Note: Descriptions are shown in the official language in which they were submitted.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
ALDH-2 INHIBITORS IN THE TREATMENT OF ADDICTION
[0001] This application is a continuation in part of U.S. Patent Application
Serial No.
11/829,836, filed July 27, 2007, which claims priority to U.S. Provisional
Patent
Application Serial No. 60/834,083, filed July 27, 2006, and U.S. Provisional
Patent
Application Serial No. 60/846,428, filed September 21, 2006, the entirety of
which are
incorporated herein by reference.
Field of the Invention
[0002] The present invention relates to novel ALDH-2 inhibitors, and to their
use in
treating mammals for dependence upon drugs of addiction, for example addiction
to
dopamine-producing agent such as cocaine, opiates, amphetamines, nicotine, and
alcohol. ALDH-2 inhibitors have also been shown to be effective in treating
obesity.
The invention also relates to methods for the preparation of such compounds,
and to
pharmaceutical compositions containing them.
Background
[0003] Today, dependence upon drugs of addiction causes major health problems
worldwide. For example, alcohol abuse and alcohol dependency can cause liver,
pancreatic and kidney disease, heart disease, including dilated
cardiomyopathy,
polyneuropathy, internal bleeding, brain deterioration, alcohol poisoning,
increased
incidence of many types of cancer, insomnia, depression, anxiety, and even
suicide.
Heavy alcohol consumption by a pregnant mother can also lead to fetal alcohol
syndrome, which is an incurable condition. Additionally, alcohol abuse and
alcohol
dependence are major contributing factors for head injuries, motor vehicle
accidents,
violence and assaults, and other neurological and other medical problems.
[0004] Addiction to nicotine is estimated by the National Institute on Drug
Abuse to
kill nearly 500,000 Americans every year. This total represents about 1 in 6
of all
deaths in the U.S. caused by any means, and is more than the total of deaths
caused by
use of alcohol, cocaine, heroin, suicide, car accidents, fire and AIDS
combined.
1
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Cigarette smoking is the most popular method of using nicotine, but there are
smokeless tobacco products; for example, snuff, chewing tobacco.
[0005] Nicotine addition is linked to disease states such as leukemia,
cataracts,
pneumonia, and is the cause of about one-third of all cancer deaths, the
foremost of
which is lung cancer. In addition to cancer, cigarette smoking also causes
lung
diseases, such as bronchitis and emphysema, exacerbates asthma symptoms, and
is the
cause of chronic obstructive pulmonary diseases in general. It is also well
known that
cigarette smoking increases the risk of cardiovascular diseases, including
stroke, heart
attack, vascular disease, aneurysm, and the like.
[0006] Another major health problem is caused by cocaine abuse. Physical
effects of
cocaine use include constricted blood vessels, dilated pupils, and increased
temperature, heart rate, and blood pressure. A user of cocaine can experience
acute
cardiovascular or cerebrovascular emergencies, such as a heart attack or
stroke,
potentially resulting in sudden death. Other complications associated with
cocaine use
include disturbances in heart rhythm, chest pain and respiratory failure,
seizures and
headaches, and gastrointestinal complications such as abdominal pain and
nausea.
Because cocaine has a tendency to decrease appetite, many chronic users can
become
malnourished. Repeated use of cocaine may lead to a state of increasing
irritability,
restlessness, and paranoia. This can result in a period of full-blown paranoid
psychosis,
in which the user loses touch with reality and experiences auditory
hallucinations.
[0007] Moreover, it is well known that the concurrent abuse of nicotine,
cocaine, and
alcohol is common. It has been found that the combination of cocaine and
alcohol
exerts more cardiovascular toxicity than either drug alone in humans.
[0008] Historically, treating chemical dependence largely involved attempts to
persuade patients to discontinue use of the substance voluntarily (behavioral
therapy).
However, cocaine, morphine, amphetamines, nicotine, and alcohol, and other
types of
dopamine-producing agents are highly addictive substances, and dependence upon
such
drugs can be harder to break and is significantly more damaging than
dependence on
most other addictive substances. In particular, alcohol, cocaine, and heroin
dependence
are typically seen to be chronic relapsing disorders.
[0009] There has been some moderate success in providing effective treatments
for
tobacco addiction by the use of nicotine replacement therapy, such as nicotine
gum or
2
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
the nicotine transdermal patch. Additionally, antidepressants and
antihypertensive
drugs have been tried, with modest success. Attempts have also been made to
treat
tobacco addiction by persuading patients to discontinue the use of tobacco
voluntarily
(behavioral therapy), but this method has not proved to be very successful.
Accordingly, it is clearly desirable to find a treatment for tobacco addiction
that reduces
or prevents the craving for nicotine that does not involve nicotine
replacement therapy
or the use of antidepressants and antihypertensive drugs.
[0010] Accordingly, there has been much interest in the scientific community
in
attempting to find substances that could be employed to ameliorate dependency
on
adictive agents. Two compounds that have previously been employed for the
treatment
of alcohol abuse are known as disulfiram (AntabuseTM) and cyanamide.
Additionally,
it has been recently proposed that disulfiram can be used for the treatment of
cocaine
dependency (for example, see Bonet et al., Journal of Substance Abuse
Treatment, 26
(2004), 225-232).
[0011] More recently it has been shown that a compound known as daidzein is
effective in suppressing ethanol intake. Daidzein is the major active
component
obtained from extracts of Radix puerariae, a traditional Chinese medication
that
suppresses ethanol intake in Syrian golden hamsters. See Keung, W. M. and
Vallee, B.
L. (1993) Proc. Natl. Acad. Sci. USA 90, 10008-10012 and Keung, W. M.,
Klyosov, A.
A., and Vallee, B. L. (1997) Proc. Natl. Acad. Sci. USA 94, 1675-1679, and
U.S.
Patents 5,624,910 and 6,121,010.
[0012] It has been shown that daidzin is an isoflavone of the formula:
HO ::xc oH OH
Removal of the sugar provides a compound known as daidzein, which has also
been
shown to be effective in suppressing ethanol uptake.
3
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
OH
O
HO
[0013] U.S. Patents 5,624,910 and 6,121,010 disclosed ether derivatives of
daidzin,
which were shown to be effective in treating ethanol dependency. Daidzin and
its
analogs were shown to be potent and selective inhibitors of human
mitochondrial
aldehyde dehydrogenase (ALDH-2), which is an enzyme involved in the major
enzymatic pathway responsible for ethanol metabolism in humans. It was also
found
that daidzin analogues that inhibit ALDH-2 but also inhibit the monamine
oxidase
(MOA) pathway were the least effective antidipsotropic activity.
[0014] It has now surprisingly been found that ALDH-2 inhibitors are also
useful for
the treatment of other addictive agents such as cocaine, heroin, and nicotine,
and in
particular, ameliorate the tendency of abusers to relapse.
4
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
SUMMARY OF THE INVENTION
[0015] Accordingly, in a first aspect, the invention relates to compounds of
Formula I:
R2
O
R3
)ZO)
Formula I
wherein:
R1 is optionally substituted phenyl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl;
R2 is hydrogen, hydroxy, halogen, optionally substituted lower alkoxy,
optionally substituted lower alkyl, cyano, optionally substituted
heteroaryl, C(O)ORS, -C(O)R5, -S02R15, -B(OH)2, -OP(O)(OR5)2, -
C(NR20)NHR22, -NHR4, or C(O)NHR5, in which,
R4 is hydrogen, -C(O)NHR5, or -S02R15, or -C(O)R5;
R5 is hydrogen, optionally substituted lower alkyl;
R15 is optionally substituted lower alkyl or optionally substituted phenyl; or
R2 is -O-Q-R6, in which Q is a covalent bond or lower alkylene and R6 is
optionally substituted heteroaryl;
R3 is hydrogen, cyano, optionally substituted amino, lower alkyl, lower
alkoxy,
or halo;
X, Y and Z are chosen from -CR7- and -N-, in which R7 is hydrogen, lower
alkyl, lower alkoxy, or halo;
V is oxygen, sulfur, or -NH-; and
W is -Q'-T-Q2-, wherein
Q1 is a covalent bond or Ci_6 linear or branched alkylene optionally
substituted with hydroxy, lower alkoxy, amino, cyano, or =0;
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Q2 is C1_6 linear or branched alkylene optionally substituted with
hydroxy, lower alkoxy, amino, cyano, or =O; and
T is a covalent bond, -0-, or -NH-, or
T and Q1 may together form a covalent bond,
R20 and R22 are independently selected from the group consisting of hydrogen,
hydroxy, CI-15 alkyl, C2_15 alkenyl, C2_15 alkynyl, heterocyclyl, aryl,
benzyl, and heteroaryl,
wherein the alkyl, alkenyl, alkynyl, heterocyclyl, aryl, benzyl, and
heteroaryl
moieties are optionally substituted with from 1 to 3 substituents
independently selected from halo, alkyl, mono- or dialkylamino, alkyl or
aryl or heteroaryl amide, CN, O-CI_6 alkyl, CF3, OCF31 B(OH)2,
Si(CH3)3, heterocyclyl, aryl, and heteroaryl
wherein the heterocyclyl, aryl, and heteroaryl substituent are optionally
substituted with from 1 to 3 substituents independently selected from
halo, CF3, C1_4 lower alkyl, and C1.3 alkoxy.
[0016] In a second aspect of the invention, pharmaceutical formulations are
provided
comprising a therapeutically effective amount of an ALDH-2 inhibitor of
Formula I,
and at least one pharmaceutically acceptable carrier.
[0017] In a third aspect of the invention, methods of using the compounds of
Formula I
in the treatment of addiction. The method comprises administering to a mammal
in
need thereof a therapeutically effective dose of a compound of Formula I. The
addiction may be to an agent such as, but are not limited to, cocaine,
opiates,
amphetamines, nicotine, and alcohol.
[0018] In one preferred embodiment, the invention relates to a group of
compounds of
Formula I in which X, Y and Z are all -CR6-, in which R6 is hydrogen. Within
this
group, preferred compounds include a class in which R1 is optionally
substituted
phenyl, R2 is 4-hydroxyl, R3 is hydrogen, V is oxygen, and W is methylene.
[0019] One preferred subclass within this class includes those compounds in
which R1
is phenyl substituted with from 1 to 3 substituents, which are independently
selected
from the group consisting of carboxyl, carboxylic ester, carboxamido, cyano,
tetrazolyl,
halo, or lower alkyl substituted by halo, particularly monosubstituted
compounds in
6
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
which the substitution is at the 3-position and disubstituted compounds in
which the
substitutions are at the 3,5-positions.
[0020] Within this subclass are also compounds wherein the R1 phenyl group is
monosubstitued at the 3-position with -CO2R20 wherein R20 is C1_3 alkyl
optionally
substituted with from 1 to 3 substituents independently selected from halo,
mono- or
dialkylamino, and aryl, heteroaryl, cycloalkyl or heterocyclyl optionally
substituted
with from 1 to 3 substituents independently selected from halo, CF3, Ci4 lower
alkyl,
and C1_3 alkoxy. Within this subclass, compounds wherein R20 is a
monosubstitued,
five or six-membered monocyclic heterocyclic moiety are preferred.
[0021] Another preferred class included compounds in which R1 is optionally
substituted phenyl, R2 is 4-NHR4, R3 is hydrogen, V is oxygen, and W is
methylene.
One preferred subclass includes those compounds in which R1 is phenyl
substituted
with from 1 to 3 substituents which are independently selected from the group
consisting of carboxyl, carboxamido, cyano, tetrazolyl, halo, or lower alkyl
substituted
by halo, particularly monosubstituted compounds in which the substitution is
at the 3-
position and disubstituted compounds in which the substitutions are at the 3,5-
positions. More preferred are those compounds where R4 is -S02R5, more
preferably
where R5 is methyl.
[0022] In another preferred group, R1 is optionally substituted heteroaryl,
particularly
where R1 is a five or six membered heteroaryl ring that includes oxygen and
nitrogen
atoms, V is oxygen, W is methylene, preferably where R2 is 4-hydroxy and R3 is
hydrogen. Within this group, one preferred subgroup includes those compounds
in
which R1 is 1,3-oxazolyl, 1,3-thiazolyl, or (1,2,4-oxadiazol-3-yl), which are
optionally
substituted by phenyl substituted by carboxyl, carboxamido, cyano, tetrazolyl,
halo, or
lower alkyl substituted by halo, for example trifluoromethyl, particularly
monosubstituted compounds in which the substitution is at the 3-position and
disubstituted compounds in which the substitutions are at the 3,5-positions.
[0023] At present, the compounds for use in the invention include, but are not
limited
to:
3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid;
3 - { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzenecarbonitrile;
3-(4-hydroxyphenyl)-7-[(3-(5H-1,2,3,4-tetrazol-5-yl)phenyl)methoxy]chromen-
4-one;
7
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -1[3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzamide;
3-[(3- {4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzene-carbonitrile;
3-[(3- {4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzamide;
3 -(4-hydroxyphenyl)-7- 1[3 -(trifluoromethyl)phenyl]methoxy} chromen-4-one;
3 -(4-hydroxyphenyl)-7- 1[4-methoxy-3 -
(trifluoromethyl)phenyl]methoxy} chromen-4-one;
7-1[3 -fluoro-5-(trifluoromethyl)phenyl]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- 1[5 -(2-methoxyphenyl)(1,2,4-oxadiazol-3-
yl)]methoxy} chromen-4-one;
3 -(4-hydroxyphenyl)-7-[(5-phenyl(1,2,4-oxadiazol-3-yl))methoxy]chromen-4-
one;
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)} methoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)} methoxy)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4-hydroxyphenyl)chromen-4-one;
7-({5-[4-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
(4-hydroxyphenyl)chromen-4-one;
7-({5-[2,5-bis(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
prop-2-enyl 3-(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-
oxadiazol-5-yl)benzoate;
prop-2-enyl 3- {[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
methyl 4- {[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
methyl 3- {[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
ethyl 4- { [3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
methylethyl 3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
4-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid;
4- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzamide;
3 -(4-hydroxyphenyl)-7- { [5-(3 -methoxyphenyl)(1,2,4-oxadiazol-3-
yl)]methoxy}chromen-4-one; 3-(3-{[3-(4-hydroxyphenyl)-4-
oxochromen-7-yloxy]methyl}-1,2,4-oxadiazol-5-yl)benzoic acid.
7-({5-[3,5-bis(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
3 -(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-oxadiazol-5-
yl)benzenecarbonitrile;
8
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -(4-hydroxyphenyl)-7-[(3 -phenyl(1,2,4-oxadiazol-5-yl))methoxy]chromen-4-
one;
3-(4-hydroxyphenyl)-7-({3-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} methoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-({3-[4-chlorophenyl](1,2,4-oxadiazol-5-
yl)} methoxy)chromen-4-one;
3 -(4-hydroxyphenyl)-2-(trifluoromethyl)-7-({5-[3 -
(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)} methoxy)chromen-4-
one;
7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
(4-hydroxyphenyl)-2-(trifluoromethyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-({5-[4-methoxy-3-(trifluoromethyl)phenyl](1,2,4-
oxadiazol-3-yl)} methoxy)-2-(trifluoromethyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- 1[5-(3 -(1H-1,2,3,4-tetraazol-5-yl)phenyl)(1,2,4-
oxadiazol-3-yl)]methoxy}chromen-4-one;
3 -(3-1[3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-oxadiazol-5-
yl)benzoic acid;
3-[(3- {4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzoic acid;
3 - {4-[(methylsulfonyl)amino]phenyl} -7-({5-[3-(trifluoromethyl)phenyl](1,2,4-
oxadiazol-3-yl)}methoxy)chromen-4-one;
7- { [5-(3 -fluorophenyl)(1,2,4-oxadiazol-3 -yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 - {4-[(methylsulfonyl)amino]phenyl} -7-({2-[4-(trifluoromethyl)phenyl](1,3 -
thiazol-5-yl)} methoxy)chromen-4-one.
4-[7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]benzenecarbonitrile;
ethyl 4-[7-({4-methyl-2-[4-(trifluoromethyl)phenyl] (1,3-thiazol-5-
yl)} methoxy)-4-oxochromen-3-yl]benzoate;
7-({3 -[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-yl)} ethoxy)-3-
(4-
hydroxyphenyl)chromen-4-one;
ethyl 3 -[7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3-yl]benzoate;
3 - {4-[(methylsulfonyl)amino]phenyl} -7-({4-methyl-2-[4-
(trifluoromethyl)phenyl] (1,3-thiazol-5-yl)} methoxy)chromen-4-one;
methyl 4-[7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-
yl)} methoxy)-4-oxochromen-3-yl]benzoate;
3-(2H,3H-benzo[e] 1,4-dioxan-6-yl)-7-({5-[3-fluoro-5-
(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)} methoxy)chromen-4-
one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(6-methoxy(3-pyridyl))chromen-4-one;
9
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3-(4-hydroxyphenyl)-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3 -thiazol-5-
yl)} methoxy)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4- { [(4-methylphenyl)sulfonyl]amino}phenyl)chromen-4-one;
3-(4- { [(4-methylphenyl)sulfonyl]amino}phenyl)-7-({4-methyl-2-[4-
(trifluoromethyl)phenyl] (1,3-thiazol-5-yl)} methoxy)chromen-4-one;
methyl 3- {[3-(6-methoxy(3-pyridyl))-4-oxochromen-7-yloxy]methyl}benzoate;
methyl 3-({3-[4-(hydroxymethyl)phenyl]-4-oxochromen-7-
yloxy} methyl)benzoate;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
[4-(hydroxymethyl)phenyl]chromen-4-one;
4-[7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]benzoic acid;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4-morpholin-4-ylphenyl)chromen-4-one;
7-({5-methyl-2-[4-(trifluoromethyl)phenyl] (1,3-thiazol-4-yl)} methoxy)-3-(4-
morpholin-4-ylphenyl)chromen-4-one;
7-({3 -[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-yl)} methoxy)-3
-
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
2-fluoro-5-[7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3 -yl]benzenecarbonitrile;
ethyl 2-(3 - {4-[(ethoxycarbonyl)methoxy]phenyl} -4-oxochromen-7-
yloxy)acetate;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3 -yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]benzenecarbonitrile;
3 -(3-acetylphenyl)-7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-
oxadiazol-
3 -yl)} methoxy)chromen-4-one;
7-({5 -[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
4-[7-({5- [5 -fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3 -yl]benzamide;
3 -[2,4-bis(tert-butoxy)pyrimidin-5-yl]-7-({5- [5 -fluoro-3 -
(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)} methoxy)chromen-4-
one;
5-[7-({5- [5 -fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]-1,3-dihydropyrimidine-2,4-dione;
7-({2- [5-fluoro-3-(trifluoromethyl)phenyl]-(1,3-oxazol-4-yl)} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3-(4-hydroxyphenyl)-7-({2-[3-(trifluoromethyl)phenyl](1,3-oxazol-4-
yl)} methoxy)chromen-4-one;
7-({2- [5 -fluoro-3 -(trifluoromethyl)phenyl] (1,3-oxazol-4-yl)} methoxy)-3 -
(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- 1[2-(3,4,5-trifluorophenyl)(1,3-oxazol-4-
yl)]methoxy} chromen-4-one;
7- { [2-(3,5-difluorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [2-(3,4-difluorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [2-(4-fluorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [2-(4-chlorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
methyl 3- {[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
3-(4-hydroxyphenyl)-7-({3-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} methoxy)chromen-4-one;
3 -(4-hydroxyphenyl)-2-(trifluoromethyl)-7-({5-[3-(trifluoromethyl)phenyl]-
(1,2,4-oxadiazol-3-yl)}methoxy)chromen-4-one;
3 - { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzenecarbonitrile;
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl]isoxazol-3-
yl} methoxy)chromen-4-one;
7- { [5-(trifluoromethyl)(3 -pyridyl)]methoxy} -3-(4- { [6-(trifluoromethyl)(3
-
pyridyl)]methoxy}phenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,2,4-oxadiazol-3-
yl))methoxy]chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl)(1,2,4-oxadiazol-3-
yl))methoxy]chromen-4-one;
methyl 2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-
5-carboxylate;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy} -3 - {4-
[(methylsulfonyl)amino]-phenyl} chromen-4-one;
2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-5-
carboxylic acid;
methyl 3-({3-[4-((1Z)- 1-amino-2-methoxy-2-azavinyl)phenyl]-4-oxochromen-
7-yloxy} methyl)benzoate;
7- {2-[4-(4-chlorophenyl)pyrazolyl] ethoxy} -3 -(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl(3-pyridyl))methoxy]chromen-4-one;
7-[(2R)-2-hydroxy-3 -({ [3 -(trifluoromethyl)phenyl]methyl} amino)propoxy]-3-
(4-hydroxyphenyl)chromen-4-one;
11
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -(4-hydroxyphenyl)-7-[({ [3 -
(trifluoromethyl)phenyl]methyl} amino)methoxy]chromen-4-one;
7-((2R)-3-1[(3,5 -difluorophenyl)methyl] amino} -2-hydroxypropoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
7-(3- { [(1R)-1-(4-fluorophenyl)ethyl] amino} -2-oxopropoxy)-3-(4-
hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-(3-phenylpropoxy)chromen-4-one;
7- { [5-(3 -fluorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- { [3-(trifluoromethyl)phenyl] ethoxy} chromen-4-one;
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl](1,3,4-oxadiazol-2-
yl)} methoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(2-phenyl(1,3-oxazol-5-yl))methoxy]chromen-4-one;
7-({5-[3,5-bis(trifluoromethyl)phenyl]isoxazol-3-yl} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl]isoxazol-3-
yl} methoxy)chromen-4-one;
3- {4-[(methylsulfonyl)amino]phenyl} -7-[(2-phenyl(1,3 -oxazol-4-
yl))methoxy]chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[3-(trifluoromethyl)phenyl]-
acetamide;
7- { [5-(2-chlorophenyl)(1,3,4-thiadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
4-[7-({4-methyl-2-[4-(trifluoromethyl)phenyl] (1,3 -thiazol-5-yl)} methoxy)-4-
oxochromen-3 -yl]benzenecarbonitrile;
3 -14- [(methylsulfonyl)amino]phenyl} -7-({4-methyl-2-[4-
(trifluoromethyl)phenyl] (1,3-thiazol-5-yl)} methoxy)chromen-4-one;
3-(6-methoxy(3-pyridyl))-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-
thiazol-5-yl)} methoxy)chromen-4-one;
4-[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,3,4-oxadiazol-2-yl)}
methoxy)-
4-oxochromen-3-yl]benzenecarbonitrile;
4-[4-oxo-7-({3 -[3 -(trifluoromethyl)phenyl]isoxazol-5-yl}methoxy)chromen-3-
yl]benzenecarbonitrile;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl) methoxy)-3
-
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl) methoxy)-3
-
[4-(methylsulfonyl)phenyl]chromen-4-one;
4-[7-({5-[3 -fluoro-5 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3 -yl]benzamide;
3 -(3-acetylphenyl)-7-({5-[3-fluoro-5-(trifluoromethyl)phenyl] (1,2,4-
oxadiazol-
3 -yl)} methoxy)chromen-4-one;
12
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,3,4-oxadiazol-2-yl)} methoxy)-3
-
(4-hydroxyphenyl)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl) methoxy)-3
-
(5-hydropyrazol-4-yl)chromen-4-one;
ethyl 3 -[7-({3 -[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-
yl)} ethoxy)-4-oxochromen-3 -yl]benzoate;
3-(4-hydroxyphenyl)-7-({2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-
yl)} methoxy)chromen-4-one;
7-[2-(3-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} ethoxy)-3-
(4-
hydroxyphenyl)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4- { [(4-methylphenyl)sulfonyl]amino}phenyl)chromen-4-one;
7- { [5-(2-chlorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
7- { [5-(4-fluorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-(4-pyridylmethoxy)chromen-4-one;
3 -14- [(methylsulfonyl)amino]phenyl} -7-({2-[4-(trifluoromethyl)phenyl](1,3 -
thiazol-5-yl)} methoxy)chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[2-(trifluoromethyl)phenyl]-
acetamide;
3 -(4-hydroxyphenyl)-7- 12-oxo-2-[2-(trifluoromethyl)phenyl] ethoxy} chromen-
4-one;
3-(1H-indazol-5-yl)-7-({5- [5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-
oxadiazol-3-yl)}methoxy)chromen-4-one;
3 -(4-hydroxyphenyl)-7-(2-phenylethoxy)chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]ethanenitrile;
7-[2-(4-chlorophenoxy)ethoxy] -3 -(4-hydroxyphenyl)chromen-4-one;
5- {4-[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3-yl]phenyl} -1,3,5,6-
tetrahydropyrimidine-2,4-dione;
N- [(1 R)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
3 -(4-hydroxyphenyl)-7-(2-pyridylmethoxy)chromen-4-one;
2-fluoro-5-[7-({5 -[5 -fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3 -yl]benzenecarbonitrile;
7-(2-pyridylmethoxy)-3-[4-(2-pyridylmethoxy)phenyl]chromen-4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(4-pyridyl)(1,2,4-oxadiazol-3 -yl))ethoxy]chromen-
4-one;
13
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -(4-hydroxyphenyl)-7- [(5 -(3 -pyridyl)(1,2,4-oxadiazol-3 -
yl))ethoxy]chromen-
4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(2-pyridyl)(1,2,4-oxadiazol-3 -yl))ethoxy]chromen-
4-one;
3 -(4-hydroxyphenyl)-7- 1[5-(trifluoromethyl)(3 -pyridyl)]methoxy} chromen-4-
one;
7- { [5-(4-chlorophenyl)isoxazol-3 -yl]methoxy} -3-(4-hydroxyphenyl)chromen-
4-one;
7- { [5-(3,4-dichlorophenyl)isoxazol-3-yl]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [5-(4-chlorophenyl)isoxazol-3 -yl]methoxy} -3-(4-hydroxyphenyl)chromen-
4-one;
7-[(2R)-2-hydroxy-3 -(1[3-(trifluoromethyl)phenyl]methyl} amino)propoxy]-3-
(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-[2-({ [3 -
(trifluoromethyl)phenyl]methyl} amino)ethoxy]chromen-4-one;
7-((2R)-3-1[(3,5 -difluorophenyl)methyl] amino} -2-hydroxypropoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
methyl 2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-
4-carboxylate;
2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-4-
carboxylic acid;
N-[(1 S)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3 -yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy} -3 - {4-
[(methylsulfonyl)amino]-phenyl} chromen-4-one;
7- {3-[4-(4-chlorophenyl)pyrazolyl]propoxy} -3-(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(3-phenylpropoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl(3-pyridyl))methoxy]chromen-4-one;
7-((2R)-2-hydroxy-3-phenylpropoxy)-3-(4-hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4-oxadiazol-2-
yl))methoxy]chromen-4-one;
3 -[(2-hydroxy-3- {4-[(methylsulfonyl)amino]phenyl} -4-oxochromen-7-
yloxy)methyl]benzoic acid;
7- { [5-(4-fluorophenyl)(1,3,4-oxadiazol-2-yl)]ethoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4-oxadiazol-2-yl))ethoxy]chromen-
4-one;
14
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -(4-hydroxyphenyl)-7- [(3 -(3 -pyridyl)(1,2,4-oxadiazol-5 -
yl))methoxy]chromen-4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(3 -pyridyl)(1,3,4-oxadiazol-2-yl))ethoxy]chromen-
4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(4-pyridyl)(1,2,4-oxadiazol-3 -yl))ethoxy]chromen-
4-one;
(2-1[3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} (1,3 -oxazol-4-yl))-N-
methylcarboxamide;
4-1[3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -7-methoxychromen-
2-one;
7- { [5-(4-fluorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 - {4-
[(methylsulfonyl)amino]-phenyl} chromen-4-one;
7-1[5-(3 -aminophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
ethyl 1- {2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]ethyl }pyrazole-4-
carboxylate;
7- {2-[4-(3 -chlorophenyl)piperazinyl] ethoxy} -3 -(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(2- {4-[3-
(trifluoromethyl)phenyl]piperazinyl} ethoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl)isoxazol-3-yl)methoxy]chromen-4-one;
7-({3 -[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-yl)} ethoxy)-3-
(4-
hydroxyphenyl)chromen-4-one;
7-[2-(4-fluorophenyl)ethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
7-((1R)-1- {3-[3-fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-one;
7-((1 S)-1- {3 -[3 -fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- {2-[3 -(trifluoromethyl)pyrazolyl] ethoxy} chromen-4-
one;
7-(1- {3-[3 -fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)} -
isopropoxy)-3-(4-hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(3-(1H-1,2,3,4-tetraazol-5-
yl)phenyl)methoxy]chromen-4-one;
prop-2-enyl 3- {[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate
3 -(4-aminophenyl)-7-({5-[3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-
yl)} methoxy)chromen-4-one;
methyl 3- {[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
(4-aminophenyl)chromen-4-one;)
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -1[3 -(4-aminophenyl)-4-oxochromen-7-yloxy]methyl} benzenecarbonitrile;
3 -1[3 -(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzamide;
prop-2-enyl 3-[(3- {4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzoate
methyl 3 -[(3- {4-[(methylsulfonyl)amino]phenyl} -4-oxochromen-7-
yloxy)methyl]benzoate;
7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
3-[(3- {4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]-
benzenecarbonitrile;
3 - { [3 -(4-methylsulfonylaminophenyl)-4-oxochromen-7-
yloxy]methyl}benzamide;
3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid;
3 -(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-oxadiazol-5-
yl)benzoic acid;
methyl 3-({3-[4-(acetylamino)phenyl]-4-oxochromen-7-
yloxy} methyl)benzoate;
3 -(4-hydroxyphenyl)-7- {2-[4-(4-methoxyphenyl)piperazinyl]ethoxy} chromen-
4-one;
7- {2-[4-(4-fluorophenyl)piperazinyl]ethoxy}-3-(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(2-piperazinylethoxy)chromen-4-one;
N-(3 -fluorophenyl)(4- {2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy] ethyl} -
piperazinyl)carboxamide;
7-[2-(4- { [(3-fluorophenyl)amino]thioxomethyl}piperazinyl)ethoxy]-3-(4-
hydroxyphenyl)chromen-4-one;
N-(2,4-difluorophenyl)(4- {2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]ethyl} piperazinyl)carboxamide;
7-(2- {2-[3 -fluoro-5-(trifluoromethyl)phenyl](1,3 -oxazol-5-yl)} ethoxy)-3-(4-
hydroxyphenyl)chromen-4-one;
7-(3- {2-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}propoxy)-3-(4-
hydroxyphenyl)chromen-4-one;
7-[2-(4-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
7-[2-(3-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- {2-oxo-2-[2-(trifluoromethyl)phenyl] ethoxy} chromen-
4-one;
3 -(4-hydroxyphenyl)-7- {2-oxo-2-[2-(trifluoromethyl)phenyl] ethoxy} chromen-
4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[3-(trifluoromethyl)phenyl]-
acetamide;
16
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
N-[(1 S)- 1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[2-(trifluoromethyl)-
phenyl]acetamide;
N-(3-fluorophenyl)-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]acetamide;
N-[(1R)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
3 -(4-hydroxyphenyl)-7-[2-hydroxy-3-({ [3 -
(trifluoromethyl)phenyl]methyl} amino)-propoxy]chromen-4-one;
7-(3-j[(3,5 -difluorophenyl)methyl] amino} -2-hydroxypropoxy)-3-(4-
hydroxyphenyl)chromen-4-one;
7-(2- { [(4-fluorophenyl)ethyl] amino} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(2-hydroxy-3-phenylpropoxy)chromen-4-one;
7-((1R)-1- {3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-one
2-morpholinoethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-
yloxy)methyl)benzoate;
ethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-
yloxy)methyl)benzoate;
2-(dimethylamino)ethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-
chromen-7-yloxy)methyl)benzoate; and
2-(4-methylpiperazin-1-yl)ethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-
4H-chromen-7-yloxy)methyl)benzoate.
SUMMARY OF THE FIGURES
[0024] FIG 1 depicts how increasing doses of 3-[(3-{4-
[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid
administered as described in the protocol described in Example 32 reduced the
number
of bar presses (plotted as the number of infusions).
DETAILED DISCRIPTION OF THE INVENTION
Definitions and General Parameters
[0025] As used in the present specification, the following words and phrases
are
generally intended to have the meanings as set forth below, except to the
extent that the
context in which they are used indicates otherwise.
17
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0026] The term "alkyl" refers to a monoradical branched or unbranched
saturated
hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19
or 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl,
n-
propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl,
and the like.
[0027] The term "substituted alkyl" refers to:
1) an alkyl group as defined above, having 1, 2, 3, 4 or 5 substituents,
preferably 1
to 3 substituents, selected from the group consisting of alkenyl, alkynyl,
alkoxy,
cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,
carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -S02-alkyl, S02-aryl and -SO2-
heteroaryl. Unless otherwise constrained by the definition, all substituents
may
optionally be further substituted by 1, 2, or 3 substituents chosen from
alkyl,
carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino,
substituted amino, cyano, and -S(O)õR, where R is alkyl, aryl, or heteroaryl
and
n is 0, 1 or 2; or
2) an alkyl group as defined above that is interrupted by 1-10 atoms
independently
chosen from oxygen, sulfur and NRa , where Ra is chosen from hydrogen, alkyl,
cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl.
All substituents may be optionally further substituted by alkyl, alkoxy,
halogen,
CF3, amino, substituted amino, cyano, or -S(O)õR, in which R is alkyl, aryl,
or
heteroaryl and n is 0, 1 or 2; or
3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5 substituents
as
defined above and is also interrupted by 1-10 atoms as defined above.
[0028] The term "lower alkyl" refers to a monoradical branched or unbranched
saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms. This term
is
exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, t-
butyl, n-hexyl, and the like.
[0029] The term "substituted lower alkyl" refers to lower alkyl as defined
above having
1 to 5 substituents, preferably 1, 2, or 3 substituents, as defined for
substituted alkyl, or
18
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4, or 5
atoms as
defined for substituted alkyl, or a lower alkyl group as defined above that
has both 1, 2,
3, 4 or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4,
or 5 atoms as
defined above.
[0030] The term "alkylene" refers to a diradical of a branched or unbranched
saturated
hydrocarbon chain, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19
or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4,
5 or 6
carbon atoms. This term is exemplified by groups such as methylene (-CH2-),
ethylene
(-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and-CH(CH3)CH2-) and the
like.
[0031] The term "lower alkylene" refers to a diradical of a branched or
unbranched
saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon
atoms.
[0032] The term "lower alkylene" refers to a diradical of a branched or
unbranched
saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5, or 6 carbon
atoms.
[0033] The term"substituted alkylene" refers to:
(1) an alkylene group as defined above having 1, 2, 3, 4, or 5 substituents
selected
from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,
cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,
alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,
carboxyl, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -S02-alkyl, S02-aryl and -SO2-
heteroaryl. Unless otherwise constrained by the definition, all substituents
may
optionally be further substituted by 1, 2, or 3 substituents chosen from
alkyl,
carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino,
substituted amino, cyano, and -S(O)õR, where R is alkyl, aryl, or heteroaryl
and
n is 0, 1 or 2; or
(2) an alkylene group as defined above that is interrupted by 1-20atoms
independently chosen from oxygen, sulfur and NRa , where Ra is chosen from
hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl,
heteroaryl
19
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
and heterocycyl, or groups selected from carbonyl, carboxyester, carboxyamide
and sulfonyl; or
(3) an alkylene group as defined above that has both 1, 2, 3, 4 or 5
substituents as
defined above and is also interrupted by 1-20 atoms as defined above.
Examples of substituted alkylenes are chloromethylene (-CH(Cl)-),
aminoethylene (-CH(NH2)CH2-), methylaminoethylene (-CH(NHMe)CH2-), 2-
carboxypropylene isomers(-CH2CH(CO2H)CH2-), ethoxyethyl (-CH2CH2O-
CH2CH2-), ethylmethylaminoethyl (-CH2CH2N(CH3)CH2CH2-),1-ethoxy-2-(2-
ethoxy-ethoxy)ethane (-CH2CH2O-CH2CH2-OCH2CH2-OCH2CH2-), and the
like.
[0034] The term "aralkyl" refers to an aryl group covalently linked to an
alkylene
group, where aryl and alkylene are defined herein. "Optionally substituted
aralkyl"
refers to an optionally substituted aryl group covalently linked to an
optionally
substituted alkylene group. Such aralkyl groups are exemplified by benzyl,
phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
[0035] The term "alkoxy" refers to the group R-O-, where R is optionally
substituted
alkyl or optionally substituted cycloalkyl, or R is a group -Y-Z, in which Y
is
optionally substituted alkylene and Z is optionally substituted alkenyl,
optionally
substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl,
alkenyl,
alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Preferred alkoxy
groups are
optionally substituted alkyl-O- and include, by way of example, methoxy,
ethoxy, n-
propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,
1,2-
dimethylbutoxy, trifluoromethoxy, and the like. The term "lower alkoxy" refers
to the
group R-O-, where R is optionally substituted lower alkyl as defined above.
[0036] The term "alkylthio" refers to the group R-S-, where R is as defined
for alkoxy.
[0037] The term "alkenyl" refers to a monoradical of a branched or unbranched
unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms,
more
preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms
and
having 1-6, preferably 1, double bond (vinyl). Preferred alkenyl groups
include ethenyl
or vinyl (-CH=CH2), 1-propylene or allyl (-CH2CH=CH2), isopropylene (-
C(CH3)=CH2), bicyclo[2.2.1]heptene, and the like. In the event that alkenyl is
attached
to nitrogen, the double bond cannot be alpha to the nitrogen.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0038] The term "lower alkenyl" refers to alkenyl as defined above having from
2 to 6
carbon atoms.
[0039] The term "substituted alkenyl" refers to an alkenyl group as defined
above
having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents,
selected from
the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,
cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio,
heteroarylthio,
heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO2-alkyl, S02-aryl
and -
S02-heteroaryl. Unless otherwise constrained by the definition, all
substituents may
optionally be further substituted by 1, 2, or 3 substituents chosen from
alkyl, carboxyl,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted
amino, cyano, and -S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1
or 2.
[0040] The term "alkynyl" refers to a monoradical of an unsaturated
hydrocarbon,
preferably having from 2 to 20 carbon atoms, more preferably 2 to 10 carbon
atoms and
even more preferably 2 to 6 carbon atoms and having at least 1 and preferably
from 1-6
sites of acetylene (triple bond) unsaturation. Preferred alkynyl groups
include ethynyl,
(-C=CH), propargyl (or prop- l-yn-3-yl, -CH2C=CH), and the like. In the event
that
alkynyl is attached to nitrogen, the triple bond cannot be alpha to the
nitrogen.
[0041] The term "substituted alkynyl" refers to an alkynyl group as defined
above
having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents,
selected from
the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,
cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio,
heteroarylthio,
heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -SO2-alkyl, S02-aryl
and -
S02-heteroaryl. Unless otherwise constrained by the definition, all
substituents may
optionally be further substituted by 1, 2, or 3 substituents chosen from
alkyl, carboxyl,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted
amino, cyano, and -S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1
or 2.
21
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0042] The term "aminocarbonyl" refers to the group -C(O)NRR where each R is
independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R
groups
are joined to form a heterocyclic group (e.g., morpholino). Unless otherwise
constrained by the definition, all substituents may optionally be further
substituted by
1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl,
hydroxy,
alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)õR, where R is
alkyl,
aryl, or heteroaryl and n is 0, 1 or 2.
[0043] The term "acylamino" refers to the group -NRC(O)R where each R is
independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless
otherwise
constrained by the definition, all substituents may optionally be further
substituted by
1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl, aminocarbonyl,
hydroxy,
alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(O)õR, where R is
alkyl,
aryl, or heteroaryl and n is 0, 1 or 2.
[0044] The term "acyloxy" refers to the groups -O(O)C-alkyl, -O(O)C-
cycloalkyl, -
O(O)C-aryl, -O(O)C-heteroaryl, and -O(O)C-heterocyclyl. Unless otherwise
constrained by the definition, all substituents may be optionally further
substituted by
alkyl, carboxyl, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3,
amino,
substituted amino, cyano, or -S(O)õR, where R is alkyl, aryl, or heteroaryl
and n is 0, 1
or 2.
[0045] The term "aryl" refers to an aromatic carbocyclic group of 6 to 20
carbon atoms
having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl), or
multiple
condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include
phenyl,
naphthyl and the like.
[0046] The term "arylene" refers to a diradical of an aryl group as defined
above. This
term is exemplified by groups such as 1,4-phenylene, 1,3-phenylene, 1,2-
phenylene,
1,4'-biphenylene, and the like.
[0047] Unless otherwise constrained by the definition for the aryl or arylene
substituent, such aryl or arylene groups can optionally be substituted with
from 1 to 5
substituents, preferably 1 to 3 substituents, selected from the group
consisting of alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,
amino,
aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,
thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio,
heterocyclylthio, thiol,
22
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
-SO-
alkyl, -SO-aryl,-SO-heteroaryl, -S02-alkyl, S02-aryl and -S02-heteroaryl.
Unless
otherwise constrained by the definition, all substituents may optionally be
further
substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl,
aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano,
and -
S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0048] The term "aryloxy" refers to the group aryl-O- wherein the aryl group
is as
defined above, and includes optionally substituted aryl groups as also defined
above.
The term "arylthio" refers to the group R-S-, where R is as defined for aryl.
[0049] The term "amino" refers to the group -NH2.
[0050] The term "substituted amino" refers to the group -NRR where each R is
independently selected from the group consisting of hydrogen, alkyl,
cycloalkyl,
carboxyalkyl (for example, benzyloxycarbonyl), aryl, heteroaryl and
heterocyclyl
provided that both R groups are not hydrogen, or a group -Y-Z, in which Y is
optionally substituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl,
Unless
otherwise constrained by the definition, all substituents may optionally be
further
substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl,
aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano,
and -
S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0051] The term "carboxyalkyl" refers to the groups -C(O)O-alkyl or -C(O)O-
cycloalkyl, where alkyl and cycloalkyl, are as defined herein, and may be
optionally
further substituted by alkyl, alkenyl, alkynyl, alkoxy, halogen, CF3, amino,
substituted
amino, cyano, or -S(O)õR, in which R is alkyl, aryl, or heteroaryl and n is 0,
1 or 2.
[0052] The term "cycloalkyl" refers to carbocyclic groups of from 3 to 20
carbon atoms
having a single cyclic ring or multiple condensed rings. Such cycloalkyl
groups
include, by way of example, single ring structures such as cyclopropyl,
cyclobutyl,
cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as
adamantanyl,
bicyclo[2.2.1]heptane, 1,3,3-trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3-
trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an
aryl
group, for example indane, and the like.
23
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0053] The term "substituted cycloalkyl" refers to cycloalkyl groups having 1,
2, 3, 4 or
substituents, and preferably 1, 2, or 3 substituents, selected from the group
consisting
of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy,
amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,
keto,
thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio,
heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
-SO-
alkyl, -SO-aryl,-SO-heteroaryl, -S02-alkyl, S02-aryl and -S02-heteroaryl.
Unless
otherwise constrained by the definition, all substituents may optionally be
further
substituted by 1, 2, or 3 substituents chosen from alkyl, carboxyl,
carboxyalkyl,
aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano,
and -
S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0054] The term "halogen" or "halo" refers to fluoro, bromo, chloro, and iodo.
[0055] The term "acyl" denotes a group -C(O)R, in which R is hydrogen,
optionally
substituted alkyl, optionally substituted cycloalkyl, optionally substituted
heterocyclyl,
optionally substituted aryl, and optionally substituted heteroaryl.
[0056] The term "heteroaryl" refers to a radical derived from an aromatic
cyclic group
(i.e., fully unsaturated) having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, or 15 carbon
atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur
within at
least one ring. Such heteroaryl groups can have a single ring (e.g., pyridyl
or furyl) or
multiple condensed rings (e.g., indolizinyl, benzothiazolyl, or benzothienyl).
Examples
of heteroaryls include, but are not limited to, [1,2,4]oxadiazole,
[1,3,4]oxadiazole,
[1,2,4]thiadiazole, [1,3,4]thiadiazole, pyrrole, imidazole, pyrazole,
pyridine, pyrazine,
pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,
quinolizine,
isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline,
quinazoline,
cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline,
thiazole, isothiazole, phenazine, oxazole, isoxazole, phenoxazine,
phenothiazine,
imidazolidine, imidazoline, and the like as well as N-oxide and N-alkoxy
derivatives of
nitrogen containing heteroaryl compounds, for example pyridine-N-oxide
derivatives.
[0057] Unless otherwise constrained by the definition for the heteroaryl or
heteroarylene substituent, such heteroaryl or heterarylene groups can be
optionally
substituted with 1 to 5 substituents, preferably 1 to 3 substituents selected
from the
24
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl,
acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxyl, carboxyalkyl, arylthio,
heteroarylthio,
heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, -SO-alkyl, -SO-aryl,-SO-heteroaryl, -S02-alkyl, S02-aryl
and -
S02-heteroaryl. Unless otherwise constrained by the definition, all
substituents may
optionally be further substituted by 1-3 substituents chosen from alkyl,
carboxyl,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted
amino, cyano, and -S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1
or 2.
[0058] The term "heteroaralkyl" refers to a heteroaryl group covalently linked
to an
alkylene group, where heteroaryl and alkylene are defined herein. "Optionally
substituted heteroaralkyl" refers to an optionally substituted heteroaryl
group covalently
linked to an optionally substituted alkylene group. Such heteroaralkyl groups
are
exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-methoxythiazol-2-
ylpropyl, and
the like.
[0059] The term "heteroaryloxy" refers to the group heteroaryl-O-.
[0060] The term "heterocyclyl" refers to a monoradical saturated or partially
unsaturated group having a single ring or multiple condensed rings, having
from 1 to 40
carbon atoms and from 1 to 10 hetero atoms, preferably 1, 2, 3 or 4
heteroatoms,
selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
Heterocyclic
groups can have a single ring or multiple condensed rings, and include
tetrahydrofuranyl, morpholino, oxathiane, thiomorpholino,
tetraydropthiophenyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, triazolidino,
piperazinyl,
dihydropyridino, pyrrolidinyl, imidazolidino, heyxahydropyrimidine,
hezahydropyridazine, imidazoline, and the like.
[0061] Unless otherwise constrained by the definition for the heterocyclic
substituent,
such heterocyclic groups can be optionally substituted with 1, 2, 3, 4 or 5,
and
preferably 1, 2 or 3 substituents, selected from the group consisting of
alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,
aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,
thiocarbonyl, carboxyl, carboxyalkyl, arylthio, heteroarylthio,
heterocyclylthio, thiol,
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
-SO-
alkyl, -SO-aryl,-SO-heteroaryl, -S02-alkyl, S02-aryl and -S02-heteroaryl.
Unless
otherwise constrained by the definition, all substituents may optionally be
further
substituted by 1-3 substituents chosen from alkyl, carboxyl, carboxyalkyl,
aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano,
and -
S(O)õR, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0062] The term "thiol" refers to the group -SH.
[0063] The term "substituted alkylthio" refers to the group -S-substituted
alkyl.
[0064] The term "heteroarylthiol" refers to the group -S-heteroaryl wherein
the
heteroaryl group is as defined above including optionally substituted
heteroaryl groups
as also defined above.
[0065] The term "sulfoxide" refers to a group -S(O)R, in which R is alkyl,
aryl, or
heteroaryl. "Substituted sulfoxide" refers to a group -S(O)R, in which R is
substituted
alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
[0066] The term "sulfone" refers to a group -S(O)2R, in which R is alkyl,
aryl, or
heteroaryl. "Substituted sulfone" refers to a group -S(O)2R, in which R is
substituted
alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
[0067] The term "keto" refers to a group -C(O)-.
[0068] The term "thiocarbonyl" refers to a group -C(S)-.
[0069] The term "carboxyl" refers to a group -C(O)-OH.
[0070] "Optional" or "optionally" means that the subsequently described event
or
circumstance may or may not occur, and that the description includes instances
where
said event or circumstance occurs and instances in which it does not.
[0071] The term "compound of Formula I " is intended to encompass the
compounds of
the invention as disclosed, and the pharmaceutically acceptable salts,
pharmaceutically
acceptable esters, prodrugs, hydrates and polymorphs of such compounds.
Additionally, the compounds of the invention may possess one or more
asymmetric
centers, and can be produced as a racemic mixture or as individual enantiomers
or
diastereoisomers. The number of stereoisomers present in any given compound of
Formula I depends upon the number of asymmetric centers present (there are 2"
26
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
stereoisomers possible where n is the number of asymmetric centers). The
individual
stereoisomers may be obtained by resolving a racemic or non-racemic mixture of
an
intermediate at some appropriate stage of the synthesis, or by resolution of
the
compound of Formula I by conventional means. The individual stereoisomers
(including individual enantiomers and diastereoisomers) as well as racemic and
non-
racemic mixtures of stereoisomers are encompassed within the scope of the
present
invention, all of which are intended to be depicted by the structures of this
specification
unless otherwise specifically indicated.
[0072] "Isomers" are different compounds that have the same molecular formula.
[0073] "Stereoisomers" are isomers that differ only in the way the atoms are
arranged
in space.
[0074] "Enantiomers" are a pair of stereoisomers that are non-superimposable
mirror
images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic"
mixture.
The term "( )" is used to designate a racemic mixture where appropriate.
[0075] "Diastereoisomers" are stereoisomers that have at least two asymmetric
atoms,
but which are not mirror-images of each other.
[0076] The absolute stereochemistry is specified according to the Cahn-Ingold-
Prelog
R-S system. When the compound is a pure enantiomer the stereochemistry at each
chiral carbon may be specified by either R or S. Resolved compounds whose
absolute
configuration is unknown are designated (+) or (-) depending on the direction
(dextro-
or laevorotary) which they rotate the plane of polarized light at the
wavelength of the
sodium D line.
[0077] "Parenteral administration" is the systemic delivery of the therapeutic
agent via
injection to the patient.
[0078] The term "therapeutically effective amount" refers to that amount of a
compound of Formula I that is sufficient to effect treatment, as defined
below, when
administered to a mammal in need of such treatment. The therapeutically
effective
amount will vary depending upon the specific activity of the therapeutic agent
being
used, and the age, physical condition, existence of other disease states, and
nutritional
status of the patient. Additionally, other medication the patient may be
receiving will
effect the determination of the therapeutically effective amount of the
therapeutic agent
to administer.
27
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0079] The term "treatment" or "treating" means any treatment of a disease in
a
mammal, including:
(i) preventing the disease, that is, causing the clinical symptoms of the
disease not
to develop;
(ii) inhibiting the disease, that is, arresting the development of clinical
symptoms;
and/or
(iii) relieving the disease, that is, causing the regression of clinical
symptoms.
[0080] In many cases, the compounds of this invention are capable of forming
acid
and/or base salts by virtue of the presence of amino and/or carboxyl groups or
groups
similar thereto. The term "pharmaceutically acceptable salt" refers to salts
that retain
the biological effectiveness and properties of the compounds of Formula I, and
which
are not biologically or otherwise undesirable. Pharmaceutically acceptable
base
addition salts can be prepared from inorganic and organic bases. Salts derived
from
inorganic bases, include by way of example only, sodium, potassium, lithium,
ammonium, calcium and magnesium salts. Salts derived from organic bases
include,
but are not limited to, salts of primary, secondary and tertiary amines, such
as alkyl
amines, dialkyl amines, trialkyl amines, substituted alkyl amines,
di(substituted alkyl)
amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines,
trialkenyl
amines, substituted alkenyl amines, di(substituted alkenyl) amines,
tri(substituted
alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl)
amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted
cycloalkyl
amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)
amines,
substituted cycloalkenyl amines, disubstituted cycloalkenyl amine,
trisubstituted
cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl
amines,
diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic
amines,
triheterocyclic amines, mixed di- and tri-amines where at least two of the
substituents
on the amine are different and are selected from the group consisting of
alkyl,
substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted
cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and
the like. Also
included are amines where the two or three substituents, together with the
amino
nitrogen, form a heterocyclic or heteroaryl group.
[0081] Specific examples of suitable amines include, by way of example only,
28
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-
propyl)
amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine,
histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine,
morpholine, N-ethylpiperidine, and the like.
[0082] Pharmaceutically acceptable acid addition salts may be prepared from
inorganic
and organic acids. Salts derived from inorganic acids include hydrochloric
acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Salts derived
from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic
acid,
oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric
acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid,
ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
[0083] As used herein, "pharmaceutically acceptable carrier" includes any and
all
solvents, dispersion media, coatings, antibacterial and antifungal agents,
isotonic and
absorption delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except insofar as
any
conventional media or agent is incompatible with the active ingredient, its
use in the
therapeutic compositions is contemplated. Supplementary active ingredients can
also
be incorporated into the compositions.
Nomenclature
[0084] The naming and numbering of the compounds of the invention is
illustrated
with a representative compound of Formula I in which R1 is 5-[3-fluoro-5-
(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl) and R2 is hydroxyl:
29
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
OH
O
O/ N~O O
N
F
CF3
is named 7-({5-[3-fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)-
3 -(4-hydroxyphenyl)chromen-4-one.
Synthetic Reaction Parameters
[0085] The terms "solvent", "inert organic solvent" or "inert solvent" mean a
solvent
inert under the conditions of the reaction being described in conjunction
therewith
[including, for example, benzene, toluene, acetonitrile, tetrahydrofuran
("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane),
diethyl ether, methanol, pyridine and the like]. Unless specified to the
contrary, the
solvents used in the reactions of the present invention are inert organic
solvents.
[0086] The term "q.s." means adding a quantity sufficient to achieve a stated
function,
e.g., to bring a solution to the desired volume (i.e., 100%).
Synthesis of the Compounds of Formula I
[0087] The compounds of Formula I in which R2 is hydroxy and X, Y and Z are
all -
CR6-, in which R6 is hydrogen may be prepared as shown in Reaction Scheme I.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME I
OH
O OH
R1 WX
W is lower alkylene
andXishalo
HO R1 '-Ow--' 0", 0-11,
~I) Formula I in which R2 is hydroxy
[0088] In general, the compound of formula (1), (daidzein, commercially
available) is
dissolved in an inert solvent, for example N,N-dimethylformamide, and reacted
with
about an equimolar amount of a compound of formula RIWX, where W is lower
alkylene of 1-3 carbon atoms and X is iodo, bromo or chloro, in the presence
of a base,
for example potassium carbonate, potassium hydroxide, cesium carbonate, or the
like.
The reaction may be conducted at a temperature of about 50-100 C, for about 1-
10
hours or may also be conducted at room temperature for 3 to 24 hours. When the
reaction is substantially complete, the product of Formula I in which R2 is
hydroxy is
isolated by conventional means, for example by precipitating the product out
of
solution by addition of water.
[0089] Alternatively, the compound of formula (1) is dissolved in an inert
solvent, for
example acetone, and an aqueous base added, for example 2N potassium
hydroxide,
and the mixture sonicated for about 5-30 minutes. The mixture is then reacted
with
about an equimolar amount of a compound of formula RIWX, where W is lower
alkyene of 1-3 carbon atoms and X is iodo, bromo or chloro, in the presence of
about
an equimolar amount of potassium iodide, and the mixture reacted at about
reflux
temperature for about 1-5 days. When the reaction is substantially complete,
the
product of Formula I in which R2 is hydroxy is isolated by conventional means,
for
example by chromatography.
[0090] A method for preparing compounds of Formula I in which RI is phenyl
substituted by tetrazol-5-yl, W is methylene, and X, Y and Z are all -CR6-, in
which R6
is hydrogen is shown in Reaction Scheme II.
31
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME II
OH
O \
NC
OH
Formula I O
N N II \ (2)
NON Formula I where R' is phenyl
substituted by tetrazol-5-yl
TMS
Step 1 - Preparation of a Compound of Formula (2)
[0091] In general, a mixture of the compound of Formula I in which R1 is
benzonitrile,
dibutyltin oxide, and azidotrimethylsilane is subjected to microwaves. The
reaction is
conducted at a temperature of about 150 C for about 10-30 minutes. When the
reaction
is substantially complete, the product of formula (2) is isolated by
conventional means,
for example by chromatography on silica gel.
Step 2 - Preparation of a Compound of Formula I
[0092] The purified product of formula (2) is suspended in an aqueous solvent,
for
example acetonitrile/water, and a catalytic amount of a strong acid added, for
example
trifluoroacetic acid. Removal of the solvents provides the compound of Formula
I in
which R1 is phenyl substituted by tetrazol-5-yl.
[0093] Similarly, the compound of Formula I in which R1 is [1,2,4]-oxadiazol-3-
yl
substituted by benzonitrile at the 5-position is converted to a compound of
Formula I in
which R1 is [1,2,4]-oxadiazol-3-yl substituted by tetrazol-5-ylphenyl.
[0094] Compounds of Formula I in which R2 is NHR5 in which R5 is hydrogen may
be prepared from an intermediate having a nitro group precursor, as shown in
Reaction
Scheme III.
32
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME III
O
NO2 O
NH2
R~/\O \ O
R/ \O O
(3) Formula I
Step 1 - Preparation of a Compound of Formula I
[0095] In general, a nitro derivative of formula (3) (prepared as described in
Reaction
Scheme I but using a commercially available nitro daidzein derivative as the
starting
material) is suspended in an aqueous solvent, for example a mixture of
tetrahydrofuran
and water, and reacted with sodium dithionite. The reaction is conducted at a
temperature of about 50-70 C overnight. When the reaction is substantially
complete,
the amine of Formula I is isolated by conventional means, for example by
chromatography on silica gel.
[0096] Alternatively, the compound of formula (3) can be suspended in acetic
acid
followed by the slow addition of zinc over 20 to 40 minutes. As this reaction
will be
exothermic, the suspension is cooled in an ice-water bath. Once all the zinc
has been
added the reaction is allowed to warm to room temperature under continued
stirring.
After the reaction is complete, the amine of Formula I is isolated by
conventional
means, for example by filtration with Celite to remove side products, followed
by
washing with ETOAc, drying with Na2SO4, filtering, and solvent removal.
[0097] It should be noted that if the compound of formula (3) has a carboxyl
group
present on the R1 moiety, the carboxyl group may be protected as an allyl or
alkyl, i.e.,
tert-butyl ester before carrying out the reduction of the nitro group. It will
be
understood that the protecting group may be placed on the carboxyl group
before of the
R1W group to the Formula I core using, a Pro-R1WX compound as a reactant, or
after
attachment, for example by reacting the acidic compound of Formula I, with 2-
methylpropan-2-ol, MgS04, and H2SO4 in dichloromethane. Such a protecting
group
protects the carboxyl group in any subsequent reaction in which the amine is,
for
33
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
example acylated, and is easily removed after acylation via conventional
hydrolysis
conditions.
[0098] Conversion of a compound of Formula I in which W is methylene, X, Y and
Z
are all -CR6-, in which R6 is hydrogen, and R2 is NH2 to a corresponding
compound of
Formula I in which R2 is NHSO2R5 is shown in Reaction Scheme IV.
REACTION SCHEME IV
O
NH2 NHSO2R15
R1/ O O R00
Formula I
Formula I in which R4 is -SO2R15
[0099] In general, the compound of Formula I in which R2 is amino is suspended
in an
inert solvent, for example dichloromethane, and a tertiary base added, for
example
pyridine. The mixture is cooled to about 0 C, a compound of formula R15S02C1
added,
and the mixture reacted for about 1-2 hours. When the reaction is
substantially
complete, the compound of Formula I in which R4 is -S02R15 is isolated by
conventional means, for example by chromatography on silica gel.
[0100] Similarly, reaction of a compound of Formula I in which R2 is amino
with an
acylating agent of formula C1C(O)R5 provides compounds of Formula I in which
R2 is -
NHR4 where R4 is -C(O)R5. Reaction with a compound of formula C1C(O)NHR5 or
RSNCO provides compounds of Formula I in which R4 is -C(O)NHR5.
[0101] When a carboxyl group present on the R1 moiety has been protected as an
allyl
or alkyl ester before carrying out the reduction of the nitro group,
conversion of a
compound of Formula I in which W is methylene, X, Y and Z are all -CR6-, in
which
R6 is hydrogen, and R1 is an allyl ester derivative to a corresponding
compound of
Formula I in which R1 is an acid derivative is shown in Reaction Scheme V.
34
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME V
o I \
NHSOzR"
o I \ O o
Formula I in which R1 is an allyl ester derivative
0 NHSOzR"
HO \ O O
Formula I in which R' is a benzoic acid derivative
[0102] In general, when the R1 moiety has been protected as an allyl ester the
derivative of Formula I is dissolved in an inert solvent, for example
tetrahydrofuran,
and a base, for example morpholine, and tetrakis(triphenyl-
phosphine)palladium(0)
added. The reaction is conducted at about room temperature for about 1-12
hours.
When the reaction is substantially complete, the compound of Formula I in
which R1 is
a benzoic acid derivative is isolated by conventional means, for example by
flash
chromatography on silica gel. When R1 moiety has been protected as an alkyl
i.e., tert
butyl, ester, the derivative of Formula I is suspended in HCO2H and heated at
50 C for
1 hour followed by gradually increased heat to 80 C taking for approximately 2
to 3
hours. Once the reaction is complete, the suspension is allowed to cool to
ambient
temperature and stirred for an additional 7 to 10 hours. After stirring, water
is added
and the reaction mixture stirred at least for 1 h under ice-water bath
cooling. The
resulting precipitate is collected by filtration and the residue repeatedly
washed with
water. After drying, crude product is collected and may be purified by
recrystalization
in DMF with methanol.
[0103] If desired, additional modification of the R1 carboxylic group can be
carried out
by reaction of the compound with an alcohol of the desired moiety as shown in
Reaction Scheme VI.
REACTION SCHEME VI
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
O
NHS02R15
CI
O R200g, CI 6 0
CI
HO \ O \ O
Formula I in which R1 is a benzoic acid derivative
O
NHSOR15
R20 O O
Formula I in which R1 is an ether derivative
[0104] The acidic compound of Formula I is first dissolved in an appropriate
solvent
such as THE or DMF along with a base such as triethylamine and 2,4,6-
trichlorbenzyoyl chloride. This solution is allowed to react at room
temperature for
approximately 1 hour under a nitrogen atmosphere. Once this stage of the
synthesis is
complete, a solution of the R20OH reactant and dimethylaminopyridine in
solvent is
added and the combined mixture stirred at room temperature for an additional
hour.
After the addition of water, the modified compound of Formula I can be
collected from
the separated organic phase using conventional methods.
[0105] The compounds of formula RIWLG are either commercially available, or
are
made by methods well known in the art. For example, to prepare compounds of
Formula I in which R1 is oxazole substituted with optionally substituted
phenyl, the
synthesis starts from a compound of formula (4) (which is a compound of
formula
RIWLG in which R1 is optionally substituted 1,3-oxazole, W is methylene), and
LG is
Cl, the preparation of which is shown in Reaction Scheme VII.
REACTION SCHEME VII
36
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
O CI N
CI CI + II I ~-R
O H2N/x\R O
(a) (b) (4)
where R is optionally substituted phenyl.
[0106] In general, 1,3-dichloroacetone (a) is reacted with an appropriately
substituted
benzamide derivative of formula (b), in which R is optionally substituted
phenyl. The
reaction is conducted at a temperature of about 100-140 C, for about 1-6
hours. When
the reaction is substantially complete, the compound of formula (4) is
isolated by
conventional means, for example by flash chromatography on silica gel or
recrystallization from an inert solvent.
[0107] The compound of formula (4) is then reacted with a compound of formula
(1),
(daidzein, commercially available) as shown in Reaction Scheme I above, to
provide a
compound of Formula I.
[0108] Similarly, a compound of formula R1WLGI in which R1 is optionally
substituted
1,3,4-oxadiazole, W is methylene and LG is Cl can be prepared as shown in
Reaction
Scheme VIII
REACTION SCHEME VIII
II R O CI
R NHNHZ O
N
(d) (4a)
where R is optionally substituted phenyl
[0109] The hydrazide of formula (c), which is commercially available or made
by
means well known in the art, is suspended in 2-chlorotrimethoxyethane (d) in
the
presence of an organic acid, for example acetic acid. The mixture is carried
out a
temperature of about 140-180 C, in a microwave oven. When the reaction is
37
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
substantially complete, the compound of formula (4a) is isolated by
conventional
means.
[0110] Similarly, a compound of formula R1WLG in which R1 is optionally
substituted
1,2,4-oxadiazole, W is alkylene, and LG is Cl can be prepared as shown in
Reaction
Scheme IX
38
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME IX
CI CI
R NH2 R YN CI
R-CN NH2OH 10 0. 1
N~ Ch) NCO Rs
(e) (f) OH
(g)
(4b)
where R is optionally substituted phenyl and R5 is hydrogen or lower alkyl
Step 1
[0111] In general, the nitrile of formula (e) , in which R is optionally
substituted
phenyl, is reacted with aqueous hydroxylamine (formula (f)) in a protic
solvent, for
example ethanol. The reaction is conducted at a temperature of about 50-100 C,
for
about 2 hours. When the reaction is substantially complete, the compound of
formula
(g) is isolated by conventional means.
Step 2
[0112] The compound of formula (g) is then reacted with a compound of formula
(h),
in which R5 is hydrogen or lower alkyl. The reaction is conducted at a
temperature of
about 50-100 C, for about 2 hours. When the reaction is substantially
complete, the
compound of formula (4b) is isolated by conventional means.
[0113] The compound of formula (4b) is then reacted with a compound of formula
(1),
(daidzein, commercially available) as shown in Reaction Scheme I above, to
provide a
compound of Formula I.
[0114] Alternatively, a compound of formula R1WLG in which Rl is optionally
substituted 1,2,4-oxadiazole, W is alkylene, and LG is Cl may also be prepared
as
shown in Reaction Scheme X
39
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME X
CI OH
R CI
R NH2
RS
(g)
N (h') N\O Rs
OH
(4b)
where R is optionally substituted phenyl and R5 is hydrogen or lower alkyl
[0115] The compound of formula (g) is reacted with the compound of formula
(h'), in
which R5 is hydrogen or lower alkyl. The compound of formula (h') is placed in
as
suitable solvent such a dichloromethane and cooled to approximately 0 C. After
20 to
40 minutes, the compound of formula (g') is added and the coupling reaction
allowed to
proceed fro 1 to 2 hours. CBr4 and Ph3P are then added and the dehydration
allowed to
proceed for an additional 4 to 6 hours. Solid triphenylphosine oxide is
removed and the
remaining solvent evaporated and the compound of formula (4b) is isolated by
conventional means.
[0116] As before, the compound of formula (4b) is then reacted with a compound
of
formula (1), (daidzein, commercially available) as shown in Reaction Scheme I
above,
to provide a compound of Formula I.
[0117] Similarly, a compound of formula R1WLG in which R1 is isoxazole, W is
methylene, and LG is Cl can be prepared as shown in Reaction Scheme XI
REACTION SCHEME XI
O
/N O
R + HO/ N)" O/\ iL "--
(i) CI (j) R O
(k)
/N /N
O 10 O \
R OH R Br
(1) (4c)
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 1
[0118] In general, the acetylene derivative of formula (i), in which R is
optionally
substituted phenyl, is reacted with ethyl chlorooximidoacetate (formula (j))
in an inert
solvent, for example tetrahydrofuran, in the presence of a base, for example
triethylamine. The reaction is conducted at a temperature of about 0-25 C, for
about
10-24 hours. When the reaction is substantially complete, the compound of
formula (k)
is isolated by conventional means.
Step 2
[0119] In general, the ester derivative of formula (k), in which R is
optionally
substituted phenyl, is reacted with a reducing agent, for example sodium
borohydride in
a protic solvent, for example ethanol. The reaction is initially conducted at
a
temperature of about 0 C, and then at room temperature for about 1-2 hours.
When the
reaction is substantially complete, the compound of formula (1) is isolated by
conventional means.
Step 3
[0120] In general, the hydroxymethyl derivative of formula (1), in which R is
optionally
substituted phenyl, is reacted with a brominating agent, for example carbon
tetrabromide in the presence of triphenylphosphine. The reaction is conducted
at a
temperature of about 0 C for about 1-2 hours. When the reaction is
substantially
complete, the compound of formula (4c) is isolated by conventional means.
[0121] An alternative method of preparing compounds of Formula I is shown in
Reaction Scheme XII.
41
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME XII
O
R'WLG /
HO O
RWO O
(5) (6)
RZ
\ RZ /
(6) + I / 1 \
(HO)2B R WO O
(7)
Formula l
Step 1
[0122] In general, the compound of formula (5), 7-hydroxy-3-iodochromen-4-one,
is
reacted with a compound of formula RIWLG, wherein LG is a leaving group such
as
halogen or tosylate in a polar solvent, for example N,N-dimethylformamide, in
the
presence of sodium iodide and a mild base, for example potassium carbonate.
The
reaction is conducted at a temperature of about 40-80 C, for about 1 hour or
may be
conducted at room temperature for a longer period, 2 to 24 hours. When the
reaction is
substantially complete, the compound of formula (6) is isolated by
conventional means,
for example by flash chromatography on silica gel or recrystallization from an
inert
solvent.
Step 2
[0123] The compound of formula (6) is then reacted with the boronic acid of
formula
(7), which are either commercially available or prepared by means well known
in the
art. In general, the reaction is conducted in an inert solvent, for example
dimethoxymethane, in the presence of tetrakistriphenylphosphine palladium and
aqueous sodium carbonate. The reaction is conducted at a temperature of about
60-
100 C, for about 1 hour. When the reaction is substantially complete, the
compound of
42
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Formula I is isolated by conventional means, for example by flash
chromatography on
silica gel or recrystallization from an inert solvent.
[0124] As will be evident to one of ordinary skill in the art, the compound of
fomula
(7) may first be reacted with the compound of formula (5) to produce a desired
compound of formula (5a) as shown below:
R2
O I \
HO O
(5')
which may then be reacted with a compound of formula R1WX as described above.
[0125] One method of preparing the starting material 3-iodo-7-methoxychromen-4-
one
is shown in Reaction Scheme XIII.
REACTION SCHEME XIII
0 0
/ / N
O \ O- 10-
\O \ OH
(8) (9)
O
i
\ \
O O HO O
(5a) (5)
Step 1
[0126] In general, the compound of formula (8), 1-(2-hydroxy-4-
methoxyphenyl)ethan-
1-one, is reacted with the dimethylacetal of N,N-dimethylformamide. The
reaction is
conducted at a temperature of about 50-100 C, for about 2 hours. When the
reaction is
substantially complete, the compound of formula (9) is isolated by
conventional means,
43
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
for example by filtration of the precipitated product, 3-(dimethylamino)-1-(2-
hydroxy-
4-methoxyphenyl)prop-2-en-1-one.
Step 2
[0127] The compound of formula (9) is then reacted with N-iodosuccinimide in
an inert
solvent, for example chloroform, in the presence of silica gel. The reaction
is
conducted at a temperature of about 0 C, for about 1 hour. When the reaction
is
substantially complete, the compound of formula (5a), 3-iodo-7-methoxychromen-
4-
one, is isolated by conventional means, for example by filtering off the
silica gel,
washing the solid with chloroform, and removal of the solvent.
Step 3
[0128] The compound of formula (5a) is then reacted with boron tribromide to
convert
the methoxy group to a hydroxyl group. In general, the compound of formula
(5a) is
dissolved in an inert solvent, for example chloroform, cooled to about -80 C,
and
reacted with boron tribromide for about 1 hour. The mixture is then allowed to
warm
to about room temperature, and stirred for about 2-5 days. When the reaction
is
substantially complete, the compound of formula (5), 3-iodo-7-hydroxychromen-4-
one,
is isolated by conventional means.
[0129] It will be appreciated by those of skill in the art that various Q1 and
Q2 linking
groups can be added to either the R1WX reactant or the compound of formula (6)
prior
to the final synthesis of the compound of Formula I. Such alkylation
techniques are
well within the skill of one of ordinary skill in the art and will be readily
apparent.
Simiarly, methods for subsequent modification of the R1, R2, or R3,
substituent after the
synthesis of a compound of Formula I will also be readily apparent to one of
ordinary
skill.
[0130] For example, a method of making compounds wherein Q1 is methylene, T is
NH, and Q2 is ethylene is shown in Reaction Scheme XIX:
44
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
REACTION SCHEME XIX
OH \ OH
X Qz Xz O
X1 and X2 are
independently halo Qz
HO O O O
(10)
OH
Rl-Ql-z
R N O
H
Formula I in which T is NH and NR2 is hydroxy
Step 1
[0131] The commercially available compound of formula (1) is dissolved in an
inert
solvent, for example acetone, and an aqueous base added, for example 2N
potassium
hydroxide. The mixture is then reacted with about an equimolar amount of a
compound of formula X1Q2X2, where X1 and X2 are independently iodo, bromo or
chloro. The mixture is reacted at about reflux temperature for about 1-5 days.
The
solvent is then evaporated and the residue purified using conventional methods
such as
column chromatography to provide the compound of formula (10).
Step 2
[0132] The compound of formula (10) is the reacted with a compound of formula
R1Qi-NH2 in an inert solvent such as DMF. The reaction takes place at a
temperature
of approximately 50 C to 80 C for 12 to 48 hours. When the reaction is
substantially
complete, the compound of Formula I is isolated by conventional means, for
example
by solvent evaporation followed byt TLC.
[0133] As will be apprant to one of ordinary skill in the art, this type of
reaction can be
modified so that a modified Q1 linking group is added to an appropriately
halogenated
R1 derivative according the the method described in Step 2 to provide a
compound of
the formula R'-Q1-X.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0134] In another variation of the synthesis, oxirane derivatives of desired
Q1 and/or Q2
linking groups may be used to produce compounds of Formula I wherein either or
both
of the Q moieties are hydroxy substituted. For example, a method of making
compounds wherein Q1 is methylene, T is NH, and Q2 is 2-hydroxy propylene is
shown
in Reaction Scheme XX:
REACTION SCHEME XX
O R2 O R2
HO I 0 K2C0 DM F V-/,-"o O
800C
(5') (11)
H
RNH2 RAN O O
(11) DIPEA, EtOH
reflux 0
R2
Formula I wherein Q1 is methylene,
Q2 is 2-hydroxypropylene, and T is NH
Step 1
[0135] The compound of formula (5') is reacted with epichlorohydrin and K2CO3
in a
suitable solvent such as DMF. The reaction takes place at a temperature
ranging from
60 C to 90 C and is carried out for 1 to 6 hours. When the reaction is
substantially
complete, the solvent is removed by evaporation and the compound of formula
(11)
collected as a precipitate from the residue by treatedment with H20. The
precipitate
may be collected conventional means, for example by flash chromatography on
silica
gel or recrystallization from an inert solvent.
46
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 2
[0136] The compound of formula (11) is then reacted with an amino derivative
of the
desired R1Q1 segment, such as the Rimethylamino compound shown in Reaction
Scheme X. The reactents are dissolved in a protic solvent such as ethanol and
a
catalytic amound of base such as DIPEA (N,N'-diisopropylethylamine) is added.
The
reaction may be carried out by stirring overnight at at emperature of 70 C to
85 C.
When the reaction is substantially complete, the solvent is removed by
evaporation and
the compound of Formula I collected and purified by conventional means such as
silica
gel column chromatography followed by recrystalization from an inert solvent.
[0137] In instances where compounds wherein T is a covalent bond, the compound
of
formula (11) can be reacted with a magnesioum brominde derivative of the
desired
R1Q1 segment. In this type of reaction, the magnesium bromide derivative is
slowly
added to a cooled (-60 to -30 C) solution of Cul in THF. To this solution is
then
slowly added the compound of formula (11) in THF. The reaction mixture is
stirred at
-60 to -30 C 1 to 2 hours then quenched with saturated NH4C1 aqueous solution
and
H2O and extracted with EtOAc. The organic layer is further washed with brine,
then
dried over Na2SO4 and evaporated in vacuo. The compound of Formula I is then
collected and purified by conventional means such as prep-TLC.
Utility, Testing and Administration
General Utility
[0138] The compounds of Formula I are generally effective in the treatment of
conditions that respond to administration of ALDH-2 inhibitors. Specifically,
the
compounds of Formula I are useful in the treatment of addictions to dopamine-
producing agents of addiction such as, for example, cocaine, opiates,
amphetamines,
nicotine, and alcohol.
[0139] While not wishing to be bound by theory, it is believed that ALDH-2
inhibitors
are effective in treating addiction as a consequence of their ability to
normalize the
increased dopamine levels associated with various addictive behaviors. See,
N.D.
Volkow et al., Dopamine in drug abuse and addiction: results from imaging
studies and
treatment implications, Mol. Psychiatry 9 (2004), pp. 557-569; and B.J.
Everitt and
M.E. Wolf, Psychomotor stimulant addiction: a neural systems perspective, J.
47
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Neurosci. 22 (2002), pp. 3312-3320.
[0140] Given this proposed mechanism of action, it is believe that ALDH-2
inhibitors
such as the compounds of Formula I will be useful in the treatment of all
addictive and
compulsive behaviors and neurological conditions associated with increased
dopamine
levels. Such behaviors and conditions include, but are not limited to,
compulsive
gambling, overeating, and shopping, obsessive compulsive disorder (OCD),
schizophrenia, attention deficit hyperactivity disorder, and the like.
Testing
[0141] Activity testing is conducted as described in those patents and patent
applications referenced above, and in the Examples below, and by methods
apparent to
one skilled in the art. For example, as described in "The Mitrochondrial
Monoamine
Oxidase-Aldehyde Dehydrogenase Pathway: A Potential Site of Action of
Daidzin", J.
Med. Chem. 2000, 43 , 4169-4179. In general, the compounds of Formula I are
assayed to determine their effects on MAO and ALDH-2 independently using the
membrane and lysate of a density-gradient-purified mitochondria preparation as
the
respective enzyme sources. The results are expressed in IC50 values.
Pharmaceutical Compositions
[0142] The compounds of Formula I are usually administered in the form of
pharmaceutical compositions. This invention therefore provides pharmaceutical
compositions that contain, as the active ingredient, one or more of the
compounds of
Formula I, or a pharmaceutically acceptable salt or ester thereof, and one or
more
pharmaceutically acceptable excipients, carriers, including inert solid
diluents and
fillers, diluents, including sterile aqueous solution and various organic
solvents,
permeation enhancers, solubilizers and adjuvants. The compounds of Formula I
may
be administered alone or in combination with other therapeutic agents. Such
compositions are prepared in a manner well known in the pharmaceutical art
(see, e.g.,
Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA
17th Ed.
(1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3rd Ed. (G.S. Banker &
C.T.
Rhodes, Eds.).
48
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Administration
[0143] The compounds of Formula I may be administered in either single or
multiple
doses by any of the accepted modes of administration of agents having similar
utilities,
for example as described in those patents and patent applications incorporated
by
reference, including rectal, buccal, intranasal and transdermal routes, by
intra-arterial
injection, intravenously, intraperitoneally, parenterally, intramuscularly,
subcutaneously, orally, topically, as an inhalant, or via an impregnated or
coated device
such as a stent, for example, or an artery-inserted cylindrical polymer.
[0144] One mode for administration is parental, particularly by injection. The
forms in
which the novel compositions of the present invention may be incorporated for
administration by injection include aqueous or oil suspensions, or emulsions,
with
sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs,
mannitol, dextrose,
or a sterile aqueous solution, and similar pharmaceutical vehicles. Aqueous
solutions
in saline are also conventionally used for injection, but less preferred in
the context of
the present invention. Ethanol, glycerol, propylene glycol, liquid
polyethylene glycol,
and the like (and suitable mixtures thereof), cyclodextrin derivatives, and
vegetable oils
may also be employed. The proper fluidity can be maintained, for example, by
the use
of a coating, such as lecithin, by the maintenance of the required particle
size in the
case of dispersion and by the use of surfactants. The prevention of the action
of
microorganisms can be brought about by various antibacterial and antifungal
agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the
like.
[0145] Sterile injectable solutions are prepared by incorporating the compound
of
Formula I in the required amount in the appropriate solvent with various other
ingredients as enumerated above, as required, followed by filtered
sterilization.
Generally, dispersions are prepared by incorporating the various sterilized
active
ingredients into a sterile vehicle which contains the basic dispersion medium
and the
required other ingredients from those enumerated above. In the case of sterile
powders
for the preparation of sterile injectable solutions, the preferred methods of
preparation
are vacuum-drying and freeze-drying techniques which yield a powder of the
active
ingredient plus any additional desired ingredient from a previously sterile-
filtered
solution thereof.
[0146] Oral administration is another route for administration of the
compounds of
49
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Formula I. Administration may be via capsule or enteric coated tablets, or the
like. In
making the pharmaceutical compositions that include at least one compound of
Formula I, the active ingredient is usually diluted by an excipient and/or
enclosed
within such a carrier that can be in the form of a capsule, sachet, paper or
other
container. When the excipient serves as a diluent, in can be a solid, semi-
solid, or
liquid material (as above), which acts as a vehicle, carrier or medium for the
active
ingredient. Thus, the compositions can be in the form of tablets, pills,
powders,
lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,
syrups, aerosols
(as a solid or in a liquid medium), ointments containing, for example, up to
10% by
weight of the active compound, soft and hard gelatin capsules, sterile
injectable
solutions, and sterile packaged powders.
[0147] Some examples of suitable excipients include lactose, dextrose,
sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,
tragacanth,
gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose,
sterile water, syrup, and methyl cellulose. The formulations can additionally
include:
lubricating agents such as talc, magnesium stearate, and mineral oil; wetting
agents;
emulsifying and suspending agents; preserving agents such as methyl- and
propylhydroxy-benzoates; sweetening agents; and flavoring agents.
[0148] The compositions of the invention can be formulated so as to provide
quick,
sustained or delayed release of the active ingredient after administration to
the patient
by employing procedures known in the art. Controlled release drug delivery
systems
for oral administration include osmotic pump systems and dissolutional systems
containing polymer-coated reservoirs or drug-polymer matrix formulations.
Examples
of controlled release systems are given in U.S. Patent Nos. 3,845,770;
4,326,525;
4,902514; and 5,616,345. Another formulation for use in the methods of the
present
invention employs transdermal delivery devices ("patches"). Such transdermal
patches
may be used to provide continuous or discontinuous infusion of the compounds
of the
present invention in controlled amounts. The construction and use of
transdermal
patches for the delivery of pharmaceutical agents is well known in the art.
See, e.g.,
U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be
constructed for continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0149] The compositions are preferably formulated in a unit dosage form. The
term
"unit dosage forms" refers to physically discrete units suitable as unitary
dosages for
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
human subjects and other mammals, each unit containing a predetermined
quantity of
active material calculated to produce the desired therapeutic effect, in
association with
a suitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule). The
compounds
of Formula I are effective over a wide dosage range and is generally
administered in a
pharmaceutically effective amount. Preferably, for oral administration, each
dosage
unit contains from 10 mg to 2 g of a compound of Formula I, more preferably
from 10
to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of
a
compound of Formula I, more preferably about 50-200 mg. It will be understood,
however, that the amount of the compound of Formula I actually administered
will be
determined by a physician, in the light of the relevant circumstances,
including the
condition to be treated, the chosen route of administration, the actual
compound
administered and its relative activity, the age, weight, and response of the
individual
patient, the severity of the patient's symptoms, and the like.
[0150] For preparing solid compositions such as tablets, the principal active
ingredient
is mixed with a pharmaceutical excipient to form a solid preformulation
composition
containing a homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it is meant
that the
active ingredient is dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit dosage forms
such as
tablets, pills and capsules.
[0151] The tablets or pills of the present invention may be coated or
otherwise
compounded to provide a dosage form affording the advantage of prolonged
action, or
to protect from the acid conditions of the stomach. For example, the tablet or
pill can
comprise an inner dosage and an outer dosage component, the latter being in
the form
of an envelope over the former. The two components can be separated by an
enteric
layer that serves to resist disintegration in the stomach and permit the inner
component
to pass intact into the duodenum or to be delayed in release. A variety of
materials can
be used for such enteric layers or coatings, such materials including a number
of
polymeric acids
51
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0152] and mixtures of polymeric acids with such materials as shellac, cetyl
alcohol,
and cellulose acetate.
[0153] Compositions for inhalation or insufflation include solutions and
suspensions in
pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof,
and
powders. The liquid or solid compositions may contain suitable
pharmaceutically
acceptable excipients as described supra. Preferably the compositions are
administered
by the oral or nasal respiratory route for local or systemic effect.
Compositions in
preferably pharmaceutically acceptable solvents may be nebulized by use of
inert gases.
Nebulized solutions may be inhaled directly from the nebulizing device or the
nebulizing device may be attached to a face mask tent, or intermittent
positive pressure
breathing machine. Solution, suspension, or powder compositions may be
administered, preferably orally or nasally, from devices that deliver the
formulation in
an appropriate manner.
[0154] The following examples are included to demonstrate preferred
embodiments of
the invention. It should be appreciated by those of skill in the art that the
techniques
disclosed in the examples which follow represent techniques discovered by the
inventor
to function well in the practice of the invention, and thus can be considered
to
constitute preferred modes for its practice. However, those of skill in the
art should, in
light of the present disclosure, appreciate that many changes can be made in
the
specific embodiments which are disclosed and still obtain a like or similar
result
without departing from the spirit and scope of the invention.
52
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 1
Preparation of a Compound of Formula R1WX
A. Preparation of a Compound of Formula (4) in which R is Phenyl
CI N
0
(4)
[0155] A 50 mL round bottomed flask equipped with a condenser was charged with
benzamide (a compound of formula (b), 363.4 mg, 3.0 mmol) and 1.3-
dichloroacetone
(457.1 mg, 3.6 mmol, 1.2 equiv.). This mixture was heated at 130 C for 1 hour
under a
nitrogen atmosphere. After cooling to room temperature, the resulting mixture
was
purified by recrystallization from acetonitrile (6 mL). The suspension was
heated
under reflux reaction condition for 5 minutes and cooled down to ambient
temperature.
The resulting solid was filtered through a glass filter, and the crystals on
the filter were
washed with acetonitrile (2 mL). The desired product, 4-(chloromethyl)-2-
phenyl-1,3-
oxazole, was obtained as a colorless powder.
B. Preparation of other Compounds of Formula (4) in which R is Phenyl
[0156] Similarly, following the procedures of Example IA, substituting other
compounds of formula (b) for benzamide, other compounds of formula R1WLG were
prepared. For example:
4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole;
2-(3,5-difluorophenyl)-4-(chloromethyl)-1,3-oxazole;
2-(3,4-difluorophenyl)-4-(chloromethyl)- 1,3 -oxazole;
4-(chloromethyl)-2-(4-fluorophenyl)-1,3-oxazole;
4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole;
4-(chloromethyl)-2-[3-(trifluoromethyl)phenyl]-1,3-oxazole; and
4-(chloromethyl)-2-(3,4,5-trifluorophenyl)-1,3-oxazole.
53
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
C. Preparation of a Compound of Formula (4a) in which R is 4-Fluorophenyl
~CI
F \ / \ II
N
[0157] 4-Fluorobenzenecarbohydrazide (0.3 g, 2mmol) was suspended in chloro-
1,1,1-
trimethoxyethane (2 ml). To the suspension was added acetic acid (1 ml), and
the
solution was heated in a microwave for Minutes at 160 C. The solvent was
removed
under reduced pressure, and the residue purified using Biotage, eluting with
20% ethyl
acetate/hexanes, to provide 5-(chloromethyl)-3-(4-fluorophenyl)-1,2,4-
oxadiazole in
89% yield.
D. Preparation of a Compound of Formula (4b) in which R is 5-Fluoro-3-
Trifluoromethyllphenyl and R5 is Methyl
F
N CI
N__--O
F3C
Step 1
[0158] To a solution of 5-fluoro-3-(trifluoromethyl)benzenecarbonitrile (15.0
g, 79.3
mmol) in ethanol (30 ml) was added a solution of 50% hydroxylamine in water
(10 ml,
151.5 mmol), and the resulting mixture was heated at 80 C for 2 hours. The
mixture
was cooled to room temperature, solvent removed under reduced pressure, and 30
ml of
water added. The suspension was sonicated and the solid filtered off, washed
with
water (2 x 20 ml), and dried under reduced pressure, to provide [5-fluoro-3-
(trifluoromethyl)-phenyl](hydroxyimino)methylamine as a white solid. MS 223.1
(M+H).
Step 2
[0159] To a solution of [5-fluoro-3-(trifluoromethyl)phenyl](hydroxyimino)-
methylamine (8.884 g, 40 mmol) in a mixture of anhydrous dichloromethane/N,N-
54
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
dimethylformamide (60/20m1) was added 2-chloropropanoyl chloride (6.0 ml, 58.7
mmol) and diisopropylethylamine (14.0 ml, 80.3 mmol), and the mixture was
stirred at
room temperature for two hours. The mixture was then refluxed overnight with
stirring, cooled to room temperature, and solvent removed under reduced
pressure. The
residue was fractionally distilled under vacuum, and the portion boiling at 95-
105 C/0.8-1.0 mm Hg retained, to provide 5-(chloroethyl)-3-[5-fluoro-3-
(trifluoromethyl)phenyl]-1,2,4-oxadiazole as a yellow oil, MS 295.1 (M+H).
[0160] Alternatively, the product can be purified by flash chromatography over
silica
gel, eluting with ethyl acetate/hexanes (1/4).
E. Preparation of a Compound of Formula (4c) in which R is 3-
trifluoromethyllphenyl
Br
COC
F3C
Step 1 - Preparation of a Compound of Formula (k)
[0161] To a stirred solution of ethyl chlorooximidoacetate (6.68 g, 44.09
mmol) in
tetrahydrofuran (90 mL) in an ice bath was added 3-
(trifluoromethyl)phenylacetylene
(5.0 g, 29.39 mmol) slowly, followed by triethylamine (8.19 mL, 58.78 mmol)
dropwise. The resulting mixture was stirred at room temperature overnight,
which was
then filtered through a layer of silica gel (top) and anhydrous Na2S04
(bottom), and
washed with ethyl acetate. The filtrate was washed with water, the organic
layer dried
over sodium sulfate, and the solvent removed under reduced pressure. The
residue was
purified by silica gel column chromatography (ethyl acetate:Hexanes = 1 : 9)
to afford
ethyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate.
[0162] Similarly prepared was ethyl 5-(2-pyridyl)isoxazole-3-carboxylate.
Step 2 - Preparation of a Compound of Formula (1)
[0163] To a stirred solution of ethyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-
carboxylate (2 g, 7 mmol) in ethanol (70 mL) in an ice bath was added sodium
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
borohydride (1.06 g, 28 mmol) portionwise. The resulting mixture was stirred
at room
temperature for 1.5 hours, which was then quenched with saturated ammonium
chloride
aqueous solution. Solvent was removed from the mixture under reduced pressure,
and
the residue was dissolved in ethyl acetate and washed with water. The organic
layer
was then dried over sodium sulfate, and solvent removed under reduced
pressure. The
residue was purified by silica gel column chromatography (ethyl
acetate:Hexanes = 2
3) to afford {5-[3-(trifluoromethyl)phenyl]isoxazol-3-yl}methan-l-ol.
[0164] Similarly prepared was (5-(2-pyridyl)isoxazol-3-yl)methan-l-ol.
Step 3 - Preparation of a Compound of Formula (4c)
[0165] To a stirred suspension of {5-[3-(trifluoromethyl)phenyl]isoxazol-3-
yl}methan-
1-ol (0.28 g, 1.15 mmol) and carbon tetrabromide (0.5 g, 1.5 mmol) in
methylene
chloride (10 mL) at 0 C was added dropwise a solution of triphenylphosphine
(0.41 g,
1.58 mmol) in methylene chloride (5 mL). The resulting mixture was stirred at
0 C
for 1 hour, then the reaction mixture poured into ethyl acetate and Hexanes
(ethyl
acetate:Hexanes = 1 : 4, 50 mL). The resulting suspension was filtered through
a thin
layer of silica gel and washed with ethyl acetate and Hexanes (ethyl
acetate:Hexanes =
1 : 4). The filtrate was concentrated under reduced pressure, and the residue
was
purified by silica gel column chromatography (ethyl acetate:Hexanes = 1 : 4)
to afford
3-(bromomethyl)-5-[3-(trifluoromethyl)phenyl]isoxazole.
[0166] Similarly prepared was 3-(chloromethyl)-5-(2-pyridyl)isoxazole
56
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 2
Preparation of a Compound of Formula (5)
0
HO 0
Step 1 - Preparation of a Compound of Formula (9)
[0167] A mixture of 1-(2-hydroxy-4-methoxyphenyl)ethan-l-one (20g, 120 mmol)
and
N,N-dimethylformamide dimethylacetal (23g, 181 mmol) was stirred at 90 C for 2
hours. After cooling to room temperature the reaction mixture provided a
yellow
precipitate, which was washed with ethyl acetate (3 x 30m1), water (2 x 50ml),
and
dried under reduced pressure to yield 3-(dimethylamino)-1-(2-hydroxy-4-
methoxyphenyl)prop-2-en-l-one (9) as the trans isomer; MS 222.1 (M+H)
Step 2 - Preparation of a Compound of Formula (5)
[0168] To a solution of 3-(dimethylamino)-1-(2-hydroxy-4-methoxyphenyl)prop-2-
en-
1-one (20.0g, 90.37 mmol) in anhydrous chloroform (100 ml) at 0 C was added N-
iodosuccinimide (23.5g, 99.22 mmol) and silica gel (40g). The reaction mixture
was
stirred at 0 C for 60 minutes, then the insoluble material filtered off. The
filtrate was
washed with aqueous sodium thiosulfate (0.5M, 2 x 50ml), followed by brine
(100 ml),
then dried over sodium sulfate. The solvent was removed under reduced
pressure,
providing an orange solid. To this solid was added methanol (30 ml), and the
mixture
was sonicated, filtered, the solid washed with methanol (2 x 5 ml), and the
solid dried
under reduced pressure, to give 3-iodo-7-methoxychromen-4-one as a pale yellow
solid.
[0169] This product (9.36g, 30.98 mmol) was dissolved in anhydrous chloroform
(10ml), and cooled to -78 C. To this solution was added a 1.0 M solution of
boron
tribromide in methylene chloride (90 ml, 90 mmol), and the mixture stirred for
1 hour
at -78 C. The mixture was allowed to warm to room temperature, and stirred for
4
57
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
days. The mixture was then poured into water (200 ml), and the brown solid
filtered
off, washed with water (4 x 100 ml), and chloroform (3 x 20 ml). The filtrate
was
concentrated under reduced pressure to give a yellow gel, to which was added
methylene chloride (20 ml), and the mixture sonicated. A pale yellow solid was
obtained, and was filtered off, washed with methylene chloride (2 x 5 ml), and
dried
under reduced pressure to provide 7-hydroxy-3-iodochromen-4-one.
EXAMPLE 3
Preparation of a Compound of Formula I
Step 1. Preparation of a Compound of Formula (6) in which R1 is 4-Meth. 1. 1
(trifluoromethyl)phenyl](1,3-thiazol-5-yl), and W is Methylene
S-\ I
O
N 0
F3C
[0170] A mixture of 7-hydroxy-3-iodochromen-4-one (864 mg, 3.0 mmol), 5-
(chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole) (875 mg, 3.0
mmol),
sodium iodide (450 mg, 3.0 mmol), and potassium carbonate (552 mg, 4.0 mmol)
was
dissolved in N,N-dimethylformamide (10 ml) at room temperature under nitrogen.
The
mixture was heated at 60 for 1 hour, cooled to room temperature, and water
(30 ml)
added to the mixture. The aqueous mixture was extracted with methylene
chloride (3 x
30 ml), and the combined organic layer washed with brine (30 ml), dried over
sodium
sulfate, and solvent removed from the filtrate under reduced pressure.
Crystallization
of the crude product from ethyl acetate (4 ml) gave 3-iodo-7-({4-methyl-2-[4-
(trifluoromethyl)phenyl](1,3-thiazol-5-yl)}methoxy)chromen-4-one, a compound
of
formula (6).
Step 2 - Preparation of a Compound of Formula I in which R1 is Phenyl](1,3-
thiazol-5-
yl), R2 is 4-Methylsulfonamide, R3 is Hydrogen, V is Oxygen, X, Y, and Z are -
CH-,
and W is Methylene
58
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
0 O
~ I / I \
N O
NHSO2CH3
F3C
[0171] To a mixture of 3-iodo-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-
thiazol-
5-yl)}methoxy)chromen-4-one (55.0 mg, 0.10 mmol), 4-(dihydroxyboron)-
(methylsulfonyl)phenylamine (22.5 mg, 0.15 mmol), bis-(triphenylphosphine)
palladium (II) dichloride(3.5 mg, 0.005 mmol) was added dimethoxyethane (2 ml)
and
aqueous sodium carbonate solution (2M, 0.1 ml, 2 equivs). The mixture was
refluxed
for 1 hour, cooled to ambient temperature, filtered through celite (3 g), and
the celite
washed with ethyl acetate (50 ml). The filtrate was washed with brine (30 ml),
and
dried over sodium sulfate. The solvent was removed under reduced pressure, and
the
residue chromatographed on silica gel, eluting with ethyl acetate/hexanes
50/1, after
which the product was crystallized from ethyl acetate (3 ml), to provide 3- {4-
[(methylsulfonyl)amino]phenyl} -7-( {2-[4-(trifluoromethyl)phenyl] (1,3 -
thiazol-5-
yl)} methoxy)chromen-4-one.
B.
[0172] Similarly, the following compounds of Formula I were prepared:
4-[7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]benzenecarbonitrile;
ethyl 4-[7-({4-methyl-2-[4-(trifluoromethyl)phenyl] (1,3-thiazol-5-
yl)} methoxy)-4-oxochromen-3-yl]benzoate;
7-({3 -[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-yl)} ethoxy)-3-
(4-
hydroxyphenyl)chromen-4-one;
ethyl 3 -[7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3-yl]benzoate;
3 - {4-[(methylsulfonyl)amino]phenyl} -7-({4-methyl-2-[4-
(trifluoromethyl)phenyl] (1,3-thiazol-5-yl)} methoxy)chromen-4-one;
methyl 4-[7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-
yl)} methoxy)-4-oxochromen-3-yl]benzoate;
3-(2H,3H-benzo[e] 1,4-dioxan-6-yl)-7-({5-[3-fluoro-5-
(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)} methoxy)chromen-4-
one;
59
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(6-methoxy(3-pyridyl))chromen-4-one;
3-(4-hydroxyphenyl)-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3 -thiazol-5-
yl)} methoxy)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4- { [(4-methylphenyl)sulfonyl]amino}phenyl)chromen-4-one;
3-(4- { [(4-methylphenyl)sulfonyl]amino}phenyl)-7-({4-methyl-2-[4-
(trifluoromethyl)phenyl] (1,3-thiazol-5-yl)} methoxy)chromen-4-one;
methyl 3- {[3-(6-methoxy(3-pyridyl))-4-oxochromen-7-yloxy]methyl}benzoate;
methyl 3-({3-[4-(hydroxymethyl)phenyl]-4-oxochromen-7-
yloxy} methyl)benzoate;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
[4-(hydroxymethyl)phenyl]chromen-4-one;
4-[7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]benzoic acid;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4-morpholin-4-ylphenyl)chromen-4-one;
7-({5-methyl-2-[4-(trifluoromethyl)phenyl] (1,3-thiazol-4-yl)} methoxy)-3-(4-
morpholin-4-ylphenyl)chromen-4-one;
7-({3 -[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-yl)} methoxy)-3
-
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
2-fluoro-5-[7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3 -yl]benzenecarbonitrile;
ethyl 2-(3 - {4-[(ethoxycarbonyl)methoxy]phenyl} -4-oxochromen-7-
yloxy)acetate;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3 -yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]benzenecarbonitrile;
3 -(3-acetylphenyl)-7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-
oxadiazol-
3 -yl)} methoxy)chromen-4-one;
7-({5 -[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
4-[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3 -yl]benzamide;
3 -[2,4-bis(tert-butoxy)pyrimidin-5-yl]-7-({5- [5 -fluoro-3 -
(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)} methoxy)chromen-4-
one; and
5-[7-({5- [5 -fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3-yl]-1,3-dihydropyrimidine-2,4-dione.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 4
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 2-[5-fluoro-3-
(trifluoromethyl)phenyl]-1,3-oxazole, R2 is 4-Hydroxy, R3 is Hydrogen, X, Y
and Z are
-CH-, V is Oxygen, and W is Methylene
OH
O
/
F I
N O
O
F3C
[0173] 4',7-Dihydroxyisoflavone (101.7 mg, 0.40 mmol), 4-(chloromethyl)-2-[5-
fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole, prepared as described in
Example 1
(111.8 mg, 040 mmol, 1.0 equiv.), sodium iodide (59.6 mg, 0.40 mmol, 1.0
equiv), and
potassium hydroxide powder (22.4 mg, 0.4 mmol, 1.0 equiv) were placed in a 25
mL
flask equipped with a condenser. To the flask was added dimethylsulfoxide (3
mL) at
room temperature under nitrogen. The solution was heated at 60 C for 1 hour.
To the
mixture were added water (30 mL) and the whole was extracted with ethyl
acetate (30
mL x 3). The combined organic layers were washed with brine (30 mL) and dried
with
Na2SO4, to give a crude mixture as colorless oil (204.7 mg). The crude mixture
was
purified by column-chromatography (silica gel = 25 g, eluting with
hexane/ethyl acetate
= 7:1) to give crude product (149.3 mg) as colorless crystals.
Recrystallization of this
crude product gave 7-({2-[5-fluoro-3-(trifluoromethyl)phenyl]-(1,3-oxazol-4-
yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4-one as a colorless powder.
B.
[0174] Similarly, following the procedure of Example 4A above, substituting
other
compounds of formula (4) for 4-(chloromethyl)-2-[5-fluoro-3-
(trifluoromethyl)phenyl]-
1,3-oxazole, the following compounds of Formula I were prepared:
3-(4-hydroxyphenyl)-7-({2-[3-(trifluoromethyl)phenyl](1,3-oxazol-4-
yl)} methoxy)chromen-4-one;
61
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
7-({2- [5 -fluoro-3 -(trifluoromethyl)phenyl] (1,3-oxazol-4-yl)} methoxy)-3 -
(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- 1[2-(3,4,5-trifluorophenyl)(1,3-oxazol-4-
yl)]methoxy} chromen-4-one;
7- { [2-(3,5-difluorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [2-(3,4-difluorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [2-(4-fluorophenyl)(1,3-oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one; and
7- { [2-(4-chlorophenyl)(1,3 -oxazol-4-yl)]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one.
EXAMPLE 5
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-(Trifluoromethyl)-
phenyl[1,2,4]oxadiazolyl, R2 is 4-Hydroy, R3 is Hydrogen, X, Y and Z are -CH-,
V is
Oxygen, and W is Methylene
OH
\Y O O
O
N
F3C \
[0175] A mixture of daidzein (100 mg, 0.4 mmol), 3-chloromethyl-5-(3-
trifluoromethyl(phenyl[1,2,4]oxadiazole (108 mg, 0.41 mmol) and potassium
carbonate
(0.63 mg, 0.45 mmol) in anhydrous N,N-dimethylformamide (2 ml) was heated with
stirring under argon at 80 C for 4.5 hours. After cooling to room temperature,
the
mixture was quenched with about 12 ml of water, and stirred for 30 minutes.
The
precipitate formed was filtered off, washed three times with water, and dried
under
vacuum to provide crude product (152 mg). Chromatography of the crude product
on
silica gel, eluting with 5% to 50% ethyl acetate/hexanes, provided pure 3-(4-
62
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
hydroxyphenyl)-7-({5-[3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)chromen-4-one.
iH NMR (400 MHz, DMSO-d6) 6: 9.58 (s, 1H), 8.48-8.39 (m, 3H), 8.12 (d, 1H, J =
8.0 Hz), 8.08 (d, 1H, J = 8.8 Hz), 7.92 (t, 1H, J = 8.8 Hz), 7.42-7.3 8 (m,
3H), 7.23 (d,
1H, J = 9.2 Hz), 6.82 (d, 2H, J = 8.8 Hz), 5.61 (s, 2H). LC/MS analysis: tR =
21.98 min
(linear gradient B 5% - 90%), (ESI) m/z 481.5 (M + H)+.
B. Alternative Preparation of a Compound of Formula I in which R1 is 3-
(Trifluoromethyl)phenylF1,2,4]oxadiazolyl, R2 is 4-Hydroxy, R3 is Hydrogen, X,
Y and
X are -CH-, V is Oxygen, and W is Methylene
[0176] To a suspension of daidzein (2.0 g, 7.87 mmol) in acetone (80 ml) 2 N
aqueous
potassium hydroxide (3.94 ml, 7.87 mmol) was added, and the mixture was
sonicated
for a few minutes. To this mixture was added 3-chloromethyl-5-(3-
trifluoromethylphenyl)-[1,2,4]oxadiazole (2.17 g, 8.26 mmol), and the reaction
mixture
was refluxed for 3 days. The mixture was concentrated under reduced pressure,
and the
residue dissolved in methanol, mixed with silica gel, and the solvent removed
under
reduced pressure. Purification by flash column chromatography, eluting with
methylene chloride/methanol (95/5 to 90/10) provided pure 3-(4-hydroxyphenyl)-
7-({5-
[3-(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl)}methoxy)chromen-4-one as a
white
solid.
C. Preparation of Compounds of Formula I in which R3 is Hydrogen, X, Y and Z
are -CH-, and V is Oxygen, varying R1 and R2
[0177] Similarly, following the procedures of Example 5A or 5B above,
replacing 3-
chloromethyl-5-(3-trifluoromethylphenyl)-[1,2,4]oxadiazole by other compounds
of
formula R1CH2X, where R1 and X are as defined above, the following compounds
of
Formula I were prepared.
3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid; 1H
NMR (400 MHz, DMSO-d6) & 13.1 (br s, 1H), 9.59 (br s, 1H), 8.38 (s,
1H), 8.08 (s, 1H), 8.05 (d, 1H, J= 9.0 Hz), 7.94 (d, 1H, J= 7.8 Hz), 7.75
(d, 1H, J= 7.7 Hz), 7.56 (dd, 1H, J= 7.5 Hz, J= 7.8 Hz), 7.40 (d, 2H, J
= 8.7 Hz), 7.29 (d, 1H, J= 1.9 Hz), 7.18 ( dd, 1H, J= 1.9 Hz, J= 9.0
Hz), 6.82 (d, 2H, J= 8.7 Hz), 5.37 (s, 2H). (ESI) m/z 389 (M + H)+.
63
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -(4-hydroxyphenyl)-7-[(5 -phenyl(1,2,4-oxadiazol-3 -yl))methoxy]chromen-4-
one; iH NMR (300 MHz, DMSO-d6) 6: 9.58 (s, 1H), 8.41 (s, 1H), 8.15
(d, 2H, J = 7.2 Hz), 8.08 (d, 1H, J = 9.0 Hz), 7.72-7.63 (m, 3H), 7.42-
7.38 (m, 3H), 7.23 (d, 1H, J = 9.0 Hz), 6.82 (d, 2H, J = 8.7 Hz), 5.58 (s,
2H). (ESI) m/z 413.4 (M + H)+.
3 - { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzenecarbonitrile;
(ESI) m/z 370 (M + H)+.
3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzamide; iH NMR
(300 MHz, DMSO-d6) 5 9.56 (s, 1H), 8.41 (s, 1H), 8.35 (d, 2H, J= 8.1
Hz), 8.09-8.01 (m, 3H), 7.40 (m, 3H), 7.22 (dd, 1H, J= 8.8, 2.1 Hz),
6.82 (d, 2H, J= 8.7 Hz), 5.61 (s, 2H). (ESI) m/z 481.6 (M + H)+
3 -(4-hydroxyphenyl)-7- { [5-(2-methoxyphenyl)(1,2,4-oxadiazol-3-
yl)]methoxy}chromen-4-one; iH NMR (400 MHz, DMSO-d6) & 9.57
(s, 1H), 8.40 (s, 1H), 8.07 (d, 1H, J= 8.8 Hz), 8.03 (dd, 1H, J= 8.0, 1.6
Hz), 7.69 (m, 1H), 7.42-7.15 (m, 6H), 6.82 (d, 2H, J= 8.4 Hz), 5.56 (s,
2H), 3.95 (s, 3H). (ESI) m/z 443.3 (M + H)+
3 -(4-hydroxyphenyl)-7- { [3-(trifluoromethyl)phenyl]methoxy} chromen-4-one;
(K-28-AR-1) iH NMR (400 MHz, DMSO-d6) 5 9.55 (s, 1H), 8.39 (s,
1H), 8.06 (d, 1H, J= 8.8 Hz), 7.89 (s, 1H), 7.84-7.66 (m, 3H), 7.41 (d,
2H, 8.4 Hz), 7.29 (s, 1H), 7.20 (d, 1H, J= 8.4Hz), 6.82 (d, 2H, J= 8.4
Hz), 5.40 (s, 2H). (ESI) m/z 413 (M + H)+.
3 -(4-hydroxyphenyl)-7- 1[4-methoxy-3 -
(trifluoromethyl)phenyl]methoxy}chromen-4-one; (DM-K-4-P3); iH
NMR (300 MHz, DMSO-d6) 5 9.54 (s, 1H), 8.43-8.40 (m, 2H), 8.26 (d,
1H,J=1.8Hz),8.07(d,1H,J=8.9Hz),7.54(d,1H,J=8.9Hz),7.41
(d, 2H, J= 8.7 Hz), 7.37 (d, 1H, J= 2.4 Hz), 7.21 (dd, 1H, J= 2.4 Hz, J
= 8.9 Hz), 6.82 (d, 2H, J= 8.7 Hz), 5.56 (s, 2H), 4.03 (s, 3H). (ESI) m/z
511 (M + H)+
7- { [3 -fluoro-5-(trifluoromethyl)phenyl]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one; (DM-K-28-AR-2), (ESI) m/z 431 (M +
H)+.
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4-hydroxyphenyl)chromen-4-one; iH NMR (400 MHz, DMSO-d6) 5
9.57 (s, 1H), 8.42 (s, 1H), 8.33 (d, 1H, J= 8.4 Hz), 8.26 (s, 1H), 8.17 (d,
1H, J= 8.4 Hz), 8.08 (d, 1H, J= 8.8 Hz), 7.41 (m, 3H), 7.22 (dd, 1H, J
= 9.2, 2.0 Hz), 6.82 (d, 2H, J= 8.8 Hz), 5.62 (s, 2H), (ESI) m/z 499 (M
+ H) +
64
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
7-({5-[4-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
(4-hydroxyphenyl)chromen-4-one; iH NMR (300 MHz, DMSO-d6) &
9.54 (s, 1H), 8.55-8.48 (m, 1H), 8.44-8.40 (m, 2H), 8.07 (d, 1H, J= 8.9
Hz), 7.83 (dd, 1 H, J = 9.8 Hz, J = 9.5 Hz), 7.41 (d, 2H, J = 8.6 Hz), 7.3 8
(d, 1H, J= 2.4 Hz), 7.21 (dd, 1H, J= 2.4 Hz, J= 8.9 Hz), 6.82 (d, 2H, J
= 8.6 Hz), 5.59 (s, 2H), (ESI) m/z 499 (M + H)+.
7-({5-[2,5-bis(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one; 1H NMR (400 MHz, DMSO-d6) & 9.57
(s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 8.38-8.31 (m, 2H), 8.08 (d, 1H, J=
9.0 Hz), 7.41 (d, 2H, 8.7 Hz), 7.40 (s, 1H), 7.22 (dd, 1H, J= 1.9 Hz, J
9.0 Hz), 6.82 (d, 2H, J= 8.7Hz), 5.66 (s, 2H), (ESI) m/z 549 (M + H)+.
prop-2-enyl 3-(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-
oxadiazol-5-yl)benzoate; (ESI) m/z 497 (M + H)+.
prop-2-enyl 3- {[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
LGMS analysis: tR = 23.62 min (isocratic, 65%B), (ESI) m/z 429 (M +
H)+.
methyl 3-1[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyllbenzoate; 1H
NMR (400 MHz, DMSO-d6) 5 9.54 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H),
8.05 (d, 1H, J= 8.8 Hz), 7.96 (d, 1H, J= 7.7 Hz), 7.79 (d, 1H, J= 7.5
Hz), 7.60 (dd, 1H, J= 7.5 Hz, J= 7.7 Hz), 7.41 (d, 2H, J= 8.5 Hz), 7.27
(s, 1H), 7.18 (dd, 1H, J= 1.5 Hz, J= 9.0 Hz), 6.82 (d, 2H, J= 8.5 Hz),
5.38 (s, 2H), 3.88 (s, 3H), (ESI) m/z 403 (M + H)+.
ethyl4-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;, (ESI)
m/z 417 (M + H)+.
methylethyl 3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoate;
iH NMR (400 MHz, DMSO-d6) 5 9.56 (s, 1H), 8.39 (s, 1H), 8.08 (s,
1H), 8.05 (d, 1H, J= 9.0 Hz), 7.95 (d, 1H, J= 7.8 Hz), 7.78 (d, 1H, J=
7.7 Hz), 7.58 (dd, 1H, J= 7.6 Hz, J= 7.9 Hz), 7.41 (d, 2H, J= 8.3 Hz),
7.28 (d, 1H, J= 1.9 Hz), 7.18 (dd, 1H, J= 1.9 Hz, J= 9.0 Hz), 6.82 (d,
2H, J= 8.3 Hz), 5.37 (s, 2H), 5.18-5.14 (m, 1H), 1.33 (d, 6H, J= 6.3
Hz), (ESI) m/z 431 (M + H)+.
methyl 4- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzoate.
4-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid; (ESI)
m/z 3 89 (M + H)+.
4-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzamide; 1H NMR
(400 MHz, DMSO-d6) 5 9.54 (s, 1H), 8.38 (s, 1H), 8.07-8.04 (m, 3H),
7.87 (d, 1H, J= 8.0 Hz), 7.66 (d, 1H, J= 7.6 Hz), 7.51 (m, 1H), 7.41 (m,
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3H), 7.28 (d, 1H, J= 2.0 Hz), 7.18 (dd, 1H, J= 9.2, 2.0 Hz), 6.82 (d,
2H, J= 8.4 Hz), 5.33 (s, 2H), (ESI) m/z 388/389.
3-(4-hydroxyphenyl)-7-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)chromen-4-one; iH NMR (300 MHz, DMSO-d6) & 9.56 (s,
I H), 8.41 (s, I H), 8.35 (d, 2H, J= 8.1 Hz), 8.09-8.01 (m, 3H), 7.40 (m,
3H), 7.22 (dd, 1H, J= 8.8, 2.1 Hz), 6.82 (d, 2H, J= 8.7 Hz), 5.61 (s,
2H), (ESI) m/z 481.6 (M + H)+.
3 -(4-hydroxyphenyl)-7- { [5-(3 -methoxyphenyl)(1,2,4-oxadiazol-3-
yl)]methoxy} chromen-4-one;
7-({5-[3,5-bis(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one; iH NMR (400 MHz, DMSO-d6) & 9.57
(d, 1H, J= 1.6 Hz), 8.69 (s, 2H), 8.56 (s, 1H), 8.41 (d, 1H, J= 2.0 Hz),
8.07 (dd, 1H, J= 8.8, 2.0 Hz), 7.40 (m, 3H), 7.22 (d, 1H, J= 8.8 Hz),
6.82 (d, 2H, J= 6.4 Hz), 5.63 (s, 2H), (ESI) m/z 549.1 (M + H)+
3 -(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-oxadiazol-5-
yl)benzenecarbonitrile;, (ESI) m/z 438 (M + H)+
3 -(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-oxadiazol-5-
yl)benzoic acid;
7- { [5-(3 -fluorophenyl)(1,2,4-oxadiazol-3 -yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one. iH NMR (300 MHz, DMSO-d6) 5
9.55 (s, 1H), 8.40 (s, 1H), 8.08 (d, 1H, J= 8.7 Hz), 8.00 (d, 1H, J= 7.8
Hz), 7.94 (d, 1H, J= 9.0 Hz), 7.73-7.60 (m, 2H), 7.42-7.38 (m, 3H),
7.21 (dd, 1H, J= 9.0, 2.4 Hz), 6.82 (d, 2H, J= 8.7 Hz), 5.59 (s, 2H),
(ESI) m/z 431 (M + H)+.
3-(4-hydroxyphenyl)-7-[(3-phenyl(1,2,4-oxadiazol-5-yl))methoxy]chromen-4-
one; (ESI) m/z 413.4(M + H)+.
3-(4-hydroxyphenyl)-7-({3-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)}methoxy)chromen-4-one; (ESI) m/z 481.6 (M + H)+.
3-(4-hydroxyphenyl)-7-({3-[4-chlorophenyl](1,2,4-oxadiazol-5-
yl)}methoxy)chromen-4-one; (ESI) m/z 447.2 (M + H)+.
3 -(4-hydroxyphenyl)-2-(trifluoromethyl)-7-({5-[3-(trifluoromethyl)phenyl]-
(1,2,4-oxadiazol-3-yl)}methoxy)chromen-4-one; iH NMR (300 MHz,
DMSO-d6) 5 9.64 (s, 1H), 8.45 (d, 1H, J= 7.8 Hz), 8.39 (s, 1H), 8.17-
7.83 (m, 3H), 7.53 (d, 1H, J= 2.4 Hz), 7.27 (dd, 1H, J= 8.7, 2.1 Hz),
66
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
7.08 (d, 2H, J= 8.7 Hz), 6.82 (d, 2H, J= 8.4 Hz), 5.65 (s, 2H), (ESI) m/z
549 (M + H)+.
7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
(4-hydroxyphenyl)-2-(trifluoromethyl)chromen-4-one; iH NMR (400
MHz, DMSO-d6) 5 9.67 (s, 1H), 8.32 (d, 1H, J= 8.4 Hz), 8.25 (s, 1H),
8.17 (d, 1H, J= 8.4 Hz), 8.02 (d, 1H, J= 8.4 Hz), 7.54 (d, 1H, J= 1.6
Hz), 7.27 (dd, 1H, J= 8.8, 2.4 Hz), 7.08 (d, 2H, J= 8.0 Hz), 6.82 (d, 2H,
J= 8.8 Hz), 5.66 (s, 2H). (ESI) m/z 567 (M + H)+
3-(4-hydroxyphenyl)-7-({5-[4-methoxy-3-(trifluoromethyl)phenyl](1,2,4-
oxadiazol-3-yl)}methoxy)-2-(trifluoromethyl)chromen-4-one; (ESI) m/z
579 (M + H)+.
3 - { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} benzenecarbonitrile;
3 -(3- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-oxadiazol-5-
yl)benzoic acid.
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl]isoxazol-3-
yl} methoxy)chromen-4-one;
7- { [5-(trifluoromethyl)(3 -pyridyl)]methoxy} -3-(4- { [6-(trifluoromethyl)(3
-
pyridyl)]methoxy}phenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,2,4-oxadiazol-3-
yl))methoxy]chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl)(1,2,4-oxadiazol-3-
yl))methoxy]chromen-4-one;
methyl 2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-
5-carboxylate;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy} -3 - {4-
[(methylsulfonyl)amino]-phenyl} chromen-4-one;
2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-5-
carboxylic acid;
methyl 3-({3-[4-((1Z)- 1-amino-2-methoxy-2-azavinyl)phenyl]-4-oxochromen-
7-yloxy} methyl)benzoate;
7- {2-[4-(4-chlorophenyl)pyrazolyl] ethoxy} -3 -(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl(3-pyridyl))methoxy]chromen-4-one;
7-[(2R)-2-hydroxy-3 -({ [3 -(trifluoromethyl)phenyl]methyl} amino)propoxy]-3-
(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-[({ [3 -
(trifluoromethyl)phenyl]methyl} amino)methoxy]chromen-4-one;
7-((2R)-3-1[(3,5 -difluorophenyl)methyl] amino} -2-hydroxypropoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
67
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
7-(3- { [(1 R)-1-(4-fluorophenyl)ethyl]amino } -2-oxopropoxy)-3-(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-(3 -phenylpropoxy)chromen-4-one;
7-1[5-(3 -fluorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- 1[3 -(trifluoromethyl)phenyl] ethoxy} chromen-4-one;
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl](1,3,4-oxadiazol-2-
yl)} methoxy)chromen-4-one;
3 -(4-hydroxyphenyl)-7- [(2-phenyl(1,3 -oxazol-5-yl))methoxy]chromen-4-one;
7-({5-[3,5-bis(trifluoromethyl)phenyl]isoxazol-3-yl} methoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-({5-[3-(trifluoromethyl)phenyl]isoxazol-3-
yl} methoxy)chromen-4-one;
3 - {4-[(methylsulfonyl)amino]phenyl} -7-[(2-phenyl(1,3 -oxazol-4-
yl))methoxy]chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[3-(trifluoromethyl)phenyl]-
acetamide;
7- { [5-(2-chlorophenyl)(1,3,4-thiadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
4-[7-({4-methyl-2-[4-(trifluoromethyl)phenyl] (1,3 -thiazol-5-yl)} methoxy)-4-
oxochromen-3 -yl]benzenecarbonitrile;
3 -14- [(methylsulfonyl)amino]phenyl} -7-({4-methyl-2-[4-
(trifluoromethyl)phenyl] (1,3-thiazol-5-yl)} methoxy)chromen-4-one;
3-(6-methoxy(3-pyridyl))-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-
thiazol-5-yl)} methoxy)chromen-4-one;
4-[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,3,4-oxadiazol-2-yl)}
methoxy)-
4-oxochromen-3-yl]benzenecarbonitrile;
4-[4-oxo-7-({3-[3-(trifluoromethyl)phenyl]isoxazol-5-yl}methoxy)chromen-3-
yl]benzenecarbonitrile;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl) methoxy)-3
-
{4-[(methylsulfonyl)amino]phenyl} chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl) methoxy)-3
-
[4-(methylsulfonyl)phenyl]chromen-4-one;
4-[7-({5-[3 -fluoro-5 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3-yl)}
methoxy)-
4-oxochromen-3 -yl]benzamide;
3 -(3-acetylphenyl)-7-({5 -[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-
oxadiazol-
3 -yl)} methoxy)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,3,4-oxadiazol-2-yl)} methoxy)-3
-
(4-hydroxyphenyl)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl) methoxy)-3
-
(5-hydropyrazol-4-yl)chromen-4-one;
68
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
ethyl 3 -[7-({3 -[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-
yl)} ethoxy)-4-oxochromen-3 -yl]benzoate;
3-(4-hydroxyphenyl)-7-({2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-
yl)} methoxy)chromen-4-one;
7-[2-(3-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} ethoxy)-3-
(4-
hydroxyphenyl)chromen-4-one;
7-({5-[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-
3 -
(4- { [(4-methylphenyl)sulfonyl]amino}phenyl)chromen-4-one;
7- { [5-(2-chlorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
7- { [5-(4-fluorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-(4-pyridylmethoxy)chromen-4-one;
3 -14- [(methylsulfonyl)amino]phenyl} -7-({2-[4-(trifluoromethyl)phenyl](1,3 -
thiazol-5-yl)} methoxy)chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[2-(trifluoromethyl)phenyl]-
acetamide;
3 -(4-hydroxyphenyl)-7- 12-oxo-2-[2-(trifluoromethyl)phenyl] ethoxy} chromen-
4-one;
3-(1H-indazol-5-yl)-7-({5- [5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-
oxadiazol-3-yl)}methoxy)chromen-4-one;
3 -(4-hydroxyphenyl)-7-(2-phenylethoxy)chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]ethanenitrile;
7-[2-(4-chlorophenoxy)ethoxy] -3 -(4-hydroxyphenyl)chromen-4-one;
5- {4-[7-({5-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3-yl]phenyl} -1,3,5,6-
tetrahydropyrimidine-2,4-dione;
N- [(1 R)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
3 -(4-hydroxyphenyl)-7-(2-pyridylmethoxy)chromen-4-one;
2-fluoro-5-[7-({5 -[5 -fluoro-3 -(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -
yl)} methoxy)-4-oxochromen-3 -yl]benzenecarbonitrile;
7-(2-pyridylmethoxy)-3-[4-(2-pyridylmethoxy)phenyl]chromen-4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(4-pyridyl)(1,2,4-oxadiazol-3 -yl))ethoxy]chromen-
4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(3 -pyridyl)(1,2,4-oxadiazol-3 -
yl))ethoxy]chromen-
4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(2-pyridyl)(1,2,4-oxadiazol-3 -yl))ethoxy]chromen-
4-one;
69
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3 -(4-hydroxyphenyl)-7- 1[5-(trifluoromethyl)(3 -pyridyl)]methoxy} chromen-4-
one;
7- { [5-(4-chlorophenyl)isoxazol-3 -yl]methoxy} -3-(4-hydroxyphenyl)chromen-
4-one;
7- { [5-(3,4-dichlorophenyl)isoxazol-3 -yl]methoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
7- { [5-(4-chlorophenyl)isoxazol-3 -yl]methoxy} -3-(4-hydroxyphenyl)chromen-
4-one;
7-[(2R)-2-hydroxy-3 -(j[3 -(trifluoromethyl)phenyl]methyl} amino)propoxy]-3-
(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-[2-({ [3 -
(trifluoromethyl)phenyl]methyl} amino)ethoxy]chromen-4-one;
7-((2R)-3-1[(3,5 -difluorophenyl)methyl] amino} -2-hydroxypropoxy)-3 -(4-
hydroxyphenyl)chromen-4-one;
methyl 2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-
4-carboxylate;
which was hydrolyzed under standard hydrolysis conditions to give:
2- { [3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -1,3-oxazole-4-
carboxylic acid;
N-[(1 S)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3 -yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
7- { [5-(4-fluorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy} -3 - {4-
[(methylsulfonyl)-
amino]phenyl} chromen-4-one;
7- {3-[4-(4-chlorophenyl)pyrazolyl]propoxy} -3-(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(3-phenylpropoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl(3-pyridyl))methoxy]chromen-4-one;
7-((2R)-2-hydroxy-3-phenylpropoxy)-3-(4-hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4-oxadiazol-2-
yl))methoxy]chromen-4-one;
3 -[(2-hydroxy-3- {4-[(methylsulfonyl)amino]phenyl} -4-oxochromen-7-
yloxy)methyl]-benzoic acid;
7- { [5-(4-fluorophenyl)(1,3,4-oxadiazol-2-yl)]ethoxy} -3-(4-
hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4-oxadiazol-2-yl))ethoxy]chromen-
4-one;
3-(4-hydroxyphenyl)-7-[(3-(3-pyridyl)(1,2,4-oxadiazol-5-
yl))methoxy]chromen-4-one;
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
3-(4-hydroxyphenyl)-7-({3-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} methoxy)chromen-4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(3 -pyridyl)(1,3,4-oxadiazol-2-yl))ethoxy]chromen-
4-one;
3 -(4-hydroxyphenyl)-7- [(5 -(4-pyridyl)(1,2,4-oxadiazol-3 -yl))ethoxy]chromen-
4-one;
(2-1[3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} (1,3 -oxazol-4-yl))-N-
methylcarboxamide;
4-1[3 -(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl} -7-methoxychromen-
2-one;
7- { [5-(4-fluorophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 - {4-
[(methylsulfonyl)amino]-phenyl} chromen-4-one;
7-1[5-(3 -aminophenyl)(1,3,4-oxadiazol-2-yl)]methoxy} -3 -(4-
hydroxyphenyl)chromen-4-one;
ethyl 1- {2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]ethyl }pyrazole-4-
carboxylate;
7- {2-[4-(3 -chlorophenyl)piperazinyl] ethoxy} -3 -(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(2- {4-[3-
(trifluoromethyl)phenyl]piperazinyl} ethoxy)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(5-(2-pyridyl)isoxazol-3-yl)methoxy]chromen-4-one;
7-({3 -[3 -fluoro-5-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-5-yl)} ethoxy)-3-
(4-
hydroxyphenyl)chromen-4-one;
7-[2-(4-fluorophenyl)ethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
7-((1R)-1- {3-[3-fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-one;
7-((1 S)-1- {3 -[3 -fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-
yl)} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- {2-[3 -(trifluoromethyl)pyrazolyl] ethoxy} chromen-4-
one; and
7-(1- {3-[3 -fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)} -
isopropoxy)-3-(4-hydroxyphenyl)chromen-4-one.
D. Preparation of a Compound of Formula (3)
[0178] Similarly, following the procedures of Example 5A or 5B above,
replacing 3-
hydroxy isoflavone by commercially available isoflavones in which the 3-phenyl
group
is substituted with a nitro group and/or replacing 3-chloromethyl-5-(3-
trifluoromethylphenyl)-[1,2,4]oxadiazole by other compounds of formula R1CH2X,
71
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
where R1 and X are as defined above, the following compounds of formula (3)
were
prepared.
methyl 3-{[3-(4-nitrophenyl)-4-oxochromen-7-yloxy]methyl}benzoate; (ESI)
m/z 432 (M + H)+.
3-(4-nitrophenyl)-7-({5-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)chromen-4-one; (ESI) m/z 510.5 (M + H)+.
7-({5-[5-fluoro-3-(trifluoromethyl)phenyl] (1,2,4-oxadiazol-3 -yl)} methoxy)-3
-
(4-nitrophenyl)chromen-4-one; (ESI) m/z 528.1 (M + H)+.
prop-2-enyl 3-(3- { [3 -(4-nitrophenyl)-4-oxochromen-7-yloxy]methyl} -1,2,4-
oxadiazol-5-yl)benzoate; (ESI) m/z 458 (M + H)+.
3 - { [3 -(4-nitrophenyl)-4-oxochromen-7-yloxy]methyl}benzenecarbonitrile;
(ESI) m/z 399 (M + H)+.
methyl 3-{[3-(4-nitrophenyl)-4-oxochromen-7-yloxy]methyl}benzoate; (ESI)
m/z 432 (M + H)+.
7-(benzothiazol-2-ylmethoxy)-3-(4-hydroxyphenyl)chromen-4-one, and
3-[3-(4-nitrophenyl)-4-oxochromen-7-yloxymethyl]benzoic acid allyl ester.
E Preparation of Compounds of Formula I in which R2 is 4-IlydroM, R3 is
Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is Methylene, varying RI
[0179] Similarly, following the procedures of Example 5A or 5B above,
replacing 3-
hydroxy isoflavone by commercially available isoflavones in which the 3-phenyl
group
is substituted with a nitro group and/or replacing 3-chloromethyl-5-(3-
trifluoromethylphenyl)-[1,2,4]oxadiazole by other compounds of formula R1CH2X,
where R1 and X are as defined above, other compounds of Formula I are
prepared.
EXAMPLE 6
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is (3-(1H-1,2,3,4-
Tetrazol-5-yl)phenyl) 1,2,4-oxadiazol-5-yl), R2 is 4-H y, R3 is Hydrogen, X, Y
and Z are -CH-, V is Oxygen, and W is Methylene
72
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
OH
N~N\ O
N
H
O_N
[0180] A mixture of 3-(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}-
1,2,4-oxadiazol-5-yl)benzenecarbonitrile (51 mg, 0.117 mmol), dibutyltin(IV)
oxide
(15 mg, 0.059 mmol, 0.5 equiv), and azidotrimethylsilane (81 mg, 0.702 mmol, 6
equiv) was microwaved at 150 C for 20 minutes in 1,2-dimethoxyethane (0.6 ml).
The
reaction mixture was then dry-loaded onto a pre-packed column using silica gel
and
purified (silica gel, gradient, 100% CH2C12 to CH2C12/MeOH, 3:1) by flash
chromatography to obtain the desired product protected by trimethylsilyl. This
intermediate was suspended in acetonitrile (2 ml) and water (1 ml) and one
drop of
trifluoroacetic acid added. The volatile solvents were removed under vacuum to
afford
3 -(4-hydroxyphenyl)-7- { [5-(3 -(1,2,3,4-tetraazol-5-yl)phenyl)(1,2,4-
oxadiazol-3 -
yl)]methoxy}chromen-4-one (4 mg).
iH NMR (400 MHz, DMSO-d6) & 9.57 (s, 1H), 8.82 (s, 1H), 8.42-8.33 (m, 3H),
8.09
(d, 1H, J= 8.8 Hz), 7.92 (m, 1H), 7.41 (m, 3H), 7.24 (dd, 1H, J= 8.8, 1.6 Hz),
6.82 (d,
2H, J= 8.4 Hz), 5.62 (s, 2H). (ES-) m/z 479.2 (M - 1)
B. Preparation of a Compound of Formula I in which R1 is (3-(1H-1,2,3,4-
Tetraazol-5-yl)phenyl), R2 is 4-Hydroxy, R3 is Hydrogen, X, Y and X are -CH-,
V is
Oxygen, and W is Methylene
[0181] Similarly, starting with 3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]methyl}benzenecarbonitrile and following the procedure of 6A above, 3-(4-
hydroxyphenyl)-7-[(3-(1 H-1,2,3,4-tetrazol-5-yl)phenyl)methoxy]chromen-4-one
was
prepared.
iH NMR (400 MHz, DMSO-d6) & 9.56 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 8.06 (m,
2H), 7.73-7.67 (m, 2H), 7.40 (d, 2H, J= 8.4 Hz), 7.31-6.81 (m, 5H), 5.42 (s,
2H).
(ESI) m/z 435 (M + Na)+, (ES-) m/z 411.1 (M - 1)
73
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
C. Preparation of a Compound of Formula I in which R1 is (3-(1H-1,2,3,4-
Tetrazol-5-yl)phenyl)
[0182] Similarly, starting with other compounds of Formula I in which R1 is
phenyl
substituted by cyano, and following the procedure of 6A above, other compounds
of
Formula I in which R1 is 3-(1H-1,2,3,4-tetrazol-5-yl)phenyl are prepared.
EXAMPLE 7
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is Prop-2-enyl 3-
benzoate
and R2 is Amino
/ NHZ
O
O
\ / O \ O
[0183] A suspension of 3-[3-(4-nitrophenyl)-4-oxo-4H-chromen-7-
yloxymethyl]benzoic acid allyl ester (164.6 mg, 0.36 mmol), prepared as
described in
Example 5d, and sodium dithionite (188 mg, 1.08mmol) in tetrahydrofuran (8 ml)
and
water (4 ml) was heated at 60-65 C for 1 hour. Additional sodium dithionite
(1. 13 g,
6.48 mmol) was added in 5 portions over 2 hours. The reaction mixture was
stirred at
60-65 C overnight. 1H NMR of the reaction mixture showed that the product was
obtained without starting material. The reaction mixture was mixed with silica
gel (2
g), solvent removed under reduced pressure, and the mixture applied to a
column. The
silica gel mixture was purified by flash chromatography, eluting with
methylene
chloride/methanol (98/2) to give prop-2-enyl 3-{[3-(4-aminophenyl)-4-
oxochromen-7-
yloxy]methyl}benzoate as a yellow solid (99.6 mg, 65%);. (ESI) m/z 428 (M +
H)+.
B. Alternative preparation of a Compound of Formula I in which R1 is 3-(tert-
butoxycarbony)phenylmethyl and R2 is Amino
74
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0184] In a 3 L 3-neck round bottomed flask the starting material (58.00 g,
122.50
mmol, tert-butyl 3-((3-(4-nitrophenyl)-4-oxo-4H-chromen-7-
yloxy)methyl)benzoate,
99.8% purity) was suspended in AcOH (348 mL, Aldrich). To the suspension was
added Zn (40.04 g, 612.50 mmol, 5.0 equiv., Aldrich) over 30 min. The
suspension
was cooled with ice-water bath so that the internal temperature may be
maintained
between 20-35 C since the reaction is extremely exo-thermic. After the
addition of Zn,
the ice-water bath was removed and the reaction vessel was allowed to warm to
room
temperature (22 C). After 30 min stirring an HPLC analysis indicated formation
of the
desired product, 99.25%. The reaction mixture was stirred at the same
temperature for
I hour.
[0185] To the reaction mixture was added EtOAc (1800mL, J. T. Baker) at
ambient
temperature and the mixture was stirred for 20 min. The mixture was then
filtered
through a glass filter (350 mL with a fine lid) with Celite (30 g, Aldrich) to
remove the
side product, ZnOAc. The resulting yellow residue which formed on the Celite
was
washed with EtOAc (250 mL) on the glass filter to give a yellow filtrate
(Filtrate 1, ca.
2100 mL). Only the yellow residue on the Celite was removed and was suspended
in
EtOAc (1500 mL). The suspension was stirred for 40 min. Using the Celite and
the
glass filter used above, the suspension was filtered. The resulting yellow
residue on the
Celite was washed with EtOAc (250 mL) on the glass filter to give a very light
yellow
filtrate (Filtrate 2, ca. 1800 mL).
[0186] Filtrate 1 and Filtrate 2 were combined (ca. 3900 mL) and divided into
three
portions (ca. 1300 mL). Each portion was washed with brine (10% NaCI/H2O, 800
mL) in a 2 L separatory funnel and dried with Na2SO4 (80 g, Aldrich) in a 2 L
Erlen-
Myer Flask (x3) for 1 hour. After removal of Na2SO4 by filteration through a
piece of
cotton, the solvent was removed under a reduced pressure at 50 C. A residual
amount
of the solvent was removed by high-vacuum at 22 C for 6 h to give the desired
product
as a yellow solid (61.08 g, contaminated with -100mol% of AcOH). Similar
reactions
with similar scale were repeated another three times to consume the starting
material
and provide the final product, tert-butyl 3-((3-(4-aminophenyl)-4-oxo-4H-
chromen-7-
yloxy)methyl)benzoate.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
C. Preparation of a Compound of Formula I, varying Ri
[0187] Similarly, replacing 3-[3-(4-nitrophenyl)-4-oxochromen-7-
yloxymethyl]benzoic
acid allyl ester with other compounds of formula (3), and following the
procedure of
7A or 7B above, the following compounds of formula (4) were prepared:
[0188] 3-(4-aminophenyl)-7-({5-[3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)chromen-4-one; 1H NMR (400 MHz, DMSO-d6) & 8.46 (d, 1H, J= 7.9
Hz) 8.39 (s, 1H), 8.35 (s, 1H), 8.13 (d, 1H, J= 7.6 Hz), 8.07 (d, 1H, J= 8.9
Hz), 7.92
(dd, 1H, J= 7.9 Hz, J= 7.9 Hz), 7.37 (d, 1H, J= 1.8 Hz), 7.27 (d, 2H, J=8.3
Hz), 7.21
(dd, 1H, J= 1.8 Hz, J= 8.9 Hz), 6.61 (d, 2H, J= 8.3 Hz), 5.60 (s, 2H), 5.23
(s, 2H);
(ESI) m/z 480 (M + H)+.
[0189] methyl3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoate; (ESI)
m/z 402 (M + H)+
[0190] 7-({5-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)-3-
(4-aminophenyl)chromen-4-one;) (ESI) m/z 498.2 (M + H)+.
[0191] 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl} benzenecarbonitrile;
(ESI) m/z 369 (M + H)+.
[0192] 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzamide; (ESI) m/z
387 (M + H)+.
C. Preparation of a Compound of Formula I. varying
[0193] Similarly, replacing 3-[3-(4-nitrophenyl)-4-oxo-4H-chromen-7-
yloxymethyl]benzoic acid allyl ester with other compounds of formula (3), and
following the procedure of 7A or 7B above, other compounds of Formula I are
prepared.
76
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 8
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-(Prop-2-
enyl)benzoate, R2 is 4-[(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -
CH-,
V is Oxygen, and W is Methylene
0 0 V o
O \ \ / N/
O / \
[0194] To a mixture of prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-
yloxy]methyl}benzoate, prepared as described in Example 7A, (169.5 mg, 0.397
mmol)
and anhydrous pyridine (34.5 mg, 0.44 mmol) in dry methylene chloride (3 ml)
at 0 C
was added methanesulfonyl chloride (68.1 mg, 0.60 mmol). The mixture was then
stirred at room temperature for 21 hours, then mixed with silics gel and the
solvent
removed under reduced pressure. Flash chromatography of the silica gel
mixture,
eluting with methylene chloride/methanol (99.5/0.5) gave prop-2-enyl 3-[(3-{4-
[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate as a white
solid (160.9 mg). (ESI) m/z 506 (M + H)+.
B. Alternative preparation of a Compound of Formula I in which R1 is 3-(tert-
butoxycarbonyl)pheny, R2 is 4-[(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and
Z
are -CH-, V is Oxygen, and W is Methylene
[0195] In a 3 L 3-neck round bottomed flask, tert-butyl 3-((3-(4-aminophenyl)-
4-oxo-
4H-chromen-7-yloxy)methyl)benzoate as prepared in Example 7B (474.05 mmol) was
dissolved in pyridine (1053 mL, Aldrich) to give an orange solution. To the
solution
was added McSO2C1(81.45 g, 711.08 mmol, 1.5 equiv., Aldrich) over 10 min. The
reaction mixture was cooled with ice-water bath so that the internal
temperature may be
maintained between 20-35 C since the reaction is slightly exo-thermic. After
the
77
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
addition of McS02C1, the ice-water bath was removed and the reaction vessel
was
allowed to warm to ambient temperature (22 C).
[0196] After stirring for 1 hour, an HPLC analysis showed the desired product
and the
starting material, 98.55% and 0.30% respectively. After 1.5 hours stirring to
resulting
orange suspension was slowly added H2O (1900 mL, distilled at CVT). The
suspension
was divided into three portions (into three 3 L round bottomed flasks). To the
each
flask was added H2O (1185 mL, distilled at CVT) individually (Total amount of
H2O
added: 5455 mL, 11.5 mL/mmol). The mixtures were stirred at least 30 min at
ambient
temperature (22 C) and filtered through a 2 L filtration funnel (coarse) to
collect the
crude product. The crude product on the funnel was transferred into a 4 L
Erlen-Myer
Flask and suspended in H2O (2800 mL). After stirring for 20 min the suspension
was
filtered through a 2 L filtration funnel (coarse) to collect the crude
product. Suspending
in H2O (2800 mL) in a 4 L flask and filtration was repeated once again. The
residue on
the filtration funnel was placed in drying dishes (ca 500 mL volume) (1162 g
at this
point).
[0197] The wet crude product was dried under high-vacuum at 60 C for 54 hours
to
give dried crude product as a light yellow chunky powder. This was placed in
another
3 L 3-neck round bottomed flask and suspended in DMF (3 mL/g, 729 mL,
Aldrich).
The suspension was heated using heating mantleso that the internal temperature
may
reach to 90 C. The suspension was cooled with water-bath for 10 min. When the
internal temperature became 40 C, MeOH (1000 mL, Aldrich) was added. The
suspension was divided into 2 flasks (3 L 3-neck round bottomed flask). To the
each
flask was added MeOH (1322 mL). (Total amount of MeOH added: 3644 mL, 15
mL/g) After stirring at least for 1 hour at ambient temperature, the
suspensions were
filtered through a 2 L filtration funnel (medium). The product on the filter
was washed
with MeOH (Total 1200 mL). The residue on the filtration funnel was placed in
drying
dishes (ca 500 mL volume) (202.32 g at this point). The wet product was dried
under
high-vacuum at 60 C for 4 hours to give tert-butyl 3-((3-(4-
(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate as a light
yellow powder.
78
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
C. Preparation of Compounds of Formula I in which R2 is 4-
f(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and
W is
Methylene, varying R1
[0198] Similarly, replacing prop-2-enyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-
yloxy]methyl}benzoate with other compounds of formula (4), and following the
procedure of 8A or 8B above, the following compounds of Formula I in which R2
is 4-
[(methylsulfonyl)amino were prepared:
[0199] methyl3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzoate; 1H NMR (400 MHz, DMSO-d6) & 9.84 (br s, 1H), 8.46 (s,
1H), 8.10 (s, 1H), 8.07 (d, 1H, J= 8.9 Hz), 7.96 (d, 1H, J= 7.8 Hz), 7.80 (d,
1H, J=
7.7 Hz), 7.62-7.56 (m, 3H), 7.30 (s, 1H), 7.27 (d, 2H, J= 8.1 Hz), 7.20 (dd,
1H, J= 1.5
Hz, J= 9.0 Hz), 5.39 (s, 2H), 3.03 (s, 3H). (ESI) m/z 480 (M + H)+.
[0200] 3-{4-[(methylsulfonyl)amino]phenyl}-7-({5-[3-
(trifluoromethyl)phenyl](1,2,4-
oxadiazol-3-yl)}methoxy)chromen-4-one; 1H NMR (300 MHz, DMSO-d6) 5 9.86 (s,
1H), 8.49 (s, 1H), 8.45 (d, 1H, J= 7.8 Hz), 8.38 (s, 1H), 8.12 (d, 1H, J= 8.1
Hz), 8.08
(d, 1H, J= 9.0 Hz), 7.91 (dd, 1H, J= 7.9 Hz, J= 7.9 Hz), 7.57 (d, 2H, J= 8.6
Hz), 7.41
(d, 1H, J= 2.3 Hz), 7.28-7.21 (m, 3H), 5.61 (s, 2H), 3.03 (s, 3H). (ESI) m/z
558 (M +
H)+.
[0201] 7-({5-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)-3-
{4-[(methylsulfonyl)amino]phenyl}chromen-4-one; 1H NMR (300 MHz, DMSO-d6) 5
9.85 (s, 1H), 8.49 (s, 1H), 8.33-8.08 (m, 4H), 7.56 (d, 2H, J= 8.7 Hz), 7.42-
7.22 (m,
4H), 5.62 (s, 2H), 3.02 (s, 3H). (ESI) m/z 576.1 (M + H)+.
[0202] 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]-
benzenecarbonitrile; 1H NMR (400 MHz, DMSO-d6) 5 9.84 (s, 1H), 8.47 (s, 1H),
8.07
(d, 1H, J= 9.2 Hz), 8.00 (s, 1H), 7.86 (d, 2H, J= 7.6 Hz), 7.66 (dd, 1H, J=
7.6, 7.6
Hz), 7.57 (d, 2H, J= 8.8 Hz), 7.31-7.20 (m, 4H), 5.36 (s, 2H), 3.03 (s, 3H).
(ESI) m/z
447 (M + H)+.
79
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0203] 3-{[3-(4-methylsulfonylaminophenyl)-4-oxochromen-7-
yloxy]methyl}benzamide; iH NMR (400 MHz, DMSO-d6) & 9.83 (s, 1H), 8.46 (s,
1H),
8.06 (d, 1H, J= 8.9 Hz), 8.01 (s, 2H), 7.87 (d, 1H, J= 7.5 Hz), 7.65 (d, 1H,
J= 7.9 Hz),
7.57 (d, 2H, J= 8.6 Hz), 7.50 (dd, 1H, J= 7.7, 7.7 Hz), 7.40 (br s, 1H), 7.30
(d, 1H, J=
2.2 Hz), 7.26 (d, 2H, J= 8.6 Hz), 7.19 (dd, 1H, J= 2.2, 8.9 Hz), 5.33 (s, 2H),
3.02 (s,
3H). (ESI) m/z 465 (M + H)+.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 9
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-Benzoic acid, R2 is
4-
[(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and
W is
Methylene
0
O O \ /~
0
HO O / \ >-NH
/ \ O
[0204] To a solution of prop-2-enyl 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-
oxochromen-7-yloxy)methyl]benzoate (88.8 mg, 0.176 mmol), tetrakis(triphenyl-
phosphine)palladium(0) (10 mg, 0.009 mmol) in dry tetrahydrofuran 2 ml) was
added
morpholine (77 mg, 0.88 mmol), and the mixture was stirred at room temperature
under
argon for 2 hours. Solvent was then removed reduced pressure, and the residue
dissolved in acetone, mixed with silica gel, the solvent removed under reduced
pressure, and the silica gel eluted with methylene chloride/methanol (95/5)
containing
1% acetic acid, to provide 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-
oxochromen-7-
yloxy)methyl]benzoic acid; 1H NMR (400 MHz, DMSO-d6) & 13.1 (br s, 1H), 9.84
(s,
1H), 8.47 (s, 1H), 8.08-8.06 (m, 2H), 7.94 (d, 1H, J= 7.8 Hz), 7.76 (d, 1H, J=
7.7 Hz),
7.58-7.45 (m, 3H), 7.30 (d, 1H, J= 1.8 Hz), 7.27 (d, 2H, J= 8.5 Hz), 7.20 (dd,
1H, J=
1.8 Hz, J= 8.9 Hz), 5.38 (s, 2H), 3.03 (s, 3H). (ESI) m/z 466 (M + H)+.
B. Alternate preparation of a Compound of Formula I in which R1 is 3-Benzoic
acid, R2 is 4-f(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -CH-, V
is
Oxygen, and W is Methylene
[0205] In a 3 L 3-neck round bottomed flask tert-butyl 3-((3-(4-
(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yloxy)methyl)benzoate (157.88 g,
302.70 mmol,) was suspended in HCO2H (1026 mL, 6.5 mL/g, Aldrich). The mixture
was heated at 50 C (internal temperature) for 1 h using a heating mantle. An
HPLC
81
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
analysis showed the desired product and the starting material, 98.61% and
1.39%
respectively. The internal temperature was increased to 80 C taking for
approximately
30 min. After heating at 80 C for 2 hours an HPLC analysis showed the desired
product and the starting material, 99.82% and 0.18% respectively. The heating
mantle
was turned off and the suspension was allowed to cool down to ambient
temperature
and stirred for 8 hours (the desired product, 99.86% and the starting
material, 0.14%).
[0206] After stirring for 8 hours to the reaction mixture was added H2O (1104
mL,
distilled at CVT) at the room temperature (22 C). The mixture was divided into
two
portions (into 3 L 3-necked flask x2). To the each flask was added H2O (1500
mL).
Total amount of water added was 4104 mL at this point. The suspensions were
stirred
at least for 1 hour under ice-water bath cooling. The suspensions were
filtered through
a 2 L filtration funnel (medium). The residue was washed with H2O (total
1000mL) on
the filter. Obtained residue was put into a 4 L Erlen-Myer Flask and suspended
in H2O
(3000 mL). The mixture was stirred for 20 min and filtered through the 2 L
filtration
funnel (medium). The residue was washed with H2O (500mL) on the filter.
Suspending in H2O (3000 mL) in a 4 L flask and filtration was repeated once
again.
Obtained wet material was 197.06 g (very light brown wet powder). This was
placed in
two drying dishes and dried under high-vacuum at 60 C for 18 hours to to
provide 3-
[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic
acid.
C. Recrystallization of a Compound of Formula I in which R1 is 3-Benzoic acid,
R2
is 4-[(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen,
and
W is Meth.. ly ene
[0207] 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzoic acid from Example 9B was recrystallized from DMF (554 mL,
4
mL/g)-MeOH (4424 mL, 32 mL/g) as follows. The crude product was divided into
two
portions (69.25 g each, into 3 L 3-necked flask x2). To the each flask was
added DMF
(277 mL, Aldrich) to dissolve the crude product (light brown solution) at
ambient
temperature (22 C). To the each solution was added MeOH (2216 mL) over 10 min.
An addition of MeOH makes the solutions suspensions (creamy colored). After
stirring for 1 h the both suspensions were filtered through a 2 L glass filter
(medium).
The residue on the filter was washed with MeOH (total 1108 mL). The residue on
the
82
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
filter (very very light orange wet powder, 465.79 g) was transferred to drying
dishes
and dried under high-vacuum at 60 C for 12 h to remove MeOH. After drying for
12 h
a very light yellow powder (130.56 g, contaminated with DMF 12-14%) was
obtained.
This contaminated product was again dried under high-vacuum at 175 C for 20 h
to
remove DMF completely. The end product was obtained as a very light yellow
powder
without any DMF contamination.
D. Preparation of a Compound of Formula I in which R1 is 3-Benzoic acid, R3 is
Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is Methylene varying R2
[0208] Similarly, replacing prop-2-enyl3-[(3-{4-[(methylsulfonyl)amino]phenyl}-
4-
oxochromen-7-yloxy)methyl]benzoate with other compounds of Formula I in which
R1
is prop-2-enylbenzoate, and following the procedure of 9A or 9B above, the
following
compounds of Formula I in which R1 is benzoic acid were prepared:
[0209] 3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid; 1H
NMR (400 MHz, DMSO-d6) & 13.1 (br s, 1H), 9.59 (br s, 1H), 8.38 (s, 1H), 8.08
(s,
1H), 8.05 (d, 1H, J= 9.0 Hz), 7.94 (d, 1H, J= 7.8 Hz), 7.75 (d, 1H, J= 7.7
Hz), 7.56
(dd, 1H, J= 7.5 Hz, J= 7.8 Hz), 7.40 (d, 2H, J= 8.7 Hz), 7.29 (d, 1H, J= 1.9
Hz), 7.18
(dd, 1H, J= 1.9 Hz, J= 9.0 Hz), 6.82 (d, 2H, J= 8.7 Hz), 5.37 (s, 2H). (ESI)
m/z 389
(M + H)+.
[0210] 3-(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}-1,2,4-oxadiazol-
5-
yl)benzoic acid; 1H NMR (400 MHz, DMSO-d6) & 13.5 (s, 1H), 9.54 (br s, 1H),
8.62
(s, 1H), 8.40 (s, 1H), 8.36 (d, 1H, J= 7.7 Hz), 8.25 (d, 1H, J= 7.8 Hz), 8.08
(d, 1H, J=
8.9 Hz), 7.79 (dd, 1H, J= 7.8 Hz, J= 7.8 Hz), 7.42- 7.40 (m, 3H), 7.23 (dd,
1H, J= 1.6
Hz, J= 9.0 Hz), 6.82 (d, 2H, J= 8.4 Hz), 5.59 (s, 2H). (ESI) m/z 457 (M + H)+.
[0211] 3-{[3-(4-aminophenyl)-4-oxochromen-7-yloxy]methyl}benzoic acid; (ESI)
m/z
388 (M + H)+.
83
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 10
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-((2-
morpholinoethoxy)carbonyl)benzyl, R2 is 4-[(Methylsulfonyl)amino, R3 is
Hydrogen,
X, Y and Z are -CH-, V is Oxygen, and W is Methylene
N
0 o I ~
~I0
N_ J
0 0 \V/
[0212] In a 100 mL round bottomed flask 3-[(3-{4-
[(methylsulfonyl)amino]phenyl}-4-
oxochromen-7-yloxy)methyl]benzoic acid (315.0 mg, 0.677 mmol) was treated with
triethylamine (137.0 mg, 1.354 mmol, 2.0 equiv) and 2,4,6-trichlorobenzoyl
chloride
(198.2 mg, 0.812 mmol, 1.2 equiv) in THE (6 mL) under a nitrogen atmosphere.
The
mixture was stirred at room temperature for 1 hour. To the mixture were added
a
solution of 4-hydroxyethyl)morpholine (133.2 mg, 1.016 mmol, 1.5 equiv) in THE
(3
mL) and dimethylaminopyridine (82.7 mg, 0.677 mmol, 1.0 equiv). Again, the
mixture
was stirred at room temperature for 1 hour. To the mixture were added H2O (50
mL)
and the whole was extracted with EtOAc (50 mL x 3). The combined organic
layers
were washed with brine (50 mL) and dried with Na2SO4. The solvent was removed
under a reduced pressure to give a crude mixture. The crude mixture was
purified by a
column-chromatography (Si02 = 80 g, 2.5%MeOH/CH2C12 to 5%MeOH/CH2C12) to
give 2-morpholinoethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-
yloxy)methyl)benzoate as a colorless solid.
84
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
B. Preparation of a Compound of Formula I in which R2 is 4-
f (Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and
W is
Methylene varying
[0213] Similarly, replacing 4-hydroxyethyl)morpholine with 1-(2-hydroxyethyl)-
4-
methylpiperazine and following the procedure of 1OA above, 2-(4-
methylpiperazine)ethyl 3-((3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-
yloxy)methyl)benzoate was prepared.
C. Preparation of a Compound of Formula I in which R2 is 4-
f(Methylsulfonyl)amino, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and
W is
Methylene varying R1
[0214] Similarly, replacing 4-hydroxyethyl)morpholine with other compounds of
the
formula R20OH and following the procedure of 1OA above, other compounds of
Formula I are prepared.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 11
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-Methylbenzoate, R2
is
4-[(Methylamino)carbonylamino, R3 is Hydrogen, X, Y and Z are -CH-, V is
Oxygen,
and W is Methylene
o
O O ~NH
O \ \ / NH
[0215] A suspension of methyl 3-{[3-(4-aminophenyl)-4-oxochromen-7-
yloxy]methyl}benzoate (100 mg, 0.25 mmol) and methyl isocyanate (57 mg) in
tetrahydrofuran (1 ml) was placed in a sealed tube, and the mixture stirred at
room
temperature for 3 days. The reaction mixture was slurried with methylene
chloride, and
solvent removed under reduced pressure, to provide crude methyl 3-[(3-{4-
[(methylamino)carbonylamino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoate. The
solid was dissolved in a mixture of methanol/methylene chloride, mixed with
silica gel,
solvent removed, and the silica gel eluted with methanol/methylene chloride
(3/97) to
provide 90 mg of pure product. (ESI) m/z 459 (M + H)+.
B. Preparation of a Compound of Formula I in which R1 is 3-Methylbenzoaate, R2
is 4-acetylamino, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is
Methylene
[0216] Similarly, replacing methyl isocyanate by acetyl chloride, and
following the
procedure of 11A above, methyl 3-({3-[4-(acetylamino)phenyl]-4-oxochromen-7-
yloxy}methyl)benzoate was prepared.
86
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 12
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 2-[4-(4-
methoxyphenyl)piperazinyl], R2 is 4-Hydroxy, R3 is Hydrogen, X, Y and Z are -
CH-, V
is Oxygen, and W is Ethylene
Nz~
Me0 / O OH
Step 1
[0217] 1-(4-methoxyphenyl)piperazine was dissolved in N,N-dimethylformamide,
and
potassium carbonate and 1-bromo-2-chloroethane were added. The resulting
mixture
was stirred at room temperature overnight, the solid material filtered off,
and the
solvent removed from the filtrate under reduced pressure. The residue was
purified by
biotage chromatography eluting with 3:7 ethyl acetate:hexanes, to provide 1-[4-
(2-
chloroethyl)piperazinyl]-4-methoxybenzene.
Step 2
[0218] To a solution of 1-[4-(2-chloroethyl)piperazinyl]-4-methoxybenzene
(0.929
mmol) and 4,7-dihydroxyisoflavone (0,929 mmol) in acetone (10 ml)was added 11%
potassium hydroxide (0.5 ml), and the mixture stirred at reflux temperature
for 48
hours. Sufficient methanol was added to precipitate unreacted starting
material, which
was filtered off, and solvent was removed from the filtrate under reduced
pressure. The
residue was purified by biotage column chromatography, eluting with 5%
methanol/methylene chloride, to provide pure 3-(4-hydroxyphenyl)-7- {2-[4-(4-
methoxyphenyl)piperazinyl] ethoxy} chromen-4-one.
87
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
B.
[0219] Similarly, the following piperazinyl derivatives were prepared:
7- {2-[4-(4-fluorophenyl)piperazinyl]ethoxy}-3-(4-hydroxyphenyl)chromen-4-
one;
3-(4-hydroxyphenyl)-7-(2-piperazinylethoxy)chromen-4-one;
N-(3 -fluorophenyl)(4- {2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy] ethyl} -
piperazinyl)carboxamide;
7-[2-(4- { [(3-fluorophenyl)amino]thioxomethyl}piperazinyl)ethoxy]-3 -(4-
hydroxyphenyl)chromen-4-one;
N-(2,4-difluorophenyl)(4- {2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]ethyl} piperazinyl)carboxamide;
EXAMPLE 13
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 2-[3-fluoro-5-
(trifluoromethyl)phenyl]-1,3-oxazolel, R2 is 4-Hydroy, R3 is Hydrogen, X, Y
and Z
are -CH-, V is Oxygen, and W is Ethylene
OH
O
F
0- U \
O
F3C
Step 1
[0220] In a 50 mL round bottomed flask was placed diethyl malonate (3.72 g,
23.25
mmol, 5 equiv.) and N,N-dimethylformamide (10 mL). To the solution was added
sodium hydride (60% suspension in mineral oil, 744.0 mg, 18.6 mmol, 4.0
equiv.) at
room temperature portionwise over 10 minutes. After stirring for 30 minutes a
solution
of 4-(chloromethyl)-2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazole (1.30
g, 4.65
mmol) in N,N-dimethylformamide (10 mL) was added at 0 C over 15 minutes, and
the
reaction mixture allowed to warm up to ambient temperature. To the mixture was
added sodium iodide (697.0 mg, 4.65 mmol, 1 equiv) at room temperature. The
reaction mixture was stirred at the same temperature for 2 hours. Water was
then added
88
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
to the reaction mixture (30 mL) and the whole was extracted with ethyl acetate
(30 mL
x 3). The organic layers were combined, washed with brine (30 mL) and dried
with
sodium sulfate. After removal of the solvent under reduced pressure the crude
mixture
was purified by a silica-gel column chromatography (SiO2 = 80 g, hexane:EtOAc
=
7:1) repeatedly. The desired product, diethyl 2-({2-[5-fluoro-3-
(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}methyl)propane-1,3-dioate, was
obtained as
colorless powder (1.75 g).
Step 2
[0221] The product of Step 1 was used without further purification. The
product
(606.7 mg, 1.50 mmol) was placed in a 50 mL round bottomed flask, and lithium
chloride (127.6 mmol, 3.01 mmol, 2 equiv.), dimethylsulfoxide (5 mL) and water
(0.5
mL) added, and the mixture heated at 190-195 C for 3 hours. To the reaction
mixture
was added water (30 mL) and the whole was extracted with ethyl acetate (30 mL
x 3).
The combined organic layers were washed with brine (30 mL) and dried over
sodium
sulfate. After removal of the solvent under reduced pressure the crude mixture
was
purified by a silica-gel column chromatography (SiO2 = 80 g, hexane:EtOAc =
3:1).
The desired product, ethyl 3-{2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-
oxazol-4-
yl}propanoate, was obtained as light yellow oil (345.5 mg).
Step 3
[0222] The product of Step 2 (330.0 mg, 0.996 mmol) was placed in a 250 mL
round
bottomed flask and dissolved in tetrahydrofuran (3 mL). The solution was
treated with
lithium aluminum hydride at 0 C under nitrogen atmosphere. After stirring for
30
minutes, Celite (3 g) was added to the reaction mixture, followed by methanol
(5 mL)
and water (3 mL) successively. The resulting suspension was filtered through a
glass
filter, and the residue on the filter washed with ethyl acetate (50 mL). The
solvent was
removed under reduced pressure to give a colorless oil (298.3 mg). The crude
mixture
was purified by a silica-gel column chromatography (SiO2 = 80 g, hexane:EtOAc
=
7:1) to give 3-{2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}propan-
l-ol as a
colorless oil (255.3 mg, 0.883 mmol, 89%).
89
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 4
[0223] To 3-{2-[5-fluoro-3-(trifluoromethyl)phenyl]-1,3-oxazol-4-yl}propan-l-
ol (250.
3 mg, 0.865 mmol) was added a mixture of triphenyl phosphate (295.4 mg, 0.952
mmol, 1.1 equiv.) and methyl iodide (184.2 mg, 1.298 mmol, 1.5 equiv.). The
mixture
was heated at 130 C, while adding a further amount of methyl iodide (184.2 mg,
1.298
mmol, 1.5 equiv.). The reaction mixture was heated for a total of 2 hours, and
then
purified by column-chromatography (SiO2 = 25 g, hexane/EtOAc = 7:1) followed
by
preparative TLC (SiO2 = 6 plates, hexane/EtOAc = 15:1) to give 2-[5-fluoro-3-
(trifluoromethyl)phenyl]-4-(3-iodopropyl)-1,3-oxazole (116.1 mg, 0.291 mmol,
34%)
as a colorless oil.
Step 5
[0224] 4',7-Dihydroxyisoflavone (31.3 mg, 0.123 mmol), 2-[5-fluoro-3-
(trifluoromethyl)phenyl]-4-(3-iodopropyl)-1,3-oxazole (48.9 mg, 0.123 mmol,
1.0
equiv.) and cesium carbonate (40.0 mg, 0.123 mmol, 1.0 equiv) were placed in a
25 mL
flask. To the flask was added dimethylsulfoxide (3 mL) at room temperature to
dissolve the starting materials, and the reaction mixture stirred room
temperature for 15
hours. To the mixture were added water (30 mL) and the whole was extracted
with
ethyl acetate (30 mL x 3). The combined organic layers were washed with brine
(30
mL) and dried with sodium sulfate to give a crude mixture as colorless oil
(64.2 mg).
The crude mixture was purified by column-chromatography (SiO2 = 80 g,
hexane/EtOAc = 2:1 to 1:1) to give 7-(2-{2-[3-fluoro-5-
(trifluoromethyl)phenyl](1,3-
oxazol-5-yl)}ethoxy)-3-(4-hydroxyphenyl)chromen-4-one (49.1 mg, 0.0934 mmol,
76%) as colorless crystals.
Similarly prepared was 7-(3-{2-[3-fluoro-5-(trifluoromethyl)phenyl](1,3-oxazol-
4-
yl)}propoxy)-3-(4-hydroxyphenyl)chromen-4-one.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 14
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 4-Fluorophenyl, R2 is
4-Hydroxy, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is -
C(O)CH9_
OH
F O
O O
O
[0225] Dihydroxyisoflavone (0.2 g, 0.78 mmol) was suspended in acetone (10
ml), and
to this suspension was added 2-bromo-1-(4-fluorophenyl)ethan-1-one (0.16 g,
0.75
mmol) and 11% potassium hydroxide (0.78 mmol). The mixture was refluxed for 24
hours, and the solvent removed under reduced pressure. The residue was treated
with
water, sonicated, filtered, and air-dried. The solid was triturated with
methanol,
filtered, to afford 7-[2-(4-fluorophenyl)-2-oxoethoxy]-3-(4-
hydroxyphenyl)chromen-4-
one. If desired, the product may be further purified by preparative thin layer
chromatography, eluting with dichloromethane/methanol 15/1.
B.
[0226] Similarly, following the procedures of Example 14A above, replacing 2-
bromo-
1-(4-fluorophenyl)ethan-1-one with other haloacetophone derivatives, the
following
compounds were prepared:
7-[2-(3-fluorophenyl)-2-oxoethoxy]-3-(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7- {2-oxo-2-[2-(trifluoromethyl)phenyl] ethoxy} chromen-
4-one;
3 -(4-hydroxyphenyl)-7- {2-oxo-2-[2-(trifluoromethyl)phenyl] ethoxy} chromen-
4-one.
91
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 15
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-
Trifluoromethyllphenyl, R2 is 4-Hydroy, R3 is Hydrogen, X, Y and Z are -CH-, V
is
Oxygen, and W is
-NHC(O)CH2_
OH
O
H
F3C N\ I{ `O O
OI
[0227] Dihydroxyisoflavone (0.2 g, 0.78 mmol) was suspended in acetone (10
ml), and
to this suspension was added 2-chloro-N-[3-(trifluoromethyl)phenyl]acetamide
(0.18 g,
0.78 mmol) and 11% potassium hydroxide (0.78 mmol). The mixture was refluxed
for
24 hours, and the solvent removed under reduced pressure. The residue was
treated
with water, sonicated, filtered, and air-dried. The solid was triturated with
methanol,
filtered, to afford 2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[3-
(trifluoromethyl)phenyl]acetamide. If desired, the product may be further
purified by
preparative thin layer chromatography, eluting with dichloromethane/methanol
15/1.
B.
[0228] Similarly, following the procedures of Example 15A above, replacing 2-
chloro-
N-[3-(trifluoromethyl)phenyl]acetamide with other haloacetaamide derivatives,
the
following compounds were prepared:
N-[(1 S)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
yloxy]acetamide;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]-N-[2-(trifluoromethyl)-
phenyl]acetamide;
N-(3-fluorophenyl)-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]acetamide;
N-[(1R)-1-(4-fluorophenyl)ethyl]-2-[3-(4-hydroxyphenyl)-4-oxochromen-7-
ylox ]acetamide.
92
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 16
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is 3-
Trifluoromethyllphenyl, R2 is 4-Hydroy, R3 is Hydrogen, X, Y and Z are -CH-, V
is
Oxygen, and W is
-CH2NHCH2CH(OH)CH2_
OH
O
H O O
H
OH
Step 1
[0229] A mixture of 7-hydroxy-3-(4-methoxyphenyl)chromen-4-one (0.86 g, 3.21
mmol), epichlorohydrin (1.25 ml, 16 mmol) and potassium carbonate (0.89 g,
6.42
mmol) in dimethylformamide (20 ml) was stirred at 80 C for 3 hours. After
removing
solvent under reduced pressure, water was added to the residue, and the
precipitate
filtered off and washed with water. The crude product was purified by
chromatography
on silica gel, eluting with ethyl acetate/hexanes (1:4 to 2:3), to afford 3-(4-
methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one.
Step 2
[0230] 3-(4-Methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one (0.24 g, 0.74
mmol), 3-(trifluoromethyl)benzylamine (0.11 ml, 0.74 mmol) and
diisopropylethylamine (0.26 g, 1.47 mmol) was stirred in ethanol (15 ml) at 78
C
overnight. The solvent was removed under reduced pressure, and the residue
chromatographed on silica gel, eluting with 5% methanol/dichloromethane,
followed
by recrystallization from ethyl acetate/hexane to provide 7-[2-hydroxy-3-({[3-
(trifluoromethyl)phenyl]methyl} amino)propoxy]-3-(4-methoxyphenyl)chromen-4-
one.
93
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 3
[0231] To a stirred suspension of 7-[2-hydroxy-3-({[3-
(trifluoromethyl)phenyl]methyl} -amino)propoxy]-3 -(4-methoxyphenyl)chromen-4-
one
(38 mg, 0.076mmol) in methylene chloride at C was added boron tribromide (1M,
0.38 ml). The resulting mixture was stirred at room temperature for 4 hours,
then the
solvent removed under reduced pressure. The residue was purified by
preparative thin
layer chromatography, eluting with 10% methanol/dichloromethane, to provide 3-
(4-
hydroxyphenyl)-7-[2-hydroxy-3-({ [3-
(trifluoromethyl)phenyl]methyl} amino)propoxy]chromen-4-one.
B.
[0232] Similarly, following the procedures of Example 16A above, but
substituting 3-
(trifluoromethyl)benzylamine by 3, 5-difluorobenzylamine, the following
compound
was prepared:
7-(3-j[(3,5 -difluorophenyl)methyl] amino} -2-hydroxypropoxy)-3 -(4-
hydroxyphenyl)chromen-4-one; and
7-(2- { [(4-fluorophenyl)ethyl] amino} ethoxy)-3 -(4-hydroxyphenyl)chromen-4-
one.
94
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 17
Preparation of a Compound of Formula I
A. Preparation of a Compound of Formula I in which R1 is Phenyl, R2 is 4-
Hydroxy, R3 is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is -
CH2CH(OH)CH2-
OH
O
~OH O
Step 1
[0233] To a solution of cuprous iodide (0.14 g, 0.74 mmol) in tetrahydrofuran
(2 ml)
was added phenylmagnesium bromide in tetrahydrofuran (1M, 2.22 ml, 2.22 mmol)
dropwise at -40 C. After 5 minutes 3-(4-methoxyphenyl)-7-(oxiran-2-
ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol) in tetrahydrofuran (4 ml) was
added
slowly, and stirred at -40 C for 1 hour. The mixture was quenched with
saturated
ammonium chloride and water, extracted with ethyl acetate, the organic layer
washed
with brine, dried over sodium sulfate, and the solvent removed under reduced
pressure.
The residue was purified by preparative thin layer chromatography, eluting
with 10%
methanol/methylene chloride, followed by ethyl acetate/hexane 2/3, to provide
7-(2-
hydroxy-3-phenylpropoxy)-3-(4-methoxyphenyl)chromen-4-one.
Step 2
[0234] The product of step 1 was then reacted with boron tribromide as shown
in
Example 16, step 3, to provide 3-(4-hydroxyphenyl)-7-(2-hydroxy-3-
phenylpropoxy)chromen-4-one.
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 18
Preparation of a Compound of Formula I
A. Preparation of the R Enantiomer of a Compound of Formula I in which R1 is3-
[5-Fluoro-3-(trifluoromethyl)phen 1,2,4-oxadiazol-5-yl), R2 is 4-HydroM, R3 is
Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is -CH(CH3
F
F3C / \
N
N I
O
OH
Step 1
[0235] A solution of [5-fluoro-3-(trifluoromethyl)-
phenyl](hydroxyimino)methylamine
(28.04g, 126.24 mmol), prepared as shown in Example 1, was dissolved in
tetrahydrofuran (40 ml) and cooled to -78 C. A solution of (1S)-1-
(chlorocarbonyl)ethyl acetate (20 g, 128.82 mmol) in tetrahydrofuran (20 ml)
was
added dropwise under an atmosphere of dry nitrogen, and stirred fo 10 minutes
after the
addition was complete. A solution of diisopropylethylamine (27.0 ml, 155 mmol)
was
then added dropwise, and the reaction mixture allowed to warm to room
temperature.
The mixture was stirred for two hours, then the solvent removed under reduced
pressure. The residue was poured into ethyl acetate (150 ml), washed with
water (2 x
50 ml), brine (2 x 50 ml), and dried over sodium sulfate. Solvent was removed
under
reduced pressure, to provide 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]-1-
azavinyl (2S)-2-acetyloxypropanoate as a pale yellow oil (39.04 g, MS mz 337.1
(M+H), which was used in the next reaction with no further purification.
96
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 2
[0236] To a solution of 2-amino-2-[3-fluoro-5-(trifluoromethyl)phenyl]-1-
azavinyl
(2S)-2-acetyloxypropanoate (5.19g, 15.43 mmol) in anhydrous tetrahydrofuran
(20 ml)
at 0 C was added a solution of 1M tetrabutylammonium fluoride in
tetrahydrofuran (3
ml) dropwise under nitrogen. The reaction mixture was stirred for 3 hours at 0
C, then
poured into ethyl acetate (50 ml), washed with water (2 x 20 ml), brine (30
ml) and
dried over sodium sulfate. Solvent was removed under reduced pressure, and the
residue purified by flash chromatography, eluting with methylene chloride, to
provide
(1S)-1-{3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-oxadiazol-5-yl)}ethyl
acetate,
LCMS 319.1.
Step 3
[0237] To a solution of (1S)-1-{3-[5-fluoro-3-(trifluoromethyl)phenyl](1,2,4-
oxadiazol-5-yl)}ethyl acetate (900 mg, 2.83 mmol) in methanol (4 ml) at -15 C
was
added an aqueous solution of potassium carbonate (10M, 10 ml). The mixture was
stirred for 20 minutes, and the mixture allowed to warm to room temperature,
stirring
for 1 hour. The mixture was extracted with ethyl acetate (3 x 20 ml), and the
combined
organic phase washed with water (10 ml), brine (2 x 20 ml). Removal of the
solvent
under reduced pressure provided (1 S)-1- {3-[5-fluoro-3-
(trifluoromethyl)phenyl](1,2,4-
oxadiazol-5-yl)}ethan-1-ol, which was crystallized from hexane to yield a
white solid,
LCMS 277.2.
Step 4
[0238] To a solution of triphenylphosphine (262 mg, 1 mmol) in anhydrous
tetrahydrofuran (15 ml) at -78 C was added dropwise 40%
diethylazodicarboxylate
(0.45 ml, 1 mmol) in toluene, and the mixture stirred for 30 minutes at -78 C.
A
solution of dihydroxyisoflavone (300 mg, 1.14 mmol) in a mixture of
tetrahydrofuran
(8 ml) and N,N-dimethylformamide (3 ml) was added slowly, and the mixture
stirred
for 10 minutes. A solution of (1S)-1-{3-[5-fluoro-3-
(trifluoromethyl)phenyl](1,2,4-
oxadiazol-5-yl)}ethan-l-ol (277 mg, 1 mmol) in tetrahydrofuran (8 ml) was
added
97
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
dropwise, the mixture stirred at -78 C for 3 hours, and then allowed to warm
to room
temperature, stirring for 36 hours.
[0239] The reaction mixture was poured into ethyl acetate (40 ml), washed with
water
(10 ml), brine (2 x 10 ml), dried over sodium sulfate, and the solvent removed
under
reduced pressure. A mixture of dichloromethane/tetrahydrofuran (4 ml/1 ml) was
added to the yellow residue, and the soluble portion was flash chromatographed
over
silica gel, eluting with ethyl acetate (0-30%)/hexane, to give a white solid,
which was
further purified by preparative thin layer chromatography, eluting with
acetonitrile (2.5
97.5%/water, to provide 7-((1R)-1-{ 3-[5-fluoro-3-
(trifluoromethyl)phenyl](1,2,4-
oxadiazol-5-yl)} ethoxy)-3-(4-hydroxyphenyl)chromen-4-one; 245 mg, 0.48 mmol,
48%). MS mz 513.1 (M+H), anal HPLC > 99%, Chiralcel OJ-RH hplc 99.2% e.e.
(mass detector), and 99.0% e.e. (UV detector) in acetonitrile/water.
1H NMR (400 MHz; CDC13) 68.25 (d, 1 H, J = 9.0 Hz); 8.18 (s, 1H); 7.99 (m, 1
H);
7.91 (s, 1H); 7.49 (m, 1H); 7.42 (d, 2 H, J = 8.6 Hz); 7.09 (dd, 1H, J = 9.0,
2.3 Hz);
6.97 (d, 1H, J = 2.3 Hz); 6.88 (d, 2H, J = 9.0 Hz); 5.59 (t, 1 H, J = 6.6 Hz);
1.96 (d, 1H,
J = 6.6 Hz).
EXAMPLE 19
Preparation of a Prodrug of a Compound of Formula I
A. Preparation of the Phosphate of a Compound of Formula I in which R1 is 5-
Fluoro-3-(trifluoromethyl)phenyl](1,2-oxazol-5-yl), R2 is 4-Hydroxy, R3 is
Hydrogen,
X, Y and Z are -CH-, V is Oxygen, and W is CHz_
F
FsC / \
q ~N 11
O O/ I\OH
OH
98
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 1
[0240] To a solution of 7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-
4-
yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4-one (1 g, 2.01 mmol) in
tetrahydrofuran
(50mL) was added 1-H-tetrazole (3% wt in acetonitrile, 65 ml, 22.1 mmol),
followed
by di-tert-butyl N,N-diethylphosphoramidite (2.57 ml, 4.6 mmol). After
stirring at
room temperature for 2 hours, the reaction mixture was diluted with methylene
chloride
and washed with saturated sodium bicarbonate. The organic layer was separated,
and
the aqueous layer extracted twice more with methylene chloride. The combined
extracts were dried over sodium sulfate, and solvent removed under reduced
pressure.
The residue was purified by biotage column chromatography, eluting with ethyl
acetate/hexane mixture (1:4) to afford 3-{4-[bis(tert-
butoxy)phosphinooxy]phenyl}-7-
({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3 -oxazol-4-yl)} methoxy)chromen-4-
one.
Step 2
[0241] To a solution of the product of step 1, 3- {4-[bis(tert-
butoxy)phosphinooxy]phenyl} -7-({2-[5-fluoro-3 -(trifluoromethyl)phenyl] (1,3-
oxazol-
4-yl)} methoxy)chromen-4-one, in a mixture of tetrahydrofuran (20 mL) and
acetonitrile (10 mL) was added 6 mL of tert-butyl hydroperoxide in decane (5M-
6M).
The reaction mixture was stirred at room temperature for 1 hour, chilled in an
ice bath,
and 50mL of 5% sodium bisulfite was added. The resulting mixture was stirred
for 15
minutes, after which the ice bath was removed. The mixture was extracted with
methylene chloride, the organic extract dried over sodium sulfate, and solvent
removed
under reduced pressure. The residue was purified by biotage column
chromatography,
eluting with 1:1 ethyl Acetate/hexanes mixture, to afford ditert-butyl 4-[7-
({2-[5-
fluoro-3-(trifluoromethyl)phenyl] (1,3-oxazol-4-yl)} methoxy)-4-oxochromen-3 -
yl]phenyl phosphate.
Step 3
[0242] To a solution of 3-{4-[bis(tert-butoxy)phosphinooxy]phenyl}-7-({2-[5-
fluoro-3-
(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)chromen-4-one prepared in
Step 2
in methylene chloride (60m1) was added trifluoroacetic acid (0.15 ml, 1.99
mmol). The
reaction mixture was stirred at room temperature overnight, the solid filtered
off, and
99
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
washed with methylene chloride, to afford 100% pure (by HPLC) 4-[7-({2-[5-
fluoro-3-
(trifluoromethyl)phenyl] (1,3 -oxazol-4-yl)} methoxy)-4-oxochromen-3 -
yl]phenyl
dihydrogen phosphate.
EXAMPLE 20
Preparation of a Prodrug of a Compound of Formula I
A. Preparation of the Methyldihydrogenphosphate of a Compound of Formula I in
which R1 is 5-Fluoro-3-(trifluoromethyl)phen 1,2-oxazol-5-yl), R2 is 4-
Hydroxy, R3
is Hydrogen, X, Y and Z are -CH-, V is Oxygen, and W is CH,_
F
FsC / \
Q\/~N
v V
~ I I \
O / O ^ 11
P OH
OH
Step 1 - Preparation of di-t-butyl chloromethyl phosphate
[0243] A 100 mL round bottomed flask was charged with potassium ditert-butyl
phosphate (1.0 g, 4.03 mmol), sodium bicarbonate (677.4 mg, 8.06 mmol), n-
butylammonium sulfate (68.2 mg, 0.403 mmol), water (10 ml) and methylene
chloride
(5 ml). To the mixture was added a solution of chloromethylchlorosulfonate
(797.9
mg, 4.84 mmol) in methylene chloride (5 ml), and the mixture stirred at room
temperature for 2 hours. To the reaction product was added water (30 ml), and
the
whole was extracted with methylene chloride (30 ml x 3). The combined organic
layers were washed with brine (30 ml), dried with Na2SO4, and solvent removed
under
reduced pressure. The residue was purified by column-chromatography (silica
gel = 80
g, hexane/ethyl acetate = 1:1) to give di-t-butyl chloromethyl phosphate, as a
colorless
oil.
100
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Step 2 - Preparation of di-tert-butl(4-(7-((2-(3-fluoro-5-
(trifluoromethyl)phenyl)oxazol-4-yl)methoxy)-4-oxo-4H-chromen-3-
yl)phenoxy)methyl phosphate
[0244] In a 50 mL round bottomed flask 7-({2-[5-fluoro-3-
(trifluoromethyl)phenyl](1,3 -oxazol-4-yl)}methoxy)-3-(4-hydroxyphenyl)chromen-
4-
one (150.0 mg, 0.302 mmol) was treated with di-tert-butyl chloromethyl
phosphate
(156.2 mg, 0.604 mmol, 1.0 equiv) in the presence of potassium t-butoxide
(67.8 mg,
0.604 mmol, 1.0 equiv) and sodium iodide (89.9 mg, 0.604 mmol, 1.0 equiv) in
N,N-
dimethylformamide (2 ml), and the mixture stirred at room temperature for 15
hours.
To the mixture was added water (30 ml), and the whole was extracted with ethyl
acetate
(30 ml x 3). The combined organic layers were washed with brine (30 ml), dried
with
Na2SO4, and solvent removed under reduced pressure, to give a crude mixture
(345.1
mg). This mixture was purified by column-chromatography (SiO2 = 80 g,
hexane/EtOAc = 1:1) to give di-tert-butyl {4-[7-({2-[5-fluoro-3-
(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-
yl]phenoxy}methyl phosphate as a colorless oil.
Step 3 - Preparation of (4-(7-((2-(3-fluoro-5-(trifluoromethyl)phenyl)oxazol-4-
yl)methoxy)-4-oxo-4H-chromen-3-yl)phenoxy)methyI dihydrogen phosphate
[0245] In a 50 mL round bottomed flask ditert-butyl {4-[7-({2-[5-fluoro-3-
(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-
yl]phenoxy}methyl phosphate (119.1 mg, 0.166 mmol) was treated with
trifluoroacetic
acid (37.9 mg, 0.332 mmol, 2.0 equiv) in methylene chloride (2 ml). The
mixture was
stirred at room temperaturefor 18 hours, methylene chloride(10 ml) added, and
the
suspension thus obtained was filtered through a glass filter. The residue on
the filter
was collected to give {4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-
oxazol-4-
yl)}methoxy)-4-oxochromen-3-yl]phenoxy}methyl dihydrogen phosphate .
101
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 21
[0246] Hard gelatin capsules containing the following ingredients are
prepared:
Quantity
Ingredient (m capsule)
Active Ingredient 30.0
Starch 305.0
Magnesium stearate 5.0
The above ingredients are mixed and filled into hard gelatin capsules.
EXAMPLE 22
[0247] A tablet formula is prepared using the ingredients below:
Quantity
Ingredient (mg/tablet)
Active Ingredient 25.0
Cellulose, microcrystalline 200.0
Colloidal silicon dioxide 10.0
Stearic acid 5.0
The components are blended and compressed to form tablets.
EXAMPLE 23
[0248] A dry powder inhaler formulation is prepared containing the following
components:
Ingredient Weight %
Active Ingredient 5
Lactose 95
The active ingredient is mixed with the lactose and the mixture is added to a
dry
powder inhaling appliance.
102
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 24
[0249] Tablets, each containing 30 mg of active ingredient, are prepared as
follows:
Quantity
Ingredient (mg/tablet)
Active Ingredient 30.0 mg
Starch 45.0 mg
Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone
(as 10% solution in sterile water) 4.0 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg
Talc _ 1.0 mg
Total 120 mg
[0250] The active ingredient, starch and cellulose are passed through a No. 20
mesh
U. S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is
mixed with
the resultant powders, which are then passed through a 16 mesh U.S. sieve. The
granules so produced are dried at 50 C to 60 C and passed through a 16 mesh
U.S.
sieve. The sodium carboxymethyl starch, magnesium stearate, and talc,
previously
passed through a No. 30 mesh U.S. sieve, are then added to the granules which,
after
mixing, are compressed on a tablet machine to yield tablets each weighing 120
mg.
EXAMPLE 25
[0251] Suppositories, each containing 25 mg of active ingredient are made as
follows:
Ingredient Amount
Active Ingredient 25 mg
Saturated fatty acid glycerides to 2,000 mg
[0252] The active ingredient is passed through a No. 60 mesh U.S. sieve and
suspended
in the saturated fatty acid glycerides previously melted using the minimum
heat
necessary. The mixture is then poured into a suppository mold of nominal 2.0 g
capacity and allowed to cool.
103
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 26
[0253] Suspensions, each containing 50 mg of active ingredient per 5.0 mL dose
are
made as follows:
Ingredient Amount
Active Ingredient 50.0 mg
Xanthan gum 4.0 mg
Sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%) 50.0 mg
Sucrose 1.75 g
Sodium benzoate 10.0 mg
Flavor and Color q.v.
Purified water to 5.0 mL
[0254] The active ingredient, sucrose and xanthan gum are blended, passed
through a
No. 10 mesh U. S. sieve, and then mixed with a previously made solution of the
microcrystalline cellulose and sodium carboxymethyl cellulose in water. The
sodium
benzoate, flavor, and color are diluted with some of the water and added with
stirring.
Sufficient water is then added to produce the required volume.
EXAMPLE 27
[0255] A subcutaneous formulation may be prepared as follows:
Ingredient Quantity
Active Ingredient 5.0 mg
Corn Oil 1.0 mL
EXAMPLE 28
[0256] An injectable preparation is prepared having the following composition:
Ingredients Amount
Active ingredient 2.0 mg/ml
Mannitol, USP 50 mg/ml
104
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Gluconic acid, USP q.s. (pH 5-6)
water (distilled, sterile) q.s. to 1.0
ml
Nitrogen Gas, NF q.s.
EXAMPLE 29
[0257] A topical preparation is prepared having the following composition:
Ingredients grams
Active ingredient 0.2-10
Span 60 2.0
Tween 60 2.0
Mineral oil 5.0
Petrolatum 0.10
Methyl paraben 0.15
Propyl paraben 0.05
BHA (butylated hydroxy anisole) 0.01
Water q.s. tolOO
[0258] All of the above ingredients, except water, are combined and heated to
60) C
with stirring. A sufficient quantity of water at 60) C is then added with
vigorous
stirring to emulsify the ingredients, and water then added q.s. 100 g.
EXAMPLE 30
Sustained Release Composition
Weight Preferred
In reg dient Range % Range % Most Preferred
Active ingredient 50-95 70-90 75
Microcrystalline cellulose (filler) 1-35 5-15 10.6
Methacrylic acid copolymer 1-35 5-12.5 10.0
Sodium hydroxide 0.1-1.0 0.2-0.6 0.4
Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0
Magnesium stearate 0.5-5.0 1-3 2.0
105
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0259] The sustained release formulations of this invention are prepared as
follows:
compound and pH-dependent binder and any optional excipients are intimately
mixed(dry-blended). The dry-blended mixture is then granulated in the presence
of an
aqueous solution of a strong base which is sprayed into the blended powder.
The
granulate is dried, screened, mixed with optional lubricants (such as talc or
magnesium
stearate), and compressed into tablets. Preferred aqueous solutions of strong
bases are
solutions of alkali metal hydroxides, such as sodium or potassium hydroxide,
preferably sodium hydroxide, in water (optionally containing up to 25% of
water-miscible solvents such as lower alcohols).
[0260] The resulting tablets may be coated with an optional film-forming
agent, for
identification, taste-masking purposes and to improve ease of swallowing. The
film
forming agent will typically be present in an amount ranging from between 2%
and 4%
of the tablet weight. Suitable film-forming agents are well known to the art
and include
hydroxypropyl. methylcellulose, cationic methacrylate copolymers
(dimethylaminoethyl methacrylate/ methyl-butyl methacrylate copolymers -
Eudragit
E - Rohm. Pharma), and the like. These film-forming agents may optionally
contain
colorants, plasticizers, and other supplemental ingredients.
[0261] The compressed tablets preferably have a hardness sufficient to
withstand 8 Kp
compression. The tablet size will depend primarily upon the amount of compound
in
the tablet. The tablets will include from 300 to 1100 mg of compound free
base.
Preferably, the tablets will include amounts of compound free base ranging
from
400-600 mg, 650-850 mg, and 900-1100 mg.
[0262] In order to influence the dissolution rate, the time during which the
compound
containing powder is wet mixed is controlled. Preferably the total powder mix
time,
i.e. the time during which the powder is exposed to sodium hydroxide solution,
will
range from 1 to 10 minutes and preferably from 2 to 5 minutes. Following
granulation,
the particles are removed from the granulator and placed in a fluid bed dryer
for drying
at about 60 C.
106
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
EXAMPLE 31
MAO and ALDH-2 Assays
[0263] A mitochondrial pellet obtained from 5 g of hamster liver was
resuspended in
mL of 10 mM sodium phosphate buffer (pH 7.4), kept on ice, and sonicated for 3-
15
seconds at 90Wof power with a Branson Sonifier cell disruptor. This suspension
was
centrifuged at 105000g for 70 min in a Beckman L8 ultracentrifuge and the
supernatant, which contained ALDH-2 activity, was used for the ALDH-2 assay.
The
pellet, which contained mainly mitochondrial membrane, was washed 3 times in
30 mL
TKK buffer (10 mM Tris, 10 mM KC1, and 10 mM KPi, pH 7.4). The final pellet,
which contained only MAO but not ALDH-2 activity, was used for MAO assay.
ALDH-2 activity was assayed in 0.1 M NaPPi, pH 9.5, containing 0.15 M KC1, 1.2
mM
NAD+, 0.6 mM formaldehyde, and specified concentrations of daidzin or its
structural
analogues.
[0264] Activity was determined by following the increase in absorbance at 340
nm
with a Varian Cary 1 spectrophotometer at 25 C.23 MAO activity was assayed in
TKK
buffer containing 10 iM 5-HT, 0.4 mM sodium bisulfate, specified
concentrations of
daidzin or its structural analogues, and MAO. Enzyme reaction was initiated by
the
addition of enzyme and was allowed to proceed at 37 C for 30 min. The
reaction was
terminated by centrifugation at 4 C in a Sorvall Microspin at top speed for
15 min.
The reaction product 5-HIAL, present in the supernatant as its stable
bisulfate complex,
was liberated by diluting the supernatant 10-100-fold in 50 mM NaPPi, pH 8.8
and
analyzed by HPLC. Since 5-HIAL is relatively unstable at alkaline pH, 5-HIAL
was
liberated not more than 4 h before HPLC analysis. The overall recovery of 5-
HIAL and
5-HIAA in assay samples spiked with standard analytes were 0.78 and 0.86, and
the
intra-assay coefficient of variation of the analytical methods determined with
samples
spiked with 2 micromolar of the respective analytes are 11.2% and 7.5%. Effect
of
daidzin and its analogues on ALDH-2 and MAO activities is expressed as:
percent (%)
inhibition ) = (Ao-Ae) x 100/Ao, where Ao and Ae are enzyme activities
measured in
the absence and presence of a test compound, respectively.
[0265] Representative data for several compounds of the invention are
presented in
Table 1 below.
107
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
4-[7-({5-[3-fluoro-5- 17%
PT-1. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition
yl)}methoxy)-4-oxochromen-3- at 1 M
yl]benzenecarbonitrile;
7-({3-[5-fluoro-3- 43% No 8%
PT-2. (trifluoromethyl)phenyl](1,2,4-oxadiazol-5- inhibition inhibition
inhibition
yl)}ethoxy)-3-(4-hydroxyphenyl)chromen-4- at 1 M up to 10 M at 10 M
one;
ethyl 3 -[7-({ 5-[3 -fluoro-5 - 22%
PT-3. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition
yl)}methoxy)-4-oxochromen-3-yl]benzoate; at 1 M
3-(4-hydroxyphenyl)-7-({4-methyl-2-[4- 0.20 M
PT-4. (trifluoromethyl)phenyl](1,3-thiazol-5-
1 methox chromen-4-one;
3-(4-{[(4- 0.19%
PT-5. methylphenyl)sulfonyl]amino }phenyl)-7-({4- inhibition
methyl-2-[4-(trifluoromethyl)phenyl](1,3- at 1 M
thiazol-5-yl)}methoxy)chromen-4-one;
methyl 3- 3- 6-methox 3-pyridy1))4- 16%
PT-6. {[ ( y( inhibition
oxochromen-7-yloxy]methyl}benzoate; at 1 M
methyl 3- 3- 4- hydroxymethy1)pheny1]-4- 75%
PT-7. ({ [ ( inhibition
oxochromen-7-yloxy}methyl)benzoate; at 1 M
7-({3-[5-fluoro-3- 57%
PT-8. (trifluoromethyl)phenyl](1,2,4-oxadiazol-5- inhibition
yl)}methoxy)-3-{4- at 1 M
[(methylsulfonyl)amino]phenyl } chromen-4-one;
2-fluoro-5-[7-({5-[5-fluoro-3- 25%
PT-9. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition
yl)}methoxy)-4-oxochromen-3- at 1 M
yl]benzenecarbonitrile;
ethyl 2-(3-f4- 60%
PT-10. [(ethoxycarbonyl)methoxy]phenyl}-4- inhibition
oxochromen-7-yloxy)acetate; at 1 M
7-{[5-(4-fluorophenyl)(1,2,4-oxadiazol-3- 0.02 M No 35%
PT-11. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-({2-[3- 0.003 M No No
PT-12. (trifluoromethyl)phenyl](1,3-oxazol-4- inhibition inhibition
yl)}methoxy)chromen-4-one; up to 10 M at 10 M
7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3- 0.02 M No No
PT-13. oxazol-4-yl)}methoxy)-3-(4- inhibition inhibition
hydroxyphenyl)chromen-4-one; up to 10 M at 10 M
108
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
7-{[2-(3,5-difluorophenyl)(1,3-oxazol-4- 0.06 M No No
PT-14. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
7-{[2-(3,4-difluorophenyl)(1,3-oxazol-4- 0.12 M
PT-15. yl)]methoxy } -3 -(4-hydroxyphenyl)chromen-4-
one;
7-{[2-(4-fluorophenyl)(1,3-oxazol-4- 0.047 M No No
PT-16. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; and up to 10 M at 10 M
7-{[2-(4-chlorophenyl)(1,3-oxazol-4- 0.573 M
PT-17. yl)]methoxy } -3 -(4-hydroxyphenyl)chromen-4-
one.
3-(4-hydroxyphenyl)-7-({2-[3- 0.003 M No No
PT-18. (trifluoromethyl)phenyl](1,3-oxazol-4- inhibition inhibition
yl)}methoxy)chromen-4-one; up to 10 M at 10 M
7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3- 0.02 M No No
PT-19. oxazol-4-yl)}methoxy)-3-(4- inhibition inhibition
hydroxyphenyl)chromen-4-one; up to 10 M at 10 M
7-{[2-(3,5-difluorophenyl)(1,3-oxazol-4- 0.06 M No No
PT-20. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
7-{[2-(3,4-difluorophenyl)(1,3-oxazol-4- 0.12 M
PT-2 1. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4-
one;
7-{[2-(4-fluorophenyl)(1,3-oxazol-4- 0.047 M No No
PT-22. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; and up to 10 M at 10 M
7-{[2-(4-chlorophenyl)(1,3-oxazol-4- 0.573 M
PT-23. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4-
one.
3-(4-hydroxyphenyl)-7-[(5-phenyl(1,2,4- 0.16 M No No
PT-24. inhibition inhibition
oxadiazol-3 -yl))methoxy]chromen-4-one u to 40 M u to 40 M
3-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.004 M No No
PT-25. yloxy]methyl}benzenecarbonitrile; inhibition inhibition
u to 10 M u to 10 M
3-(4-hydroxyphenyl)-7- f [3- 0.034 M
PT-26. (trifluoromethyl)phenyl]methoxy}chromen-4-
one;
3-(4-hydroxyphenyl)-7-{[4-methoxy-3- 0.02 M No No
PT-27. (trifluoromethyl)phenyl]methoxy}chromen-4- inhibition inhibition
one; up to 10 M up to 10 M
7- {[3-fluoro-5- 0.058 M
PT-28. (trifluoromethyl)phenyl]methoxy}-3-(4-
hydroxyphenyl)chromen-4-one;
109
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND ICs0 IC5, IC50
hALDH2 hMAO-A hMAO-B
7-({5-[3-fluoro-5- 0.01 M No No
PT-29. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4- up to 30 M up to 30 M
one;
7-({5-[4-fluoro-3- 0.10 M No No
PT-30. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4- up to 10 M up to 10 M
one;
7-({5-[2,5-bis(trifluoromethyl)phenyl](1,2,4- 0.02 M No No
PT-3 1. oxadiazol-3-yl)}methoxy)-3-(4- inhibition inhibition
hydroxyphenyl)chromen-4-one; up to 10 M up to 10 M
prop-2-enyl3-(3-{[3-(4-hydroxyphenyl)-4- 1.15 M No No
PT-32. oxochromen-7-yloxy]methyl}-1,2,4-oxadiazol- inhibition inhibition
5-yl)benzoate; (ESI) m/z 497 (M + H)+. up to 10 M up to 10 M
methyl 3-{[3-(4-hydroxyphenyl)-4- 0.15 M No 0.3 M
PT-33. oxochromen-7-yloxy]methyl}benzoate; inhibition
up to 30 M
PT-34. ethyl 4-{[3-(4-hydroxyphenyl)-4-oxochromen- 0.13 M 24 M 2.3 M
7 lox meth 1 benzoate;
methylethyl3-{[3-(4-hydroxyphenyl)-4- 0.02 M No No
PT-35. oxochromen-7-yloxy]methyl}benzoate; inhibition inhibition
u to 10 M u to 10 M
4-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.17 M No No
PT-36. yloxy]methyl}benzoic acid; (ESI) m/z 389 (M + inhibition inhibition
H)+. up to 40 M up to 30 M
4-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.38 M No No
PT-37. yloxy]methyl}benzamide; inhibition inhibition
up to30 M u to30 M
3-(4-hydroxyphenyl)-7-({5-[4- 0.6 M No No
PT-38. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
yl)}methoxy)chromen-4-one; up to 30 M up to 30 M
7-({5-[3,5-bis(trifluoromethyl)phenyl](1,2,4- 0.13 M No No
PT-39. oxadiazol-3-yl)}methoxy)-3-(4- inhibition inhibition
hydroxyphenyl)chromen-4-one; up to 10 M up to 10 M
3-(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.022 M No No
PT-40. yloxy]methyl}-1,2,4-oxadiazol-5- inhibition inhibition
yl)benzenecarbonitrile; up to 10 M up to 10 M
3-(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.01 M No No
PT-4 1. yloxy]methyl}-1,2,4-oxadiazol-5-yl)benzoic inhibition inhibition
acid; up to 10 M up to 10 M
7-{[5-(3-fluorophenyl)(1,2,4-oxadiazol-3- 0.062 M No No
PT-42. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one. up to 10 M up to 10 M
110
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
3-(4-hydroxyphenyl)-7-[(3-phenyl(1,2,4- 0.47 M No No
PT-43. oxadiazol-5-yl))methoxy]chromen-4-one; inhibition inhibition
u to30 M u to30 M
3-(4-hydroxyphenyl)-7-({3-[4- 0.27 M No No
PT-44. chlorophenyl](1,2,4-oxadiazol-5- inhibition inhibition
yl)}methoxy)chromen-4-one; up to 30 M up to 30 M
3-(4-hydroxyphenyl)-7-({5-[3- 0.098 M No 7%
PT-45. (trifluoromethyl)phenyl]isoxazol-3- inhibition inhibition
yl}methoxy)chromen-4-one; up to 10 M at 10 M
7-{[5-(trifluoromethyl)(3-pyridyl)]methoxy}-3- 10%
PT-46. (4-{[6-(trifluoromethyl)(3- inhibition
pyridyl)]methoxy}phenyl)chromen-4-one; at 1 M
methyl2-{[3-(4-hydroxyphenyl)-4- 0.005 M No 34%
PT-47. oxochromen-7-yloxy]methyl}-1,3-oxazole-5- inhibition inhibition
carboxylate; up to 10 M at 10 M
7-{[5-(4-fluorophenyl)(1,2,4-oxadiazol-3- 0.14 M
PT-48. yl)]methoxy}-3-{4-[(methylsulfonyl)amino]-
hen 1 chromen-4-one;
2-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.016 M No
PT-49. yloxy]methyl}-1,3-oxazole-5-carboxylic acid; inhibition
up to 10 M
methyl 3-(f3-[4-((lZ)-l-amino-2-methoxy-2- 47%
PT-50. azavinyl)phenyl]-4-oxochromen-7- inhibition
yloxy}methyl)benzoate; at 1 M
PT-5 1. 7-{2-[4-(4-chlorophenyl)pyrazolyl]ethoxy}-3- 0.11 M
(4-hydroxyphenyl)chromen-4-one;
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl(3 - 0.01 M No
PT-52. pyridyl))methoxy]chromen-4-one; inhibition
up to 10 M
7-[(2R)-2-hydroxy-3-({[3- 0.016 M No 19%
PT-53. (trifluoromethyl)phenyl]methyl} amino)propoxy inhibition inhibition
]-3-(4-hydroxyphenyl)chromen-4-one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[({[3- 0.005 M No
PT-54. (trifluoromethyl)phenyl]methyl} amino)methoxy inhibition
]chromen-4-one; up to 10 M
7-((2R)-3-{[(3,5- 0.008 M No 14%
PT-55. difluorophenyl)methyl]amino }-2- inhibition inhibition
hydroxypropoxy)-3-(4- up to 10 M at 10 M
hydroxyphenyl)chromen-4-one;
7-(3-{[(1R)-1-(4-fluorophenyl)ethyl]amino }-2- 0.008 M 36% 29%
PT-56. oxopropoxy)-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10M at 10M
3-(4-hydroxyphenyl)-7-(3- 0.02 M No 27%
PT-57. inhibition inhibition
phenylpropoxy)chromen-4-one;
up to 10 M at 10 M
111
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
7-{[5-(3-fluorophenyl)(1,3,4-ohadiazol-2- 0.011 M No 25%
PT-58. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to lO M at 10 M
3-(4-hydroxyphenyl)-7-{[3- 0.67 M No 24%
PT-59. inhibition inhibition
(trifluoromethyl)phenyl] ethoxy } chromen-4-one;
up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-({5-[3- 0.042 M No 13%
PT-60. (trifluoromethyl)phenyl](1,3,4-ohadiazol-2- inhibition inhibition
yl)}methoxy)chromen-4-one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[(2-phenyl(1,3-oxazol- 0.096 M No 17%
PT-61. 5-yl))methoxy]chromen-4-one; inhibition inhibition
up to 10 M at 10 M
7-({5-[3,5-bis(trifluoromethyl)phenyl]isoxazol- 0.072 M No no
PT-62. 3-yl}methoxy)-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-({5-[3- 0.098 M No 7%
PT-63. (trifluoromethyl)phenyl]isoxazol-3- inhibition inhibition
yl}methoxy)chromen-4-one; up to 10 M at 10 M
7-{[5-(2-chlorophenyl)(1,3,4-thiadiazol-2- 43% No 8%
PT-64. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
inhibition
one; at 1 M up to 10 M at 10 M
4-[7-({4-methyl-2-[4- 30% No 25%
PT-65. (trifluoromethyl)phenyl](1,3-thiazol-5- inhibition inhibition
inhibition
yl)}methoxy)-4-oxochromen-3- at 1 M up to 10 M at 10 M
yl]benzenecarbonitrile;
3-{4-[(methylsulfonyl)amino]phenyl}-7-({4- 48% No 25%
PT-66. methyl-2-[4-(trifluoromethyl)phenyl](1,3- inhibition inhibition
inhibition
thiazol-5-yl)}methoxy)chromen-4-one; at 1 M up to 10 M at 10 M
3-(6-methoxy(3-pyridyl))-7-({4-methyl-2-[4- 25% No 16%
PT-67. (trifluoromethyl)phenyl](1,3-thiazol-5- inhibition inhibition
inhibition
yl)}methoxy)chromen-4-one; at 1 M up to 10 M at 10 M
4-[7-({5-[5-fluoro-3- 33% No 14%
PT-68. (trifluoromethyl)phenyl](1,3,4-ohadiazol-2- inhibition inhibition
inhibition
yl)}methoxy)-4-oxochromen-3- at 1 M up to 10 M at 10 M
yl]benzenecarbonitrile;
4-[4-oxo-7-({3-[3- 0.18 M No
PT-69. (trifluoromethyl)phenyl]isoxazol-5- inhibition
yl}methoxy)chromen-3-yl]benzenecarbonitrile; up to 10 M
7-({5-[3-fluoro-5- 20% No 11%
PT-70. (trifluoromethyl)phenyl](1,2,4-ohadiazol-3- inhibition inhibition
inhibition
yl)}methoxy)-3-{4- at 1 M up to 10 M at 10 M
[(methylsulfonyl)amino]phenyl } chromen-4-one;
7-({5-[3-fluoro-5- 8% No 11%
PT-71. (trifluoromethyl)phenyl](1,2,4-ohadiazol-3- inhibition inhibition
inhibition
yl)}methoxy)-3-[4- at 1 M up to 10 M at 10 M
(methylsulfonyl)phenyl] chromen-4-one;
112
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
4-[7-({5-[3-fluoro-5- 14% No No
PT-72. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
inhibition
yl)}methoxy)-4-oxochromen-3-yl]benzamide; at 1 M up to 10 M at 10 M
3-(3-acetylphenyl)-7-({5-[3-fluoro-5- 18% No 10%
PT-73. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
inhibition
yl)}methoxy)chromen-4-one; at 1 M up to 10 M at 10 M
7-({5-[3-fluoro-5- 0.005 M No 22%
PT-74. (trifluoromethyl)phenyl](1,3,4-oxadiazol-2- inhibition inhibition
yl)}methoxy)-3-(4-hydroxyphenyl)chromen-4- up to 10 M at 10 M
one;
7-({5-[3-fluoro-5- 14% No No
PT-75. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
inhibition
yl)}methoxy)-3-(5-hydropyrazol-4-yl)chromen- at 1 M up to 10 M at 10 M
4-one;
ethyl3-[7-({3-[3-fluoro-5- 0.063 M No 21%
PT-76. (trifluoromethyl)phenyl](1,2,4-oxadiazol-5- inhibition inhibition
yl)}ethoxy)-4-oxochromen-3-yl]benzoate; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-({2-[4- 0.122 M
PT-77. (trifluoromethyl)phenyl](1,3-thiazol-5-
1 methox chromen-4-one;
PT-78. 7-[2-(3 -fluorophenyl)-2-oxoethoxy]-3-(4- 0.139 M
h drox hen 1 chromen-4-one;
7-({5-[3-fluoro-5- 0.048 M No 18%
PT-79. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition inhibition
yl)}ethoxy)-3-(4-hydroxyphenyl)chromen-4- up to 10 M at 10 M
one;
7-{[5-(2-chorophenyl)(1,3,4-oxadiazol-2- 0.004 M No No
PT-80. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to lO M at 10 M
7-{[5-(4-fluorophenyl)(1,3,4-oxadiazol-2- 0.0004 M No 12%
PT-8 1. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10M at 10M
3-(4-hydroxyphenyl)-7-(4- 0.005 M No 15%
PT-82. pyridylmethoxy)chromen-4-one; inhibition inhibition
up to at 10M
3-{4-[(methylsulfonyl)amino]phenyl}-7-({2-[4- 0.025 M
PT-83. (trifluoromethyl)phenyl](1,3-thiazol-5-
yl) } methoxy)chromen-4-one;
2-[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.015 M No 20%
PT-84. yloxy]-N-[2-(trifluoromethyl)phenyl]- inhibition inhibition
acetamide; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-{2-oxo-2-[2- 0.07 M No No
PT-85. (trifluoromethyl)phenyl]ethoxy}chromen-4-one; inhibition inhibition
up to 10 M at 10 M
113
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
3-(1H-indazol-5-yl)-7-({5-[5-fluoro-3- 68%
PT-86. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition
yl)}methoxy)chromen-4-one; at 1 M
3-(4-hydroxyphenyl)-7-(2- 0.040% No 21%
PT 87. phenylethoxy)chromen-4-one; inhibition inhibition inhibition
at 1 M up to 10 M at 10 M
2-[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.023 M 6.2 M 35%
PT 88. yloxy]ethanenitrile; inhibition
at 10 M
7-[2-(4-chlorophenoxy)ethoxy]-3-(4- 0.022 M 34% 32%
PT-89. hydroxyphenyl)chromen-4-one; inhibition inhibition
up to 10 M at 10 M
N-[(1R)-1-(4-fluorophenyl)ethyl]-2-[3-(4- 0.006 M No 12%
PT-90. hydroxyphenyl)-4-oxochromen-7- inhibition inhibition
yloxy]acetamide; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-(2- 0.007 M No 11%
PT-91. inhibition inhibition
pyridylmethoxy)chromen-4-one;
up to at 10M
2-fluoro-5-[7-({5-[5-fluoro-3- 24%
PT-92. (trifluoromethyl)phenyl](1,2,4-oxadiazol-3- inhibition
yl)}methoxy)-4-oxochromen-3- at 1 M
yl]benzenecarbonitrile;
PT-93. 7-(2-pyridylmethoxy)-3-[4-(2- 0.017 M
pyridylmethoxy)phenyl]chromen-4-one;
3-(4-hydroxyphenyl)-7-{[5-(trifluoromethyl)(3- 0.02 M No No
PT-94. inhibition inhibition
pyridyl)]methoxy} chromen-4-one;
up to at 10M
7- 5- 4-chloro heny1)isoxazol-3-y1]methoxy} 57%
PT-95. {[ ( p inhibition
3-(4-hydroxyphenyl)chromen-4-one; at 1 M
7-{[5-(3,4-dichlorophenyl)isoxazol-3- 47%
PT-96. yl]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition
one; at 1 M
PT-97. 7-{[5-(4-chlorophenyl)isoxazol-3-yl]methoxy}- 57%
inhibition
3-(4-hydroxyphenyl)chromen-4-one; at 1 M
7-[(2R)-2-hydroxy-3-({[3- 0.016 M No 19%
PT-98. (trifluoromethyl)phenyl]methyl} amino)propoxy inhibition inhibition
]-3-(4-hydroxyphenyl)chromen-4-one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[2-({[3- 0.005 M No
PT-99. (trifluoromethyl)phenyl]methyl}amino)ethoxy]c inhibition
hromen-4-one; up to 10 M
114
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
7-((2R)-3-{[(3,5- 0.008 M No 14%
PT-100. difluorophenyl)methyl]amino }-2- inhibition inhibition
hydroxypropoxy)-3-(4- up to 10 M at 10 M
hydroxyphenyl)chromen-4-one;
methyl2-{[3-(4-hydroxyphenyl)-4- 0.005 M No 34%
PT-101. oxochromen-7-yloxy]methyl}-1,3-oxazole-4- inhibition inhibition
carboxylate; up to 10 M at 10 M
2-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.016 M No
PT-102. yloxy]methyl}-1,3-oxazole-4-carboxylic acid; inhibition
up to 10 M
N-[(1S)-1-(4-fluorophenyl)ethyl]-2-[3-(4- 0.008 M 36% 29%
PT-103. hydroxyphenyl)-4-oxochromen-7- inhibition inhibition
yloxy]acetamide; up to 10 M at 10 M
7-{[5-(4-fluorophenyl)(1,2,4-oxadiazol-3- 0.016 M No No
PT-104. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
7-{[5-(4-fluorophenyl)(1,2,4-oxadiazol-3- 0.14 M
PT-105. yl)]methoxy}-3-{4-[(methylsulfonyl)-
amino hen 1 chromen-4-one;
PT-106. 7-{3-[4-(4-chlorophenyl)pyrazolyl]propoxy}-3- 0.11 M
(4-hydroxyphenyl)chromen-4-one;
3 -(4-hydroxyphenyl)-7-(3 - 0.02 M No 27%
PT-107. inhibition inhibition
phenylpropoxy)chromen-4-one;
up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[(6-pyrazolyl(3- 0.010 M No
PT-108. pyridyl))methoxy]chromen-4-one; inhibition
up to 10 M
7-((2R)-2-hydroxy-3-phenylpropoxy)-3-(4- 0.014 M 26% 26%
PT-109. hydroxyphenyl)chromen-4-one; inhibition inhibition
up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4- 0.007 M No No
PT-110. inhibition inhibition
oxadiazol-2-yl))methoxy]chromen-4-one;
up to 10 M at 10 M
3-[(2-hydroxy-3-{4- 0.003 M No 30%
PT-111. [(methylsulfonyl)amino]phenyl}-4- inhibition inhibition
oxochromen-7-yloxy)methyl]-benzoic acid; up to 10 M at 10 M
7-{[5-(4-fluorophenyl)(1,3,4-oxadiazol-2- 0.005 M No No
PT-112. yl)]ethoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4- 0.017 M No 30%
PT-113. inhibition inhibition
oxadiazol-2-yl))ethoxy]chromen-4-one;
up to at 10M
L 3-(4-hydroxyphenyl)-7-[(3-(3-pyridyl)(1,2,4- 0.032 M No No
PT-114. oxadiazol-5-yl))methoxy]chromen-4-one; inhibition inhibition
up to 10 M L! -0 M
115
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
TABLE 1 - ALDH-2 AND MOA INHIBITION
COMPOUND IC5o IC5o IC50
hALDH2 hMAO-A hMAO-B
3-(4-hydroxyphenyl)-7-({3-[3- 0.038 M No No
PT-115. (trifluoromethyl)phenyl](1,2,4-oxadiazol-5- inhibition inhibition
yl)}methoxy)chromen-4-one; up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[(5-(3-pyridyl)(1,3,4- 0.015 M No 33%
PT-116. inhibition inhibition
oxadiazol-2-yl))ethoxy]chromen-4-one;
up to 10 M at 10 M
3-(4-hydroxyphenyl)-7-[(5-(4-pyridyl)(1,2,4- 0.098 M No No
PT-117. inhibition inhibition
oxadiazol-3-yl))ethoxy]chromen-4-one;
up to at 10M
(2-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.023 M No No
PT-118. yloxy]methyl}(1,3-oxazol-4-yl))-N- inhibition inhibition
methylcarboxamide; up to 10 M at 10 M
4-{[3-(4-hydroxyphenyl)-4-oxochromen-7- 0.068 M No No
PT-119. inhibition inhibition
yloxy]methyl } -7-methoxychromen-2-one;
up to 10 M at 10 M
7-{[5-(4-fluorophenyl)(1,3,4-oxadiazol-2- 0.276 M
PT-120. yl)]methoxy}-3-{4-[(methylsulfonyl)amino]-
phenyl chromen-4-one;
7-{[5-(3-aminophenyl)(1,3,4-oxadiazol-2- 0.011 M No No
PT-121. yl)]methoxy}-3-(4-hydroxyphenyl)chromen-4- inhibition inhibition
one; up to 10 M at 10 M
ethyll-{2-[3-(4-hydroxyphenyl)-4- 0.012 M No No
PT-122. oxochromen-7-yloxy]ethyl}pyrazole-4- inhibition inhibition
carboxylate; up to 10 M at 10 M
7-{2-[4-(3-chlorophenyl)piperazinyl]ethoxy}-3- 0.011 M No
PT-123. (4-hydroxyphenyl)chromen-4-one; inhibition
up to 10 M
3-(4-hydroxyphenyl)-7-(2-{4-[3- 0.018 M No 21%
PT-124. (trifluoromethyl)phenyl]piperazinyl}ethoxy)chr inhibition inhibition
omen-4-one; up to 10 M at 10 M
EXAMPLE 32
Reduction of Alcohol Dependency
Animals
[0266] The strains of alcohol-preferring rats are housed individually in
stainless-steel
wire mesh cages (26 ' 34 '20 cm) under constant temperature of 21 1 C and
reversed
12 hour light-12 hour dark cycle (10:00-22:00 dark). These rats consume
significantly
more alcohol than their respective control strains: the selectively-bred
alcohol non-
preferring (NP), the low alcohol-drinking (LAD) rat, and the Wistar rat. The
FH and P
116
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
rats were derived from the Wistar rat. Water and food (Agway Prolab
Rat/Mouse/Hamster 3000 formula, Agway, Syracuse, USA) were provided ad lib.
Establishment of Baseline
[0267] Following the standard method (Murphy et al., 1988; Rezvani and Grady,
1994;
Rezvani et al., 1995), alcohol-preferring rats are given 1 day access to water
in a
Richter tube followed by 3 days of free access to a solution of 10% (v/v)
ethanol given
as the only source of fluid. Thereafter, the rats were given a choice between
alcohol and
water for the remainder of the study. All experiments involve 24 hour free
access to
food, water, and alcohol in a two-bottle choice paradigm.
Experimental protocol
[0268] After establishment of a stable baseline for alcohol and water intakes,
animals
are maintained on a continuous access to alcohol and water via a two-bottle
choice
paradigm for about 2 months. Then, rats receive a single i.p. injection of the
saline
vehicle, or a test compound at 09:30 am. Alcohol and water intakes are
measured at 6
and 24 hours after the injection. Food intake is measured 24 hours after the
injection.
Chronic Systemic Administration
[0269] A chronic experiment is conducted with adult male P rats. After
establishment
of stable baselines for alcohol and water intakes, and following a cross-over
design, the
test drug or vehicle is given i.p. once a day for 10 consecutive days. Alcohol
and water
intakes are measured at 6 and 24 hours after the treatment, whereas food
intake is
measured 24 hours after the treatment. Each rat receives both treatments, and
a
washout period of 3 days is imposed between treatments.
Statistical analysis
[0270] The results are expressed as means standard error of means (SEM).
Alcohol
intake (g/kg) is calculated by multiplying the volume of alcohol consumed by
10% and
117
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
0.7893 (ethanol density)/animal body weight in kg. Alcohol preference,
expressed as a
percentage, is calculated as follows:
(volume of alcohol consumed in ml/total fluid intake in ml) x 100 (Rezvani et
al., 1990;
Rezvani and Grady, 1994). Statistical differences between different groups are
determined using analysis of variance followed by Newman-Keuls protected t-
test.
EXAMPLE 33
Reduction of Cocaine Dependency and Relapse
[0271] Intravenous cocaine (0.35mg/kg/inj) was used in an operant self
administration
and reinstatement model in rats. In this model, rats addicted to cocaine
repeatedly
pressed a lever to obtain an intravenous dose (iv) of cocaine. When cocaine
was
removed, rats stopped pressing the lever. However, rats resumed lever pressing
for
cocaine (reinstatement) if subjected to a small intraperitoneal (ip) dose
(10mg/kg) of
cocaine that normally has no effect in naive animals. This is a valid animal
model of
relapse in cocaine addicted humans, and tests the ability of compounds of
Formula Ito
block cocaine craving and relapse.
[0272] Male Sprague-Dawley rats with jugular vein catheterization were used.
Rats
were presented with a choice of two levers in the test/training chamber.
Depression of
the active lever resulted in delivery of a cocaine reinforcer, while
depression of the
inactive lever did not result in reinforcement. During the initial 15 hour
fixed ratio
(FR) 1 training session (FRI stands for one lever press equals one
reinforcement
delivery), a food pellet was taped to the active lever to facilitate lever
pressing, and
each active lever press resulted in the delivery of a single 45 mg food pellet
(Noyes,
Lancaster, NH). The following day the reinforcer was switched to FR1 lever
pressing
for cocaine (0.35 mg/kg/inj, delivered in 0.27 sec). Cocaine reinforcement was
delivered on a modified FRI schedule such that each drug infusion was
accompanied
by illumination of a stimulus over the active lever and a 20 second timeout
during
which active lever presses were counted but did not result in reinforcer
delivery. After
20 seconds the stimulus light turned off and the first lever press again
resulted in drug
118
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
delivery. Depression of the inactive lever did not have any consequence. Daily
training sessions for each group lasted 2 hours, or until a subject earned 200
drug
infusions, whichever came first. The subjects remained in drug self-
administration
training mode until acquisition criterion was met (average presses on the
active lever
varied by < 10% over 3 consecutive training days). This typically takes 10-14
days.
Extinction and Reinstatement
[0273] For extinction and reinstatement experiments, rats were required to
display
stable responding (variability not higher than 15% in 2 consecutive sessions)
on the
FR1 schedule of reinforcement. After achieving this criteria, extinction
procedures
began such that lever presses no longer resulted in delivery of the
reinforcer. When
average responding across three consecutive extinction sessions fell to 15% of
responding during maintenance, subjects were tested for reinstatement. In
cocaine-
experienced animals, reinstatement was primed with a non-contingent injection
of
cocaine (10 mg/kg ip) immediately before the reinstatement session. In order
to
increase statistical power and therefore decrease animal usage, a second
extinction
period was initiated 3-4 days after the first, which allowed for additional
within-
subjects comparisons. Experiments used a between-session-training and testing
method
in which animals were trained to self administer drug. Their behavior was then
extinguished and then reinstatement was primed on different days.
Results
Effect of 3-f(3-{ 4-[(methylsulfonyl)aminolphenyl}-4-oxochromen-7-
yloxy)methyll-
benzoic acid (Compound A) on cocaine induced relapse
[0274] Ip injections of the ALDH-2 inhibitor 3-[(3-{4-
[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid dose
dependently blocked relapse for cocaine. Animals were trained to self
administer
cocaine (0.35 mg/kg/inj) until they reached stable responding. They were then
trained
in the same chambers but cocaine was no longer available. Once they dropped
their
lever presses responding to a minimal level (extinction), they were then given
a priming
dose of cocaine (10 mg/kg) and consequently their responding lever presses
significantly increased (relapse). Those same animals receiving 3-[(3-{4-
119
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid (7.5
and
mg/kg) prior to the priming injection of cocaine did not show an increase in
their
lever presses responding (did not relapse).
Table 2 - Lever presses (Avg Std. error)
Extinction-no Vehicle prior to Cmpd A (7.5 Cmpd-A (10
drug available cocaine priming mg/kg) prior to mg/kg) prior to
dose (10mg/kg) cocaine priming cocaine priming
dose (10 mg/kg) (10 mg/kg) dose
N=15 n=15 N=9 N=6
6.11+0.58 59.75+14.86# 24.94+7.92* 19.83+11.30*
#, Significantly different from Extinction, p< 0.01
*, Significantly different from Vehicle, p< 0.05
[0275] The following compounds of Formula I were similarly tested, and similar
results were obtained:
[0276] 7-({5-[3-fluoro-5-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-
yl)}methoxy)-3-
(4-hydroxyphenyl)chromen-4-one; and
[0277] 3-(3-{[3-(4-hydroxyphenyl)-4-oxochromen-7-yloxy]methyl}-1,2,4-oxadiazol-
5-
yl)benzoic acid.
[0278] Similar results are obtained in testing other compounds of Formula I.
EXAMPLE 34
Reduction of Nicotine Dependency
Biological material:
[0279] Wistar-derived male rats (250-300 g) were housed in groups of two and
maintained in a temperature-controlled environment on a 12 hour: 12 hour light
cycle
120
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
(0600h on-I800h off), upon arrival in the laboratory. Animals were given free
access
to food and water during a one-week habituation period to the laboratory.
Animals
used in the research studies were handled, housed, and sacrificed in accord
with the
current NIH guidelines regarding the use and care of laboratory animals, and
all
applicable local, state, and federal regulations and guidelines. Animals were
handled
daily for several days to desensitize them to handling stress before
experimental testing.
The sample sizes (n=8) provided reliable estimates of drug effects.
Drug Treatments:
[0280] The Wistar-derived rats received several doses of 3-[(3-{4-
[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid (0.00,
7.5, 10, and 15 mg/kg) administered intraperitonealy (i.p.), and a positive
control
compound, mecamylamine (1.5 mg/kg, subcutaneously (s.c.). The compounds were
administered 30 minutes prior to SA sessions. 3-[(3-{4-
[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid was
administered at 2 ml/kg for the 7.5 mg/kg (3.75 mg/ml) and 10 mg/kg (5 mg/ml),
doses,
and at 3 ml/kg for the 15 mg/kg dose (5 mg/ml). The compound was dissolved in
corn
oil (VEH), and sonicated for at least 30-minutes, up to 2 hours prior to
administration.
Mecamylamine was dissolved in 0.09% isotonic saline and administered at a
volume of
1 ml/kg.
Apparatus:
[0281] Food training and nicotine self-administration took place in 8 standard
Coulbourn operant chambers. Each chamber was housed in a sound-attenuated box.
Operant chambers were equipped with two levers, mounted 2 cm above the floor,
and a
cue light mounted 2 cm above the right lever on the back wall of the chamber.
For
food training, a food hopper was located 2-cm to the left/right of either
lever, in the
middle of the back wall. Intravenous infusions were delivered in a volume of
0.1 ml
over a I second interval via an infusion pump (Razel, CT) housed outside of
the sound
attenuated chamber.
121
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
Food Training:
[0282] Lever pressing was established as demonstrated by the method of Hyytia
et al.,
(1996). Initially, rats were restricted to 15 grams of food daily
(approximately 85% of
their free-feeding body weight). After the second day of food restriction,
rats were
trained to respond for food under a fixed-ratio 1 (FR1) schedule of
reinforcement (1
food pellet for each lever press) with a 1 second time-out (TO-is) after each
reinforcement. Training sessions were given twice per day, and TO periods were
gradually increased to 20 seconds. Once rats obtained a steady baseline
responding at a
FR1-TO20s schedule of reinforcement, they were returned to ad libitum food
prior to
preparation for intravenous jugular catheter implant surgery.
Sum
[0283] Rats were anesthetized with a ketamine/xylazine mixture and chronic
silastic
jugular catheters were inserted into the external jugular vein and passed
subcutaneously
to a polyethylene assembly mounted on the animal's back. The catheter assembly
consisted of a 13-cm length of silasitic tubing (inside diameter 0.31 mm;
outside
diameter 0.64 mm), attached to a guide cannula that was bent at a right angle.
The
cannula was embedded into a dental cement base and anchored with a 2 x 2 cm
square
of durable mesh. The catheter was passed subcutaneously from the rats back to
the
jugular vein where it was inserted and secured with a non-absorbable silk
suture. Upon
successful completion of surgery, rats were given 3-5 days to recover before
self-
administration sessions started. During the recovery period, rats remained ad
libitum
food access, and had catheter lines flushed daily with 30 units/ml of
heparinized saline
containing 66 mg/ml of Timentin to prevent blood coagulation and infection in
the
catheters.
Nicotine Self-Administration:
[0284] Following successful recovery from catheter implant surgery, rats were
again
food deprived to 85% of their free-feeding body weight. Once self-
administration
sessions began, subjects were trained to IV self-administer nicotine in 1-hour
baseline
sessions, 5 days per week, under a FR1-TO-20 schedule of reinforcement until
stable
responding was achieved. Stable responding is defined as less than 20%
variability
122
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
across 3 consecutive sessions. After acquisition of stable responding for
nicotine,
various doses of 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-
yloxy)methyl]benzoic acid were tested using a within-subjects Latin square
design.
Rats were allowed to self-administer nicotine after treatment with each dose
of 3-[(3-
{4-[(methylsulfonyl)amino]phenyl}-4-oxochromen-7-yloxy)methyl]benzoic acid for
1
test session, and subsequently "rebaselined" for 1-3 days before the next dose
probe
during one test self-administrations sessions. Following the testing of the
first
compound, rats received the positive control compound, mecamylamine (1.5
mg/kg),
administered according to a crossover design.
[0285] During SA sessions, rats were flushed with saline before test session
to ensure
catheter patency, and again flushed after test sessions with 30 units/ml of
heparinized
saline containing 66 mg/ml of Timentin, to prevent blood coagulation and
infection in
the catheters. If catheter patency was in question, demonstrated by an
unexpected shift
in response rates, or inability to draw blood from the catheter, 0.1 ml of a
short-acting
anesthetic (Brevital) was infused. Animals with patent catheters exhibited
rapid loss of
muscle tone within 3-seconds. Rats with catheters no longer patent according
to the
Brevital test were removed from the experiment.
Data Analysis
[0286] Data was collected on-line from multiple operant chambers, and reported
as
mean cumulative number of bar presses for nicotine. The data was analyzed
using the
StatView statistical package on a PC-compatible computer.
Results
Effect of 3-f(3-{ 4-[(methylsulfonyl)aminolphenyl}-4-oxochromen-7-
yloxy)methyll-
benzoic acid on Nicotine Self Administartion
[0287] Increasing doses of 3-[(3-{4-[(methylsulfonyl)amino]phenyl}-4-
oxochromen-7-
yloxy)methyl]benzoic administered as described in the above protocol reduced
the
number of bar presses (plotted as the number of infusions) for nicotine
administration,
as shown in Figure 1.
123
CA 02712750 2010-07-21
WO 2009/094028 PCT/US2008/051862
[0288] Similar results are obtained in testing other compounds of Formula I.
124
