about 0.degree. C., in an organic solvent
such as methylene chloride, chloroform, acetonitrile, toluene, and
the like, to yield the corresponding compound of formula (VI).
[0125] The compound of formula (VI) is reduced by reacting with a
suitable reducing agents such as LAH, BH.sub.3, lithium
borohydride, sodium borohydride, DiBAL-H, and the like, to yield
the corresponding compound of formula (Ia).
[0126] The compound of formula (Ia) is optionally further reacted
with a suitably substituted compound of formula (VII), a known
compound or compound prepared by known methods, in the presence of
a strong base such as NaH, LiHMDS, NaHMDS, n-butyl lithium, and the
like, in an organic solvent such as THF, dioxane, and the like, to
yield the corresponding compound of formula (Ib).
[0127] Compounds of formula (I) wherein R.sup.1 is selected from
the group consisting of alkyl, hydroxy substituted alkyl, alkenyl,
hydroxy substituted alkenyl, alkynyl, hydroxy substituted alkynyl,
alkoxyalkyl, alkoxy-carbonyl, alkyl-carbonyl, aryl-carbonyl,
heteroaryl-carbonyl, heterocycloalkyl-carbonyl,
alkyl-carbonyl-alkyl, NR.sup.AR.sup.B-carbonyl,
NR.sup.AR.sup.B-alkoxy-alkyl may be prepared by reacting a suitably
substituted compound of formula (VI) wherein Y is H or a lower
alkyl by reacting the compound of formula (VI) wherein Y is H or
lower alkyl with a suitably substituted nucleophile, a known
compound or compound prepared by known methods, in an organic
solvent such as THF, dioxane, and the like.
[0128] One skilled in the art will recognize that compounds of
formula (I) wherein R.sup.3 is alkyl may be similarly according to
the process described in Scheme 1 above, by substituting a suitably
substituted compound of formula (IVa) ##STR56##
[0129] for the compound of formula (IV).
[0130] Compounds of formula (I) wherein R.sup.3 is alkyl may be
optionally may be prepared according to the process outlined in
Scheme 2. ##STR57## ##STR58##
[0131] Accordingly, a suitably substituted compound of formula
(XX), a known compound or compound prepared by known methods, is
reduced with a suitable reducing agent such as hydrogen gas, in the
presence of a catalyst such as Pd on carbon, in an organic solvent
such as ethyl acetate, methanol, ethanol, isopropyl alcohol, and
the like, to yield the corresponding compound of formula (XXI).
[0132] The compound of formula (XXI) is reacted with a reducing
agent such as LAH, DiBAL-H, borane or source of borane, and the
like, in an organic solvent such as THF, dioxane, and the like, to
yield the corresponding compound of formula (XXII).
[0133] One skilled in the art will recognize that the reduction of
the double bond, carbonyl and ester groups on the compound of
formula (XX) may alternatively be completed in any order and/or in
one or more steps, according to known methods other than those
described herein, to yield the corresponding compound of formula
(XXII).
[0134] The compound of formula (XXII) is reacted with a suitable
protecting group reagent, according to known methods, to yield the
corresponding compound of formula (XXIII), wherein PG.sup.2 is the
corresponding protecting group such as TBS, TIPS, and the like. For
example, the compound of formula (XXII) may be reacted with TBSCI
in the presence of a base such as TEA, DIPEA, pyridine, and the
like, to yield the corresponding compound of formula (XXIII),
wherein PG.sup.2 is TBS.
[0135] The compound of formula (XXIII) is oxidized according to
known methods, to yield the corresponding compound of formula
(XXIV). For example, the compound of formula (XXIII) may be
subjected to Swern oxidation by reacting with (COCl).sub.2 in DMSO
in the presence of TEA, to yield the corresponding compound of
formula (XXIV).
[0136] The compound of formula (XXIV) Is reacted suitably
substituted compound of formula (XXV), a known compound or compound
prepared by known methods, wherein W.sup.1 is Br or Cl, in an
anhydrous organic solvent such as THF, dioxane, and the like, to
yield the corresponding compound of formula (XXVI).
[0137] The compound of formula (XXVI) is subjected to dehydration
by reacting with an acid such as trifluoroacetic acid,
p-toluenesulfonic acid, and the like, to yield the corresponding
compound of formula (XXVII).
[0138] The compound of formula (XXVII) is reacted in a two step
process, first with borane or a source of borane such as
BH.sub.3.S(CH3).sub.2, Catecol borane, 9-BBN, and the like, in an
organic solvent such as THF, dioxane, diethyl ether, and the like;
and then reacted with peroxide in the presence of a base such as
NaOH, LiOH, KOH, and the like, in an organic solvent such as
THF/water mixture, ethanol, methanol, and the like, to yield the
corresponding compound of formula (XXVI II).
[0139] The compound of formula (XXVIII) is oxidized according to
known methods, to yield the corresponding compound of formula
(XXIX). For example, the compound of formula (XXVIII) may be
subjected to Swern oxidation by reacting with (COCl).sub.2 in DMSO
in the presence of TEA, to yield the corresponding compound of
formula (XXIX).
[0140] The compound of formula (XXIX) is reacted with a suitably
substituted compound of formula (XXX), a known compound or compound
prepared by known methods, wherein W.sup.2 is Br or Cl, in an
anhydrous organic solvent such as THF, dioxane, and the like, to
yield the corresponding compound of formula (XXXI).
[0141] The compound of formula (XXXI) is subjected to dehydration
by reacting with an acid such as trifluoroacetic acid,
p-toluenesulfonic acid, and the like, to yield a mixture of the
compound of formula (XXXII) and the compound of formula (Ie).
[0142] Preferably, the mixture of the compound of formula (XXXII)
and the compound of formula (Ie) is separated, according to known
methods, to isolate the compound of formula (Ie).
[0143] Compounds of formula (I) wherein R.sup.1 and R.sup.2 are
taken together with the atoms to which they are bound to form a
five to eight membered saturated ring structure, wherein the
saturated ring structure does not contain a heteroatom selected
from O, N or S, may be prepared according to the process outlined
in Scheme 3. ##STR59##
[0144] Accordingly, a suitably substituted compound of formula
(IV), a known compound or compound prepared by known methods, is
reacted with a suitably substituted compound of formula (VIII),
wherein the n is an integer from 1 to 4 a known compound or
compound prepared by known methods, in the presence of a Lewis acid
such as BF.Etherate, tin tetrachloride, titanium tetrachloride,
magnesium bromide, and the like, preferably at a temperature in the
range of about -78 to about 0.degree. C., in an organic solvent
such as methylene chloride, chloroform, acetonitrile, toluene, and
the like, to yield the corresponding compound of formula (Ic).
[0145] One skilled in the art will recognize that the carbonyl on
the compound of formula (Ic) may be optionally, further reacted
with a suitably substituted nucleophile. For example, the compound
of formula (Ic) may be reacted with with a vinyl magnesium chloride
or with vinyl magnesium bromide, to yield the corresponding
compound of formula (Id) ##STR60##
[0146] Compounds of formula (I) wherein R.sup.1 and R.sup.2 are
taken together with the atoms to which they are bound to a group of
the formula ##STR61##
[0147] may be prepared according to the process outlined in Scheme
4. ##STR62##
[0148] Accordingly, a suitably substituted compound of formula
(IX), a known compound or compound prepared by known methods, is
reacted according to known methods (or example the compound of
formula (IX) is reacted with mesityl chloride or tosyl chloride, in
the presence of a base such as TEA, DIPEA<pyridine, and the
like), to yield the corresponding compound of formula (X), wherein
L.sup.2 is a suitable leaving group such as mesyl, tosyl, and the
like.
[0149] The compound of formula (X) is subjected to ring closure by
reacting with a base such as K.sub.2CO.sub.3, NaOH, NaOCH.sub.3,
and the like, to yield the corresponding compound of formula
(XI).
[0150] One skilled in the art will recognize that compounds of
formula (I) wherein is a single bond may be prepared by reducing
the corresponding compound of formula (I) wherein is a double bond,
by known methods, for example by reacting with hydrogen gas, in the
presence of a catalyst such as 10% palladium on carbon, platinum,
and the like, wherein the hydrogen gas is added at a pressure in
the range of about 5 to about 50 psi, preferably about 30 psi, in
an organic solvent such as ethanol, ethyl acetate, and the
like.
[0151] Compounds of formula (III) wherein R.sup.4 is hydrogen and
is a double bond may be prepared according to the process outlined
in Scheme 5. ##STR63##
[0152] Accordingly, a suitably substituted compound of formula (L)
(wherein the C.sub.1-4alkyl is preferably ethyl) is reacted with a
suitably substituted compound of formula (LI), a known compound or
compound prepared by known methods is reacted with a suitably
substituted compound of formula (V), wherein X is chloro, iodo or
bromo, a known compound or compound prepared by known methods, in
the presence of a base such as potassium-t-butoxide, sodium
ethoxide, sodium t-butoxide and the like, in an organic solvent
such as t-butanol, ethanol, and the like, to yield the
corresponding compound of formula (IIIa).
[0153] One skilled in the art will recognize that the compound of
formula (IIIa) may further optionally be reduced by known methods,
for example with hydrogen gas, in the presence of a catalyst such
as 10% palladium on carbon, platinum, and the like, wherein the
hydrogen gas is added at a pressure in the range of about 5 to
about 50 psi, preferably about 30 psi, in an organic solvent such
as ethanol, ethyl acetate, and the like, to yield the corresponding
compound of formula (IIIb) ##STR64##
[0154] a compound of formula (III) wherein is a single bond.
[0155] One skilled in the art will further recognize that the
compound of formula (IIIa) or the compound of formula (IIIb) may be
optionally further reacted, according to known methods (for example
with a strong base such as NaOH, LiOH, and the like, in a solvent
mixture such as THF/water, ethanol/water, and the like) to convert
the ester portion (i.e. the --C(O)--O--(C.sub.1-4alkyl) portion) to
the corresponding carboxy group (i.e. --C(O)OH group).
[0156] Compounds of formula (II) may be prepared according to the
process outlined in Scheme 6. ##STR65##
[0157] Accordingly, a suitably substituted compound of formula
(IIIc), wherein R.sup.4 is selected from the group consisting of
hydrogen and lower alkyl, a compound prepared according to any of
the processes described above, is reacted with a suitable
activating reagent, such as triflic anhydride,
N-phenyltrifluoromethane sulfonamide,
N,N-bis(trifluoromethylsulfonyl)amino-5-chloro-pyridine, and the
like, in the presence of a base such as LHMDS, KHMDS, LDA, and the
like, in an aprotic solvent such as THF, diethyl ether,
1,4-dioxane, and the like, to yield the corresponding compound of
formula (LIII), wherein AG1 is the corresponding activating group
to the activating reagent. (For example, when the activating
reagent is triflic anhydride, OAG.sup.1 is triflate).
[0158] The compound of formula (LIII) is reacted with a suitably
substituted boronic acid, a compound of formula (LIV), a known
compound or compound prepared by known methods, or with a suitably
substituted trialkyl tin, a compound of formula (LV), a known
compound or compound prepared by known methods, in the presence of
a catalyst such as Pd(PPh.sub.3).sub.4,
Pd(PPh.sub.3).sub.2Cl.sub.2, Pd(dppf)Cl.sub.2, and the like, in the
presence of a base such as K.sub.3PO.sub.4, TEA, DIPEA, and the
like, in an organic solvent such as 1,4-dioxane, THF, DMF, toluene,
and the like, to yield the corresponding compound of formula
(II).
[0159] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
EXAMPLE 1
4-(4-Hydroxy-phenyl)-[4-(2-morpholin-4-yl-ethoxy)-benzyl]-methyl-cyclohex--
3-enecarboxylic acid ethyl ester Compound #38
[0160] ##STR66##
[0161] A solution of vinyl triflate (70 mg, 0.1309 mmol) and
K.sub.3PO.sub.4 (42 mg, 0.1946 mmol) in 1,4-dioxane (2 mL) was
degassed by bubbling Ar(g) through the solution for 15 minutes. To
the degassed solution was then added 4-hydroxyphenyl boronic acid
(20 mg, 0.1440 mmol) and Pd(PPh.sub.3).sub.4 (4 mg,
3.27.times.10.sup.-3 mmol) and the reaction mixture was heated at
80.degree. C. for 16 hours. The reaction mixture was then
concentrated and purified by preparatory TLC using 5%
MeOH/CH.sub.2Cl.sub.2 to elute, to yield the title compound as a
foam.
[0162] MS (M+1) 478.1
EXAMPLE 2
4-(4-Hydroxymethyl-4-methyl-cyclohex-1-enyl)-phenol Compound
#25
[0163] ##STR67##
[0164] 4-benzyloxy iodobenzene (193 g, 0.625 mol),
ethynyl-trimethyl-silane (75 g, 0.76 mol), CuI (2 g, 10.5 mmol) and
Pd(PPh.sub.3).sub.2Cl.sub.2 (1 g, 1.0 mmol) were added to
diethylamine (880 mL) at 0.degree. C. The reaction mixture was
warmed to 25.degree. C. and then stirred for 6 h. The reaction
mixture was concentrated and partitioned in H.sub.2O/ethyl acetate
(100 mL/100 mL). The reaction mixture was further extracted with
ethyl acetate (300 mL.times.2). The combined organic layers were
washed by water (300 mL), dried over MgSO.sub.4 and concentrated in
vacuo. The crude product was dissolved in methanol (400 mL) and was
stirred with KOH (28 g, 0.5 mol) for 1 h at 25.degree. C.
Concentration and purification by silica gel column chromatograph
(5% ethyl acetate/Hexane) yielded 4-benzyloxy phenyl acetylene as
liquid.
[0165] To a suspended solution of NaI (70 g, 0.46 mol) and
4-benzyloxy phenyl acetylene (40 g, 0.0956 mol) was added H.sub.2O
(26 mL). The reaction mixture was then cooled to 0.degree. C. TMSCI
(60 mL, 0.475 mol) was added slowly to maintain the temperature at
0.degree. C. The reaction mixture was then stirred for another 3 h
at 0.degree. C. The reaction mixture was quenched by adding
saturated aqueous NaHCO.sub.3 (200 mL), followed by dilution with
ethyl acetate (600 mL). The combined organic layers were washed by
NaHCO.sub.3 solution, dried over Na.sub.2SO.sub.4, and purification
on SiO.sub.2 (2% .about.5% ethyl acetate/hexane) to yield
1-benzyloxy-4-(1-iodo-vinyl)-benzene.
[0166] 1-benzyloxy-4-(1-iodo-vinyl)-benzene (12.0 g, 0.035 mol),
vinyl tributyl tin (16.0 mL, 0.056 mol) and
PdCl.sub.2(CH.sub.3CN).sub.2 (150 mg, 0.0579 mmol) were dissolved
in DMF (300 mL). The reaction mixture was stirred at 25.degree. C.
for 16 h, then partitioned between ethyl acetate (800 mL) and
H.sub.2O (400 mL). The organic layer was washed by brine,
concentrated and purified on SiO.sub.2 (15% ethyl acetate/Hexane)
to yield 1-benzyloxy-4-(1-methylene-allyl)-benzene.
[0167] MS (m/z): 237 (MH.sup.+), 235 (MH.sup.-).
[0168] 1-benzyloxy-4-(1-methylene-allyl)-benzene (0.40 g, 1.694
mmol) and 2-methyl-propenal (0.355 mL) in DCM (10 mL) was cooled to
-10.degree. C. BF.sub.3.OCH.sub.2CH.sub.3 (0.322 mL, 1.778 mmol)
was added and the reaction mixture stirred for 3 h. The mixture was
then quenched by aqueous saturated NaHCO.sub.3 solution. After
extraction with ethyl acetate (2.times.100 mL), the reaction
mixture was dried over MgSO.sub.4 and purified on SiO.sub.2 to
yield 4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-ene
carbaldehyde.
[0169] MS (m/z): 307 (MH.sup.+), 305 (MH.sup.-).
[0170] To a cooled solution of
4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-ene carbaldehyde (0.41
g, 1.33 mmol) in THF (10.0 mL) was added to LAH (0.100 g, 2.70
mmol) and the reaction mixture stirred at 0.degree. C. for 3 h. The
reaction mixture was then quenched by methanol followed by aqueous
HCl (1 N, 2 mL) until all of the black/brown precipitate was
dissolved. The resulting mixture was extracted with ethyl acetate
(2.times.30 mL). The combined organic layers were washed with
brine, dried over MgSO.sub.4 and purified by SiO.sub.2 (50% ethyl
acetate/hexane) to yield
[4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-enyl]-methanol as a
liquid.
[0171] MS (m/z): 309 (MH.sup.+), 307 (MH.sup.-)
[0172] To a solution of
[4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-enyl]-methanol (102 mg,
0.331 mmol) in DCM (5.0 mL) at -78.degree. C. was added BCl.sub.3
(1.0 M in hexanes, 0.5 mL). The reaction mixture was then stirred
at -78.degree. C. for 3 h. The mixture was then quenched with
aqueous saturated NaHCO.sub.3 (30 mL), extracted with ethyl acetate
(60 mL), dried over MgSO.sub.4 and purified by SiO.sub.2
(50.about.70% ethyl acetate/Hexanes) to yield
4-(4-hydroxymethyl-4-methyl-cyclohex-1-enyl)-phenol as a
liquid.
[0173] MS (m/z): 219 (MH.sup.+), 217 (MH.sup.-).
EXAMPLE 3
and
4-{2-[4-(2-Dimethylamino-ethoxy)-phenyl]-4-hydroxymethyl-4-methyl-cycl-
ohex-1-enyl}-phenol Compound #27 and #3
[0174] ##STR68##
[0175] 1-benzyloxy-4-ethynyl-benzene (70 g, 0.3365 mol),
Bu.sub.3SnH (59 mL, 0.3365 mol) and Ph(PP.sub.3).sub.2Cl.sub.2 (120
mg, 0.1718 mmol) were stirred in THF (500 mL) at 25.degree. C. for
16 h and then refluxed for 1 h. The resulting solution was
concentrated and then purified on SiO.sub.2 (2% .about.5% ethyl
acetate/hexane) to yield
tributyl-[1-(4-benzyloxy-phenyl)-vinyl]-stannane.
[0176] To a cooled solution of
tributyl-[1-(4-benzyloxy-phenyl)-vinyl]-stannane (26.2 g, 52.6
mmol) in DMF (180 mL) at 0.degree. C. was added CuCl (8.6 g, 87.7
mmol) and CuCl.sub.2 (1.00 g, 8.13 mmol), which was then stirred at
25.degree. C. for 2 h. The reaction mixture was then diluted with
ethyl acetate (500 mL) and washed with brine (3.times.300 mL). The
reaction mixture was then dried over MgSO.sub.4 and purified by
SiO.sub.2 (20% ethyl acetate/hexane) to yield
2,3-di(4-benzyloxy-phenyl)-1,3-butadiene.
[0177] MS (m/z): 419 (MH.sup.+), 417 (MH.sup.-).
[0178] To a solution of 2,3-di(4-benzyloxy-phenyl)-1,3-butadiene
(1.2 g, 2.8 mmol) and 2-methyl-propenal (0.602 g, 8.4 mmol) in DCM
(10.5 mL) was added BF.sub.3.OCH.sub.2CH.sub.3 (0.596 mL, 4.2 mmol)
at -10.degree. C. After 3 h at -10.degree. C., the reaction mixture
was quenched with saturated aqueous NaHCO.sub.3 (10 mL). The
reaction mixture was then extracted with ethyl acetate (2 10 mL),
dried over MgSO.sub.4 and purified by SiO.sub.2 twice (15% ethyl
acetate/hexane) to yield
1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-ene
carbaldehyde.
[0179] MS (m/z): 489 (MH.sup.+), 487 (MH.sup.-).
[0180] To a solution of
1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-ene carbaldehyde
(200 mg, 0.409 mmol) in MeOH (10.0 mL) at -10.degree. C. was added
NaBH.sub.4 (100 mg, excess). The reaction mixture was stirred 30
min and then quenched with 51% HCl solution (5 mL), extracted with
ethyl acetate (50 mL) and dried over MgSO.sub.4. The reaction
mixture was then concentrated and purified on SiO.sub.2 (50% ethyl
acetate/hexane) to yield
(1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-enyl)-methanol.
[0181] MS (m/z): 491 (MH.sup.+), 489 (MH.sup.-)
[0182] To a solution of
(1-methyl-3,4-di(4-benzyloxy-phenyl)-cyclohex-3-enyl)-methanol (150
mg, 0.306 mmol) in DCM (5.0 mL) at -10.degree. C. was added
TiCl.sub.4 (0.102 mL, 3.0 eq.) and the reaction mixture stirred at
-10.degree. C. for 3 h. The reaction mixture was then diluted with
ethyl acetate (20 mL and H.sub.2O (10 mL). The organic layer was
separated, dried over MgSO.sub.4, and purified by SiO.sub.2
(50.about.100% ethyl acetate/hexane) to yield a lower TLC spot of
(1-methyl-3,4-di(4-hydroxy-phenyl)-cyclohex-3-enyl)-methanol.
[0183] MS (m/z): 311 (MH.sup.+), 309 (MH.sup.-).
[0184] To a solution of
(1-methyl-3,4-di(4-hydroxy-phenyl)-cyclohex-3-enyl)-methanol (30
mg, 1 eq.) in DMF (1 mL) was added NaH (10 mg, 1 eq.), and the
reaction mixture was then stirred for 2 h at 25.degree. C. To the
reaction mixture was then added (2-chloro-ethyl)-dimethyl-amine (12
mg, 1 eq) and the mixture stirred for 16 hours. The reaction
mixture was then partitioned between H.sub.2O/ethyl acetate (5 mL/5
mL). The organic layer was separated, dried over MgSO.sub.4,
concentrated and purified HPLC (20% .about.80% CH.sub.3CN/H.sub.2O
with 0.1% TFA) to yield
4-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-4-hydroxymethyl-4-methyl-cyclohe-
x-1-enyl}-phenol.
[0185] MS (m/z): 382 (MH.sup.+), 380 (MH.sup.-).
EXAMPLE 4
4-[6-Ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]--
phenol and
4-[2-Ethyl-4-hydroxymethyl-6-(4-methoxy-phenyl)-3-methyl-cycloh-
exyl]-phenol Compound #20 and #4
[0186] ##STR69##
[0187] To 2-ethyl-4-hydroxymethyl-3-methyl-cyclohexanol (30 g,
0.174 mol) in DMF (300 mL) was added TBSCI (26.01 g, 1.0 eq.) and
imidazole (17.7 g, 1.5 eq.). The reaction mixture was stirred at
25.degree. C. for 2 h. The reaction mixture was then partitioned
between H.sub.2O (300 mL) and diethyl ether (600 mL). The organic
layer was washed by brine (2.times.300 mL), dried over MgSO.sub.4
and purified on SiO.sub.2 (5% .about.30% ethyl acetate/hexane) to
yield
4-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-3-methyl-cyclohexanol.
[0188] To a solution of oxalyl chloride in DCM (400 mL) at
-78.degree. C. was added DMSO (15.6 mL, 3.0 eq.) and the mixture
was stirred for 30 min. To the mixture was then added
4-(tert-butyl-dimethyl-silanyloxymethyl)-2-ethyl-3-methyl-cyclohexanol
(21.1 g, 73.7 mmol) and the reaction mixture was stirred for 3 h at
-78.degree. C. Et.sub.3N (30.7 mL) was added at -78.degree. C. and
the mixture warmed to 25.degree. C. over 2 h. The reaction mixture
was then diluted with H.sub.2O (400 mL). The organic layer was
dried over MgSO.sub.4 and then concentrated to yield
2-ethyl-3-methyl-4-trimethylsilanyloxymethyl-cyclohexanone.
[0189] MS (m/z): 285 (MH.sup.+), 283 (MH.sup.-).
[0190] 1-Benzyloxy-4-iodo-benzene (5.70 g, 18.37 mmol) was
dissolved in anhydrous THF (36 mL) at -10.degree. C. Isopropyl
magnesium chloride (1.0 M, 18.37 mL) was added and the mixture was
stirred for 3 h. A solution of
2-ethyl-3-methyl-4-trimethylsilanyloxymethyl-cyclohexanone (12.0 g
in 50 mL THF) was added slowly over 30 min by syringe pump. The
reaction mixture was stirred for 30 min at 25.degree. C. and then
refluxed for 30 min. The reaction mixture was then cooled to
25.degree. C., HCl (1.0 N, 80 mL) was added slowly, followed by
addition of ethyl acetate (100 mL). The organic layer was washed
with H.sub.2O (100 mL), dried over MgSO.sub.4 and purified on
SiO.sub.2 (10.about.15% ethyl acetate/hexane) to yield
1-(4-benzyloxy-phenyl)-2-ethyl-4-hydroxymethyl-3-methyl-cyclohex-
anol.
[0191] MS (m/z): 469 (MH.sup.+), 467 (MH.sup.-)
[0192] To
1-(4-benzyloxy-phenyl)-2-ethyl-4-hydroxymethyl-3-methyl-cyclohe-
xanol (7.8 g, 0.0166 mol) was added pTSA (1.8 g, 1 eq.) in DCM (100
mL). The reaction mixture was refluxed for 8 h. DCM (200 mL) was
added and the mixture was washed with aqueous saturated NaHCO.sub.3
(3.times.300 mL). The organic layer was separated, dried over
MgSO.sub.4 and purified on SiO.sub.2 (50% ethyl acetate/hexane)
twice to yield
[4-(4-benzyloxy-phenyl)-5-ethyl-6-methyl-cyclohex-3-enyl]-methanol.
[0193] MS (m/z): 337 (MH.sup.+), 335 (MH.sup.-)
[0194] To the solution of
[4-(4-benzyloxy-phenyl)-5-ethyl-6-methyl-cyclohex-3-enyl]-methanol
(3.1 g, 6.8 mmol) in THF (50 mL) was added
BH.sub.3.S(CH.sub.3).sub.2 solution (1.0 M in THF, 10.3 mL, 1.5
eq.) at 0.degree. C. The reaction mixture was refluxed for 4 h and
then cooled to 0.degree. C. NaOH (20% aqueous, 30 mL) and
H.sub.2O.sub.2 (50% in H.sub.2O, 21 mL) were added at 0.degree. C.
The reaction mixture was then stirred at 0.about.25.degree. C. for
4 h. The reaction mixture was then diluted with ethyl
acetate/H.sub.2O (400 mL/200 mL). The organic layer was separated,
dried over MgSO.sub.4 and purified on SiO.sub.2 (50.about.100%
ethyl acetate/hexane) to yield
2-(4-benzyloxy-phenyl)-3-ethyl-5-hydroxymethyl-4-methyl-cyclohexanol.
[0195] MS (m/z): 353 (MH.sup.+), 351 (MH.sup.-)
[0196] To the solution of
2-(4-benzyloxy-phenyl)-3-ethyl-5-hydroxymethyl-4-methyl-cyclohexanol
(2.31 g) in DMF (20 mL) was added imidazole (1.17 g, 1.5 eq.) and
TBSCI (1.4 g, 1.5 eq.) at 0.degree. C. and the mixture was stirred
at 25.degree. C. for 3 h. The reaction mixture was then diluted
with water/ether (200/300 mL). The organic layer was washed by
brine (3.times.200) and purified SiO.sub.2 (10% ethyl
acetate/Hexane) to yield
2-(4-benzyloxy-phenyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-4-
-methyl-cyclohexanol.
[0197] MS (m/z): 469 (MH.sup.+), 467 (MH.sup.-)
[0198] To a solution of
2-(4-benzyloxy-phenyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-ethyl-4-
-methyl-cyclohexanol in DCM (100 mL) was added NaHCO.sub.3 (1.0 g)
to make a suspension. Dess-Martin periodate (3.2 g, 1.0 eq.) was
added at 0.degree. C. The reaction mixture was stirred at
25.degree. C. for 3 h and was then filtered and purified on
SiO.sub.2 (20% Ethyl acetate/Hexane) to yield
3-ethyl-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohe-
xanone.
[0199] MS (m/z): 467 (MH.sup.+), 465 (MH.sup.-)
[0200] To a solution of
3-ethyl-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cyclohe-
xanone (1.8 g, 3.8 mmol) in THF (10 mL) at -10.degree. C. was added
Grinard reagent (1.0 M, 7.5 mL). The reaction mixture was stirred
at 25.degree. C. for 1 h and then refluxed for 30 min. The reaction
mixture was then cooled and diluted with aqueous saturated
NH.sub.4Cl (100 mL) and ethyl acetate (100 mL). The organic layer
was separated, dried over MgSO.sub.4 and purified on SiO.sub.2
(100% ethyl acetate) to yield crude product
3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trim-
ethylsilanyloxymethyl-cyclohexanol. NMR showed S:R product ratio or
2:1. Further purification provide pure
3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsil-
anyloxymethyl-cyclohexanol.
[0201] MS (m/z): 575 (MH.sup.+), 573 (MH.sup.-)
[0202] To a solution of
3-ethyl-1-(4-methoxy-phenyl)-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsil-
anyloxymethyl-cyclohexanol (400 mg) in CHCl.sub.3 (8.0 mL) was
added pTSA (400 mg) and the reaction mixture was refluxed for 8 h.
The reaction mixture was diluted with CH.sub.3Cl (50 mL) and was
washed with aqueous saturated NaHCO.sub.3 (10 mL). The organic
layer was dried and purified on SiO.sub.2 (50% ethyl
acetate/hexane) to yield a mixture of
4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]-
-phenol and
4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-2-enyl]-
-phenol as a very close two spots as determined by TLC.
[0203] MS (m/z): 443 (MH.sup.+), 441 (MH.sup.-).
[0204] To the above mixture of
4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]-
-phenol and
4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-2-enyl]-
-phenol (380 mg) in DCM (10 mL) at -10.degree. C. was added
TiCl.sub.4 (0.180 mL) and the mixture was stirred for 3 h at
-10.degree. C. The reaction mixture was diluted with ethyl
acetate/H.sub.2O (200/100 mL). The organic layer was dried and
purified on SiO.sub.2 to yield two products
4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohe-
x-1-enyl]-phenol and
4-[2-ethyl-4-hydroxymethyl-6-(4-methoxy-phenyl)-3-methyl-cyclohexyl]-phen-
ol.
[0205] MS (m/z): 353 (MH.sup.+), 351 (MH.sup.-)
EXAMPLE 5
4-{6-ethyl-4-hydroxymethyl-5-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-
-cyclohex-1-enyl}-phenol Compound #75
[0206] ##STR70##
[0207] To iodide (66 mg, 0.2 mmol) in THF (1 mL) at -78 C was added
nBuLi (2.5 M in hexanes, 0.080 mL, 0.2 mmol) and the reaction
mixture stirred for 10 min. To the reaction mixture was then added
dropwise, TBS
(3-ethyl-4-methyl-2-(4-phenoxy-phenyl)-5-trimethylsilanyloxymethyl-cycloh-
exanone) in THF (1 mL). The reaction mixture was then quenched with
aqueous saturated NH.sub.4Cl (2 mL) and diluted with diethyl ether
(5 mL). The organic layer was washed with brine twice, dried and
concentrated to yield crude
2-(4-benzyloxy-phenyl)-3-ethyl-4-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-ph-
enyl]-5-trimethylsilanyloxy methyl-cyclohexanol which was used
without further purification.
[0208] MS (m/z): 672 (MH.sup.+), 670 (MH.sup.-)
[0209] To a solution of
2-(4-benzyloxy-phenyl)-3-ethyl-4-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-ph-
enyl]-5-trimethylsilanyloxy methyl-cyclohexanol in DCM (1 mL) was
added TiCl.sub.4 (0.033 mL, 3 eq.) and the mixture stirred until
reaction was done. The reaction mixture was diluted with ethyl
acetate (10 mL), and washed with 5% NaHCO.sub.3 aqueous solution,
then brine. The crude product s was purified on HPLC to yield
4-{6-ethyl-4-hydroxymethyl-5-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl-
]-cyclohex-1-enyl}-phenol.
[0210] MS (m/z): 450 (MH.sup.+), 448 (MH.sup.-).
EXAMPLE 6
[6-Hydroxymethyl-3,4-bis-(4-methoxy-phenyl)-cyclohex-3-enyl]-methanol
Compound #26
[0211] ##STR71## Step 1:
[0212] To the solution of 4-methoxy-phenyl-acetylene (10 g, 0.075
mol) and 4-iodo-anisole (17.65 g, 1.0 eq.) in diethylamine (150 mL)
was added Pd(PPh.sub.3).sub.2Cl.sub.2 (2.65 g, 0.05 eq.) and the
reaction mixture was stirred for 30 min at 0.degree. C. To the
reaction mixture was then added CuI (1.43 g, 0.1 eq.) and the
mixture was stirred at 6 h at 0.about.25.degree. C. The reaction
mixture was then concentrated and partitioned between ethyl
acetate/H.sub.2O (200/600 mL). The organic layer was separated,
dried and purified on SiO.sub.2 (1.about.5% ethyl acetate/hexane)
to yield 1,2-di(4-methoxy-phenyl)-acetylene.
Step 2:
[0213] Sodium hydride (1.53 g, 2.2 eq.) was added to DMSO (150 mL)
and then heated to 75.degree. C. till the solution became clear.
The reaction mixture was cooled to 0.degree. C.
1,2-di(4-methoxy-phenyl)-acetylene. (7.0 g, 1 eq.) was then added
and the reaction mixture was then heated to 90.degree. C. for 12 h.
The reaction mixture was then poured into crushed ice and extracted
by diethyl ether (500 mL). The organic layer was washed with brine,
dried and purified on SiO.sub.2 to yield
2,3-di(4-methoxyphenyl)-1,3-butadiene as 80% pure by NMR.
[0214] MS (m/z): 267 (MH.sup.+), 265 (MH.sup.-).
Step 3:
[0215] To the solution of 2,3-di(4-methoxyphenyl)-1,3-butadiene
(2.1 g) in toluene (30 mL) was added maleic anhydride (3.8 g, 5.0
eq.) and the reaction mixture refluxed for 6 h. The reaction
mixture was then diluted with ethyl acetate (500 mL) and was washed
with water (3.times.200 mL). The organic layer was dried and
concentrated to yield
5,6-bis-(4-methoxy-phenyl)-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione.
[0216] MS (m/z): 365 (MH.sup.+), 363 (MH.sup.-).
Step 4:
[0217] To the cooled solution of
5,6-bis-(4-methoxy-phenyl)-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione
(2.95 g) in THF (30 mL) at 0.degree. C. was added LAH (1.0 M in
THF, 20 mL) and the reaction mixture was stirred at 25.degree. C.
for 16. The reaction mixture was then quenched with methanol (20
mL) and aqueous HCl (10%, 30 mL) and then extracted with diethyl
ether (2.times.300 mL). The organic layer was dried and
concentrated to yield
[6-Hydroxymethyl-3,4-bis-(4-methoxy-phenyl)-cyclohex-3-enyl]-methanol.
[0218] MS (m/z): 355 (MH.sup.+), 353 (MH.sup.-)
EXAMPLE 7
5,6-Diphenyl-2,3,3a,4,7,7a-hexahydro-inden-1-one Compound #67
[0219] ##STR72##
[0220] A mixture of 2,3-diphenyl-1,3-butadiene (2.772 g, 13.44
mmol) and cyclopent-2-enone (1 eq.) was refluxed in toluene (26 mL)
for 48 h. The reaction mixture was then concentrated and purified
on SiO.sub.2 (20% ethyl acetate/hexane) to yield
5,6-diphenyl-2,3,3a,4,7,7a-hexahydro-inden-1-one.
[0221] MS (m/z): 289 (MH.sup.+), 287 (MH.sup.-).
EXAMPLE 8
5,6-Bis-(4-methoxy-phenyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-1S-ol
and
5,6-Bis-(4-methoxy-phenyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-1R-ol
Compound #61 and #57
[0222] ##STR73##
[0223] To a solution of
5,6-bis-(4-methoxy-phenyl)-2,3,3a,4,7,7a-hexahydro-inden-1-one
(50.0 mg, 0.143 mmol) in THF (5.0 mL) at -10.degree. C. was added
LAH (36 mg, 0.91 mml) and the reaction mixture was stirred at
-10.degree. C. for 1 h. The reaction mixture was then quenched with
methanol (2 mL) and aqueous HCl (1 N, 2 mL), extracted with ethyl
acetate (3.times.10 mL). The combined organic layers were dried and
purified on SiO.sub.2 to yield a mixture of
5,6-Bis-(4-methoxy-phenyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-1S-ol
and
5,6-Bis-(4-methoxy-phenyl)-2,3,3a,4,7,7a-hexahydro-1H-inden-1R-ol.
[0224] MS (m/z): 351 (MH.sup.+), 349 (MH.sup.-).
EXAMPLE 9
6,7-Diphenyl-3,4,4a,5,8,8a-hexahydro-2H-naphthalen-1-one Compound
#56
[0225] ##STR74##
[0226] A mixture of 2,3-diphenyl-1,3-butadiene (2.772 g, 13.44
mmol) and cyclohex-2-enone (1 eq.) was refluxed in toluene (26 mL)
for 48 h. The reaction mixture was then concentrated and purified
on SiO.sub.2 (20% ethyl acetate/hexane) to yield
6,7-diphenyl-3,4,4a,5,8,8a-hexahydro-2H-naphthalen-1-one
[0227] MS (m/z): 303 (MH.sup.+), 301 (MH.sup.-).
EXAMPLE 10
6-Hydroxymethyl-3,4-diphenyl-cyclohex-3-enyl)-methanol Compound
#34
[0228] ##STR75##
[0229] (6-Hydroxymethyl-3,4-diphenyl-cyclohex-3-enyl)-methanol was
prepared according to the procedure described in Example 6 (step 3)
above, with substitution of 2,3-diphenyl-1,3-butadiene for the
2,3-di(4-methoxyphenyl)-1,3-butadiene.
[0230] MS (m/z): 295 (MH.sup.+), 293 (MH.sup.-)
[0231] To the cooled solution of
6-Hydroxymethyl-3,4-diphenyl-cyclohex-3-enyl)-methanol (100 mg,
0340 mmol) in THF (3.5 mL) at -78.degree. C., was added nBuLi (2.5
M, 0.136 mL). The reaction mixture was stirred at -10.degree. C.
for 10 min. To the reaction mixture was added TsCl (77 mg, 1.2 eq.)
and the mixture stirred at -10.degree. C. to 25.degree. C. for 3 h.
The reaction mixture was quenched with aqueous saturated
NaHCO.sub.3 (10 mL) and was extracted with ethyl acetate
(3.times.10 mL). The combined organic layers were dried and
purified on SiO.sub.2 (10.about.50% ethyl acetate/hexane) to yield
6-hydroxymethyl-3,4-diphenyl-cyclohex-3-enyl)-methanol.
[0232] MS (m/z): 449 (MH.sup.+), 447 (MH.sup.-)
[0233] To a solution of
6-hydroxymethyl-3,4-diphenyl-cyclohex-3-enyl)-methanol (89 mg,
0.189 mmol) in THF (10 mL) was added LAH (1.0 M in THF, 5 mL) at
-10.degree. C. (ice/acetone) and the reaction mixture stirred at
25.degree. C. for 12 h. The reaction mixture was then quenched by
MeOH (10 mL) and then stirred for 10 min. To the reaction mixture
was then added aqueous HCl (10%, 10 mL). The reaction mixture was
then extracted with diethyl ether (300 mL). The organic layer was
washed with brine, dried and purified to yield
6-hydroxymethyl-3,4-diphenyl-cyclohex-3-enyl)-methanol and
5,6-diphenyl-1,3,3a,4,7,7a-hexahydro-isobenzofuran as a by
product.
[0234] MS (m/z): 277 (MH.sup.+), 275 (MH.sup.-).
EXAMPLE 11
4-{4-Hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohe-
xa-1,5-dienyl}-S-phenol Compound #74
[0235] ##STR76## Step 1:
[0236] To the solution of KOtBu (1.0 M in tBuOH, 10.7 mL) at 25 cC
was added Hagemann's ester (1.0 mL, 5.324 mmol). The mixture was
stirred for 10 min at 25.degree. C. and then to the mixture was
added 1-[2-(4-chloromethyl-phenoxy)ethyl]piperidine hydrochloride
(1.54 g, 5.324 mmol). The mixture was refluxed for 3 h. The tBuOH
was distilled off, then the reaction mixture was diluted with water
and diethyl ether. The layers were separated and the aqueous layer
was extracted with diethyl ether. The organic extracts were
acidified with 1 N HCl (100 mL). The layers were separated and the
diethyl ether layer was discarded. The aqueous layer was then
basicified to pH 11 with 10% NaOH (aq) and extracted with diethyl
ether to yield
2-methyl-4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-2-enecarbo-
xylic acid ethyl ester as dark amber oil.
[0237] MS (m/z): 400 (MH.sup.+).
Step 2:
[0238] A solution of
2-methyl-4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-2-enecarbo-
xylic acid ethyl ester (612.0 mg, 1.534 mmol) in EtOH (100 mL) was
reacted with 10% Pd/C (25 mg) under H.sub.2 (g) (25 psi) for 21 h
at 25.degree. C. The reaction mixture was then filtered and
concentrated to yield
4-ethylperoxymethyl-3-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclo-
xe-2-enone.
[0239] MS (m/z): 402 (MH.sup.+).
Step 3:
[0240] To a solution of KHMDS (0.5 M in toluene), 5.9 mL) in THF
(20 mL) at -78.degree. C. was added
4-ethylperoxymethyl-3-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclo-
xe-2-enone (0.985 mg, 2.453 mmol) in THF (3 mL) and the reaction
mixture stirred at -78.degree. C. for 1 h. To the reaction mixture
was then added
2-[N,N-bis(trifluoro-methyl-sulfonyl)amino]-5-chloropyridine in THF
(2 mL) and the mixture was stirred at -78.degree. C. for 1.5 h. The
reaction mixture was then quenched with water, extracted with
Et.sub.2O, dried and purified on silica gel (2%
MeOH/CH.sub.2Cl.sub.2) followed by a preparative TLC (5% MeOH/DCM)
to yield
6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-4-trifluoromethanesulfony-
loxy-cyclohex-3-enecarboxylic acid ethyl ester as white foam
solid.
[0241] MS (m/z): 534 (MH.sup.+).
Step 4:
[0242] Into a mixture of trifluoro-methanesulfonic acid
4-ethylperoxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclo-
hexa-1,5-dienyl ester (118.5 mg, 0.2219 mmol), Pd (PPh.sub.3).sub.4
(6.4 mg, 0.025 eq.) and K.sub.3PO.sub.4 (70.7 mg, 1.5 eq.) in
1,4-dioxane (5 mL) was bubbled N.sub.2 for 10 min. To the reaction
mixture was then added 4-methoxy benzene boronic acid (37.1 mg,
0.2441 mmol). The resulting mixture was heated to 8.degree. C. for
16 h, filtered through a plug of silica gel, concentrated and
purified on preparative TLC (10% MeOH/DCM) to yield
4-(4-methoxy-phenyl)-6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cycl-
ohex-3-enecarboxylic acid ethyl ester as light yellow oil.
[0243] MS (m/z): 492 (MH.sup.+).
[0244]
4-{4-Ethylperoxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-ben-
zyl]-cyclohexa-1,5-dienyl}-phenol was similarly prepared according
to the procedure described above with substitution of 4-hydroxy
benzene boronic acid for the 4-methoxy benzene boronic acid in Step
4.
[0245] MS (m/z): 478 (MH.sup.+).
[0246]
1-(2-{4-[3-Ethylperoxymethyl-6-(4-fluoro-phenyl)-2-methyl-cyclohex-
a-1,5-dienylmethyl]-phenoxy}-ethyl)-piperidine was similarly
prepared according to the procedure described above with
substitution of 4-fluorobenzene boronic acid for the 4-methoxy
benzene boronic acid in Step 4.
[0247] MS (m/z): 480 (MH.sup.+).
[0248]
5-(4-{4-Ethylperoxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)--
benzyl]-cyclohexa-1,5-dienyl}-phenyl)-1H-indole was similarly
prepared according to the procedure described above with
substitution of 5-indolyl boronic acid for the 4-methoxy benzene
boronic acid in Step 4.
[0249] MS (m/z): 501 (MH.sup.+).
Step 5:
[0250]
4-(4-Hydroxy-phenyl)-6-methyl-5-[4-(2-piperidin-1-yl-ethoxy)-benzy-
l]-cyclohex-3-enecarboxylic acid ethyl ester (38.4 mg, 0.0803 mmol,
1.0 eq.) in DCM (2 mL) at 0.degree. C. was added DIBAL (1.5 M in
toluene, 0.215 mL) and was stirred at 0.degree. C. for 10 min, then
at 25.degree. C. for 30 min. The reaction mixture was quenched at
0.degree. C. with brine, extracted with DCM, dried over MgSO.sub.4,
then purified on SiO.sub.2 (15% MeOH/DCM) to yield
4-[4-hydroxymethyl-5-methyl-6-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cycloh-
ex-3-enyl]-phenol as yellowish foam.
[0251] MS (m/z): 436 (MH.sup.+).
EXAMPLE 12
Estrogen Receptor .alpha. Flash Plate Assay
[0252] This assay monitors binding of radio-labeled estrogen to the
estrogen receptor. It is performed on a BioMek 2000 (Beckman).
Plates are read in a scintillation counter (Packard TopCount), with
decreased counts an indication of binding of a compound to the
receptor. The assay was run according to the procedure described by
Allan, et al., Anal. Biochem. (1999), 275(2), 243-247.
[0253] On day one, 100 .mu.L of Estrogen Screening Buffer (ESB,
Panvera) containing 5 mM dithiothreitol (DTT, Panvera), 0.5 .mu.g
mouse anti-estrogen receptor monoclonal antibody (SRA-1010,
Stressgen) and 50 ng purified human estrogen receptor .alpha.
(Panvera) were added to each well of a 96 well FlashPlate Plus
plate crosslinked with goat anti-mouse antibodies (NEN Life
Sciences). The plate was sealed and incubated at 4.degree. C.
overnight.
[0254] On day two, each well was washed three times with 200 .mu.L
PBS, pH 7.2, at room temperature. To each well was then added 98
.mu.L radio-labeled estrogen (0.5 nM, which equals 6 nCi for a 120
Ci/mmol batch, Amersham), diluted in ESB and 5 mM dithiothreitol
(DTT). To individual wells were then added 2.5 .mu.L test compound
diluted in 30% (v/v) dimethyl sulfoxide/50 mM HEPES, pH 7.5. The
wells were mixed three times by aspiration, the plate sealed and
incubated at room temperature for one hour. The wells were then
counted for 1 min in a TopCount scintillation counter
(Packard).
EXAMPLE 13
Estrogen Receptor .beta. Fluorescence Polarization Assay
[0255] This assay monitors binding of a fluorescent analog of
estrogen (Fluormone ES2, Panvera) to the estrogen receptor. Plates
are read in a fluorometer that can be set to polarization mode. A
decrease in fluorescence relative to vehicle control is an
indication of binding of a compound to the receptor.
[0256] It is crucial to avoid introduction of air bubbles into the
reaction in each well of the 96 well plate throughout this
procedure. (Bubbles on the surface of the reaction disrupt light
flow, affecting the polarization reading.) However, it is also
crucial to effectively mix the reaction components upon addition to
the well.
[0257] On ice, a 2.times. standard mixture of Assay Buffer
(Panvera), 10 nM DTT and 40 nM ES2 was prepared. On ice, a 2.times.
reaction mixture of Assay Buffer (Panvera), and 20 nM hER-.beta.
(Panvera) and 40 nM ES2 was also prepared.
[0258] Dilutions of test compound were prepared in 30% (v/v)
dimethyl sulfoxide/50 mM HEPES, pH 7.5. At this point, the
dilutions were 40.times. the final required concentration.
[0259] The standard mixture at 50 .mu.L was then added to each
well. The reaction mixture at 48 .mu.L was added to all wells. The
compound dilution at 2.5 .mu.L was added to the appropriate wells.
The reaction mixtures were mixed using a manual pipette, a roll of
aluminum foil adhesive cover was placed on the plate and the plate
incubated at room temperature for 1 hour.
[0260] Each well on the plate was then read in an LjL Analyst with
an excitation wavelength of 265 nm and an emission wavelength of
538.
[0261] Representative compound of the present invention were tested
according to the procedure described above for binding to the
Estrogen Receptor .alpha. and Estrogen Receptor .beta., with
results as listed in Table 6. TABLE-US-00007 TABLE 6 ER.alpha.
Binding ER.beta. Binding ID No. IC.sub.50 (.mu.M) IC.sub.50 (.mu.M)
3 6.1 5.7 4 >10 1.6 18 >10 <10 20 1.85 0.10 25 0.45 0.35
26 >10 >10 27 0.5 1.5 36 >10 6.9 38 0.037, 0.01 0.9, 0.5
39 >10 >10 43 0.045 >10, 8 45 4.5 >10 46 0.2 0.74 52
>10 5.7 57 >10 4.9 61 8.7 2.0 74 0.37 0.38
EXAMPLE 14
MCF-7 Cell Proliferation Assay
[0262] This assay was run according to the procedure described by
Welshons, et al., (Breast Cancer Res. Treat., 1987, 10(2), 169-75),
with minor modification.
[0263] Briefly, MCF-7 cells (from Dr. C. Jordan, Northwestern
University) were maintained in RPMI 1640 phenol red free medium
(Gibco) in 10% FBS (Hyclone), supplemented with bovine insulin and
non-essential amino acid (Sigma). The cells were initially treated
with 4-hydroxytamoxifen (10.sup.-8 M) and let stand at 37.degree.
C. for 24 hours. Following this incubation with tamoxifen, the
cells were treated with compounds at various concentrations.
[0264] Compounds to be tested in the agonist mode were added to the
culture media at varying concentrations. Compounds to be treated in
the antagonist mode were prepared similarly, and 10 nM
17.beta.-estradiol was also added to the culture media. The cells
were incubated for 24 hours at 37.degree. C. Following this
incubation, 0.1 .mu.Ci of .sup.14C-thymidine (56 mCi/mmol,
Amersham) was added to the culture media and the cells were
incubated for an additional 24 hours at 37.degree. C. The cells
were then washed twice with Hank's buffered salt solution (HBSS)
(Gibco) and counted with a scintillation counter. The increase in
the .sup.14C-thymidine in the compound treated cells relative to
the vehicle control cells were reported as percent increase in cell
proliferation.
EXAMPLE 15
Alkaline Phosphatase Assay in Human Endometrial Ishikawa Cells
[0265] This assay was run according to the procedure described by
Albert et al., Cancer Res, (9910), 50(11), 330-6-10, with minor
modification.
[0266] Ishikawa cells (from ATCC) were maintained in DMEM/F12 (1:1)
phenol red free medium (Gibco) supplemented with 10% calf serum
(Hyclone). 24 hours prior to testing, the medium was changed to
DMEM/F12 (1:1) phenol red free containing 2% calf serum.
[0267] Compounds to be tested in the agonist mode were added to the
culture media at varying concentrations. Compounds to be treated in
the antagonist mode were prepared similarly, and 10 nM
17.beta.-estradiol was also added to the culture media. The cells
were then incubated at 37.degree. C. for 3 days. On the fourth day,
the media was remove, 1 volume of 1.times. Dilution Buffer
(Clontech) was added to the well followed by addition of 1 volume
of Assay Buffer (Clontech). The cells were then incubated at room
temperature for 5 minutes. 1 volume of freshly prepared
Chemiluminescence Buffer (1 volume of chemiluminescent substrate
(CSPD) in 19 volume Chemiluminescent Enhancer with final
concentration of CSPD at 1.25 mM; Sigma Chemical Co.) was added.
The cells were incubated at room temperature for 10 minutes and
then quantified on a luminometer. The increase of chemiluminescence
over vehicle control was used to calculate the increase in alkaline
phosphatase activity.
[0268] Representative compound of the present invention were tested
according to the procedure described in Examples 14 and 15 above,
with results as listed in Table. 7. TABLE-US-00008 TABLE 7 MCF7
MCF7 Ishikawa Ishikawa Agonist Antagonist Agonist Antagonist ID No.
EC.sub.50 (nM) IC.sub.50 (nM) EC.sub.50 (nM) IC.sub.50 (nM) 4
>10,000 >10,000 >10,000 >10,000 18 >10,000
>10,000 >10,000 >10,000 20 480 >10,000 700 4,500 25 200
>10,000 100 10,000 26 >10,000 >10,000 >10,000
>10,000 27 >10,000 >10,000 >10,000 >10,000 38
>10,000 5000 >10,000 2100 39 >10,000 >10,000 >10,000
>10,000 43 >10,000 5000 >10,000 2700 45 >10,000
>10,000 >10,000 7000 46 >10,000 >10,000 >10,000
>10,000 52 >10,000 >10,000 >10,000 >10,000 56
>10,000 >10,000 >10,000 >10,000 61 >10,000
>10,000 >10,000 >10,000
EXAMPLE 16
[0269] As a specific embodiment of an oral composition, 100 mg of
the Compound #43, is formulated with sufficient finely divided
lactose to provide a total amount of 580 to 590 mg to fill a size 0
hard gel capsule.
[0270] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *