Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL VINYL CARB_O.~YLLC_ACTD DERIVATIVES AND THEIR USE AS ANT2D.IABETICS-ETC
FIELD OF THE INVENTION
The present invention relates to novel vinyl carboxylic acid derivatives, to
the use of
these compounds as pharmaceutical compositions, to pharmaceutical compositions
compris
ing the compounds and to a method of treatment employing these compounds and
composi
tions. More specifically, the compounds of the invention can be utilised in
the treatment
and/or prevention of conditions mediated by the Peroxisome Proliferator-
Activated Receptors
(PPAR), in particular the PPARB suptype.
BACKGROUND OF THE INVENTION
Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic
and
metabolic syndrome patients (i.e. patients that fall within the 'deadly
quartet' category of im-
paired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or
obesity).
The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately
display
moderately effective triglyceride-lowering activities although they are
neither potent nor effi-
cacious enough to be a single therapy of choice for the dyslipidaemia often
observed in Type
2 diabetic or metabolic syndrome patients. The thiazolidinediones also
potently lower circu-
lating glucose levels of Type 2 diabetic animal models and humans. However,
the fibrate
class of compounds are without beneficial effects on glycaemia. Studies on the
molecular
actions of these compounds indicate that thiazolidinediones and fibrates exert
their action by
activating distinct transcription factors of the peroxisome proliferator
activated receptor
(PPAR) family, resulting in increased and decreased expression of specific
enzymes and
apolipoproteins respectively, both key-players in regulation of plasma
triglyceride content.
Fibrates, on the one hand, are PPARa activators, acting primarily in the
liver. Thiazolidin-
ediones, on the other hand, are high affinity ligands for PPARy acting
primarily on adipose
tissue.
Adipose tissue plays a central role in lipid homeostasis and the maintenance
of
energy balance in vertebrates. Adipocytes store energy in the form of
triglycerides during
periods of nutritional affluence and release it in the form of free fatty
acids at times of
nutritional deprivation. The development of white adipose tissue is the result
of a continuous
differentiation process throughout life. Much evidence points to the central
role of PPARy
activation in initiating and regulating this cell differentiation. Several
highly specialised
proteins are induced during adipocyte differentiation, most of them being
involved in lipid
storage and metabolism. The exact link from activation of PPARy to changes in
glucose
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2
metabolism, most notably a decrease in insulin resistance in muscle, has not
yet been
clarified. A possible link is via free fatty acids such that activation of
PPARy induces
Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA
Synthetase
(ACS) in adipose tissue but not in muscle tissue. This, in turn, reduces the
concentration of
free fatty acids in plasma dramatically, and due to substrate competition at
the cellular level,
skeletal muscle and other tissues with high metabolic rates eventually switch
from fatty acid
oxidation to glucose oxidation with decreased insulin resistance as a
consequence.
PPARa is involved in stimulating ~i-oxidation of fatty acids. In rodents, a
PPARa-
mediated change in the expression of genes involved in fatty acid metabolism
lies at the
basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular
response, mainly
limited to liver and kidney and which can lead to hepatocarcinogenesis in
rodents. The
phenomenon of peroxisome proliferation is not seen in man. In addition to its
role in
peroxisome proliferation in rodents, PPARa is also involved in the control of
HDL cholesterol
levels in rodents and humans. This effect is, at least partially, based on a
PPARa-mediated
transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-
II. The
hypotriglyceridemic action of fibrates and fatty acids also involves PPARa and
can be
summarised as follows: (I) an increased lipolysis and clearance of remnant
particles, due to
changes in lipoprotein lipase and apo C-III levels, (II) a stimulation of
cellular fatty acid
uptake and their subsequent conversion to acyl-CoA derivatives by the
induction of fatty acid
binding protein and acyl-CoA synthase, (III) an induction of fatty acid ~i-
oxidation pathways,
(IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a
decrease in VLDL
production. Hence, both enhanced catabolism of triglyceride-rich particles as
well as reduced
secretion of VLDL particles constitutes mechanisms that contribute to the
hypolipidemic
effect of fibrates.
PPARB activation was initially reported not to be involved in modulation of
glucose
or triglyceride levels. (Berger et al., j. Biol. Chem. , 1999, Vol 274, pp.
6718-6725). Later it
has been shown that PPARB activation leads to increased levels of HDL
cholesterol in dbldb
mice (Leibowitz et al. FEBS letters 2000, 473, 333-336). Further, a PPARB
agonist when
dosed to insulin-resistant middle-aged obese rhesus monkeys caused a dramitic
dose-
dependent rise in serum HDL cholesterol while lowering the levels of small
dense LDL,
fasting triglycerides and fasting insulin (Oliver et al. PNAS 2001, 98, 5306-
5311).The same
paper also showed that PPARb activation increased the reverse cholesterol
transporter ATP-
binding cassette A1 and induced apolipoprotein A1-specific cholesterol efflux.
Taken
together these observations suggest that PPARB activation is useful in the
treatment and
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prevention of cardiovascular diseases and conditions including
atherosclerosis,
hypertriglyceridemia, and mixed dyslipidaemia (PCT publication WO 01/00603
(Chao et al.).
A number of compounds have been reported to be useful in the treatment of
hyper-
glycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. 5,306,726, PCT
Publications
nos. W091 /19702, WO 95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO
97/36579, WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313, WO 99/16758 and
WO 01/00603).
Glucose lowering as a single approach does not overcome the macrovascular com-
plications associated with Type 2 diabetes and metabolic syndrome. Novel
treatments of
Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the
overt hy-
pertriglyceridaemia associated with these syndromes as well as alleviation of
hyperglycae-
mia.
This indicate that research for compounds displaying various degree of PPARa,
PPARy and PPARB activation should lead to the discovery of efficacious
triglyceride and/or
cholesterol and/or glucose lowering drugs that have great potential in the
treatment of dis-
eases such as type 2 diabetes, dyslipidemia, syndrome X (including the
metabolic syndrome
,i.e. impaired glucose tolerance, insulin resistance, hypertrigyceridaemia
and/or obesity),
cardiovascular diseases (including atherosclerosis) and hypercholesteremia.
In EP 98 690 the following vinyl carboxylic acid derivatives has been
described as
thromboxane A2 synthetase inhibitors:
1
R j C CH - CH2 O ~ (CH2)~- COORS
R
wherein R1 is pyridyl, R~ is phenyl, thienyl, furyl, naphtyl, benzothienyl or
pyridyl, and
R3 is hydrogen or lower alkyl.
In WO 00/64888 diaryl acid derivatives and their pharmaceutical compositions
are
described as PPAR receptor ligands.
DEFINITIONS
In the structural formulas given herein and throughout the present
specification the
following terms have the indicated meaning:
The term "C1_6-alkyl" as used herein, alone or in combination, represent a
linear or
branched, saturated hydrocarbon chain having the indicated number of carbon
atoms. Exam-
ples of such groups include, but are not limited to methyl, ethyl, n-propyl,
isopropyl, butyl,
isobutyl, sec-butyl, tent butyl, pentyl, isopentyl, hexyl, isohexyl and the
like.
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The term "C3_6-cycloalkyl" as used herein, alone or in combination, represent
a satu-
rated monocyclic hydrocarbon group having the indicated number of carbon
atoms. Examples
of such groups include, but are not limited to cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl
and the like.
The term "C2_6-alkenyl" as used herein, represent an olefinically unsaturated
branched or straight hydrocarbon group having from 2 to the specified number
of carbon at-
oms and at least one double bond. Examples of such groups include, but are not
limited to,
vinyl, 1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl,
hexenyl, pentenyl
and the like.
The term "C2_6-alkynyl" as used herein, represent an unsaturated branched or
straight hydrocarbon group having from 2 to the specified number of carbon
atoms and at
least one triple bond. Examples of such groups include, but are not limited
to, 1-propynyl, 2-
propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.
The term "C4_6-alkenynyl" as used herein, represent an unsaturated branched or
straight hydrocarbon group having from 4 to the specified number of carbon
atoms and both
at least one double bond and at least one triple bond. Examples of such groups
include, but
are not limited to, 1-penten-4-ynyl, 3-penten-1-ynyl, 1,3-hexadiene-5-ynyl and
the like.
The term "C~_6-alkoxy" as used herein, alone or in combination, refers to a
straight or
branched configuration linked through an ether oxygen having its free valence
bond from the
ether oxygen. Examples of linear alkoxy groups are methoxy, ethoxy, propoxy,
butoxy, pentoxy,
hexoxy and the like. Examples of branched alkoxy are isopropoxy, sec-butoxy,
tert-butoxy,
isopentyloxy, isohexyloxy and the like.
The term "C3_6-cycloalkoxy" as used herein, alone or in combination, represent
a
saturated monocyclic hydrocarbon group having the indicated number of carbon
atoms linked
through an ether oxygen having its free valence bond from the ether oxygen.
Examples of
cycloalkoxy groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,
cyclohexyloxy and the
like.
The term "C~_6-alkylthio" as used herein, alone or in combination, refers to a
straight
or branched monovalent substituent comprising a C~_s-alkyl group linked
through a divalent
sulfur atom having its free valence bond from the sulfur atom and having 1 to
6 carbon atoms
e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
The term "C3_6-cycloalkylthio" as used herein, alone or in combination,
represent a
saturated monocyclic hydrocarbon group having the indicated number of carbon
atoms linked
through a divalent sulfur atom having its free valence bond from the sulfur
atom. Examples of
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cycloalkoxy groups are cyclopropylthio, cyclobutylthio, cyclopentylthio,
cyclohexylthio and the
like.
The term "C~_6-alkylamino" as used herein, alone or in combination, refers to
a
straight or branched monovalent substituent comprising a C~_6-alkyl group
linked through
5 amino having a free valence bond from the nitrogen atom e.g. methylamino,
ethylamino,
propylamino, butylamino, pentylamino and the like.
The term "C~_6-cycloalkylamino" as used herein, alone or in combination,
represent a
saturated monocyclic hydrocarbon group having the indicated number of carbon
atoms linked
through amino having a free valence bond from the nitrogen atom e.g.
cyclopropylamino,
cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.
The term "C,_6-alkoxyC,_6-alkyl" as used herein, alone or in combination,
refers to C~_
6-alkyl as defined herein whereto is attached a C~_6-alkoxy as defined herein,
e.g.
methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.
The term "aryl" as used herein refers to an aromatic monocyclic or an aromatic
fused
bi- or tricyclic hydrocarbon group e.g. phenyl, naphthyl, anthracenyl,
phenanthrenyl, azulenyl
and the like.
The term "arylene" as used herein refers to divalent aromatic monocyclic or a
divalent
aromatic fused bi- or tricyclic hydrocarbon group e.g. phenylene, naphthylene
and the like.
The term "halogen" means fluorine, chlorine, bromine or iodine.
The term "perhalomethyl" means trifluoromethyl, trichloromethyl,
tribromomethyl or
triiodomethyl.
The term "perhalomethoxy" means trifluoromethoxy, trichloromethoxy, tribromo-
methoxy or triiodomethoxy.
The term "C~_6-dialkylamino" as used herein refers to an amino group wherein
the
two hydrogen atoms independently are substituted with a straight or branched,
saturated
hydrocarbon chain having the indicated number of carbon atoms; such as
dimethylamino, N-
ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino,
di(n-
pentyl)amino and the like.
The term "acyl" as used herein refers to a monovalent substituent comprising a
C~_6-
' alkyl group linked through a carbonyl group; such as e.g. acetyl, propionyl,
butyryl, isobutyryl,
pivaloyl, valeryl and the like.
The term "heteroaryl" as used herein, alone or in combination, refers to a
monovalent substituent comprising a 5-7 membered monocyclic aromatic system or
a 8-10
membered bicyclic aromatic system containing one or more heteroatoms selected
from
nitrogen, oxygen and sulfur, e.g. furyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, triazolyl,
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pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, thiadiazolyl,
quinolyl, isoquinolyl, quinazolinyl, quinoxalinnyl, indolyl, benzimidazolyl,
benzofuranyl,
pteridinyl and purinyl and the like.
The term "heteroaryloxy" as used herein, alone or in combination, refers to a
heteroaryl as defined herein linked to an oxygen atom having its free valence
bond from the
oxygen atom e.g. pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy,
pyrazinyloxy,
pyrimidinyloxy, pyridazinyloxy, isothiazolyloxy, isoxazolyloxy, oxazolyloxy,
oxadiazolyloxy,
thiadiazolyloxy, quinolinyloxy, isoquinolinyloxy, quinazolinyloxy,
quinoxalinyloxy, indoltloxy,
benzimidazolyloxy, benzofuranyloxy, pteridinyloxy and purinyloxy and the like.
The term "aralkyl" as used herein refers to a straight or branched saturated
carbon
chain containing from 1 to 6 carbons substituted with an aromatic
carbohydride; such as
benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and
the like.
The term "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy, 2-
naphthyloxy
and the like.
The term "aralkoxy" as used herein refers to a C~_6-alkoxy group substituted
with an
aromatic carbohydride, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-
naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like.
The term "heteroaralkyl" as used herein refers to a straight or branched
saturated
carbon chain containing from 1 to 6 carbons substituted with a heteroaryl
group; such as (2-
furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-
pyridyl)methyl, 1-methyl-
1-(2-pyrimidyl)ethyl and the like.
The term "heteroaralkoxy" as used herein refers to a heteroarylalkyl as
defined
herein linked to an oxygen atom having its free valence bond from the oxygen
atom, e.g. (2-
furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-
pyridyl)methyl, 1-methyl-
1-(2-pyrimidyl)ethyl linked to oxygen, and the like.
The term "arylthio" as used herein, alone or in combination, refers to an aryl
group
linked through a divalent sulfur atom having its free valence bond from the
sulfur atom, the aryl
group optionally being mono- or polysubstituted with C~_6-alkyl, halogen,
hydroxy or C,_6-alkoxy;
e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio and the like.
Certain of the above defined terms may occur more than once in the structural
formulae, and upon such occurrence each term shall be defined independently of
the other.
The term "optionally substituted" as used herein means that the groups in
question
are either unsubstituted or substituted with one or more of the substituents
specified. When
the groups in question are substituted with more than one substituent the
substituents may
be the same or different.
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DESCRIPTION OF THE INVENTION
The present invention relates to compounds of the general formula (I):
X Y
R~
(I)
z
~Ar
I
Q \ /'O
~~R
2
wherein X is aryl, fluorenyl or heteroaryl each of which is optionally
substituted with one or
more substituents selected from
~ halogen, hydroxy, cyano, amino, C~_6-alkylamino, C~_6-dialkylamino, C3_6-
cycloalkyl-
amino or carboxy; or
~ C~_6-alkyl, C3_6-cycloalkyl, Cz_6-alkenyl, CZ_6-alkynyl, C~_6-alkoxy, C3_6-
cycloalkoxy,
C~_s-alkylthio or C3_6-cycloalkylthio each of which is optionally substituted
with halo-
gen; or
~ aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,
heteroaryloxy,
heteroaralkoxy each of which is optionally substituted with halogen,
perhalomethyl,
perhalomethoxy or C~_6-alkyl; and
Y is aryl or heteroaryl each of which is optionally substituted with one or
more substituents
selected from
~ halogen, hydroxy, cyano, amino, C~_s-alkylamino, C~_6-dialkylamino, C3_6-
cycloalkyl
amino, carboxy ; or
~ C,_6-alkyl, C3_6-cycloalkyl, C2_6-alkenyl, C~_6-alkynyl, C~_6-alkoxy, C3_6-
cycloalkoxy,
C~_6-alkylthio or C3_s-cycloalkylthio each of which is optionally substituted
with halo-
gen; or
~ aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,
heteroaryloxy,
heteroaralkoxy each of which is optionally substituted with halogen,
perhalomethyl or
perhalomethoxy; or
Y is C~_6-alkyl, C3_6-cycloalkyl, CZ_s-alkenyl, CZ_6-alkynyl, C4_6-alkenynyl;
and
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Ar is arylene which is optionally substituted with one or more halogen; and
Z is O or S; and
Q is -(CH2)~ wherein n is 0, 1, 2 or 3; and
R~ is hydrogen or halogen; or
R~ is C,_6-alkyl, C3_6-cycloalkyl, C~_6-alkoxy, C3_6-cycloalkoxy each of which
is optionally sub-
stituted with one or more substituents selected from halogen, hydroxy,
carboxy, amino or
cyano; and
R~ is hydrogen, C,_6-alkyl, C3_6-cycloalkyl, C~_6-alkenyl, CZ_s-alkynyl, C4_6-
alkenynyl or aryl;
provided that X and Y independently is not a pyridine ring; or
a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable
solvate thereof,
or any tautomeric forms, stereoisomers, mixture of stereoisomers including a
racemic mix-
ture, or polymorphs.
In one embodiment, the present invention is concerned with compounds of
formula
(I) wherein X is aryl, fluorenyl or heteroaryl each of which is optionally
substituted with one or
more substituents selected from
~ halogen; or
C~_6-alkyl, C~_6-alkoxy, or C,_6-alkylthio each of which is optionally
substituted with halogen;
or
aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,
heteroaryloxy or het-
eroaralkoxy each of which is optionally substituted with halogen,
perhalomethyl, perha-
lomethoxy or C~_6-alkyl.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein X is aryl, fluorenyl or heteroaryl each of which is
optionally substituted
with one or more substituents selected from
halogen; or
aryl, aryloxy or heteroaryl each of which is optionally substituted with
halogen, perha-
lomethyl, perhalomethoxy or C~_6-alkyl.
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In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein X is aryl, which is optionally substituted with one or more
substituents se-
lected from
~ halogen; or
~ aryl, aryloxy or heteroaryl each of which is optionally substituted with
halogen, perha-
lomethyl, perhalomethoxy or C~_6-alkyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein X is phenyl, which is optionally substituted with one or more
substituents
selected from
~ bromine; or
~ phenyl or phenyloxy.
In another embodiment, the present invention is concerned with compounds of
formula (I)
wherein X is heteroaryl, which is optionally substituted with one or more
substituents se-
lected from
~ halogen; or
~ aryl or heteroaryl each of which is optionally substituted with halogen,
perhalomethyl, per-
halomethoxy or C~_6-alkyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein X is heteroaryl, which is optionally substituted with aryl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein X is thiazolyl, which is optionally substituted with phenyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein X is fluorenyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein Y is aryl or heteroaryl each of which is optionally
substituted with one or
more substituents selected from
~ halogen; or
C~_6-alkyl, C~_6-alkoxy or C~_6-alkylthio each of which is optionally
substituted with halogen;
or
~ aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,
heteroaryloxy or het-
eroaralkoxy each of which is optionally substituted with halogen,
perhalomethyl, perha-
lomethoxy or C~_6-alkyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein Y is aryl or heteroaryl each of which is optionally
substituted with one or
more substituents selected from
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~ halogen; or
~ C~_6-alkyl, or
~ aryl or heteroaryl each of which is optionally substituted with halogen,
perhalomethyl, per-
halomethoxy or C~_6-alkyl.
5 In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein Y is aryl, which is optionally substituted with one or more
halogens.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein Y is phenyl, which is optionally substituted with one or more
halogens.
In another embodiment, the present invention is concerned with compounds of
for-
10 mula (I) wherein Y is heteroaryl, which is optionally substituted with one
or more halogens.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein Y is C~_6-alkyl.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein Y is methyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein Ar is arylene, which is optionally substituted with one or
more halogens.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein Ar is phenylene, which is optionally substituted with one
or more
halogens.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein Z is O.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein n is 1 or 2.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein R~ is hydrogen.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein R~ is C~_3-alkyl.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein R~ is C,_3-alkoxy.
In another embodiment, the present invention is concerned with compounds of
formula (I) wherein wherein R~ is hydrogen or C~_6-alkyl.
In another embodiment, the present invention is concerned with compounds of
for-
mula (I) wherein RZ is hydrogen, methyl or ethyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein alkyl is methyl or ethyl.
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In another embodiment, the present invention is concerned with compounds of
formula I wherein alkenyl is vinyl or 1-propenyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein alkynyl is 1-propynyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein alkenynyl is 1-pentene-4-yne.
In another embodiment, the present invention is concerned with compounds of
formula I wherein alkoxy is methoxy, ethoxy, isopropoxy or cyclopropoxy.
In another embodiment, the present invention is concerned with compounds of
formula I wherein aryl is phenyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein arylene is phenylene.
In another embodiment, the present invention is concerned with compounds of
formula I wherein halogen is fluorine, bromine or chlorine.
In another embodiment, the present invention is concerned with compounds of
formula I wherein perhalomethyl is trifluoromethyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein heteroaryl is, thiazolyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein aralkyl is benzyl.
In another embodiment, the present invention is concerned with compounds of
formula I wherein aryloxy is phenoxy.
In another embodiment, the present invention is concerned with compounds of
formula I wherein aralkoxy is benzyloxy.
In another embodiment, the present invention is concerned with compounds of
formula I wherein the substituents R~ and Y are arranged in a trans-
configuration.
In another embodiment, the present invention is concerned with compounds of
formula I wherein the substituents R~ and Y are arranged in a cis-
configuration.
In another embodiment, the present invention is concerned with compounds of
formula I which is a PPARS agonist.
In another embodiment, the present invention is concerned with compounds of
formula I which selective PPARB agonist.
Examples of specific compounds of the invention are:
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester,
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid,
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3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid ethyl ester,
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid,
3-{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester,
3-{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid,
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid methyl ester,
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid ethyl
ester,
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
(E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid methyl
ester,
(E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid,
(Z)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid methyl
ester,
(E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-3-chloro-phenyl}-acetic acid
ethyl ester,
(E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-3-chloro-phenyl}-acetic acid, or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mix-
ture of optical isomers, including a racemic mixture, or any tautomeric forms.
Other examples of specific compounds of the invention are:
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester,
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid,
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester,
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid, or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mix-
ture of optical isomers, including a racemic mixture, or any tautomeric forms.
Other examples of specific compounds of the invention are:
(E)-{4-[3-(4-Phenoxy-phenyl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester,
(E)-{4-[3-(4-Phenoxy-phenyl)-but-2-enyloxy]-phenyl}-acetic acid,
(E)-{3-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl
ester,
(E)-{3-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid,
(E)-{4-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl
ester,
(E)-{4-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid,
(E)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid
ethyl ester,
(E)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid,
(Z)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid
ethyl ester,
(E)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid,
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(E)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl}-acetic acid
ethyl ester,
(E)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl}-acetic acid,
(Z)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl}-acetic acid
ethyl ester,
(Z)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl}-acetic acid,
(E)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid ethyl
ester,
(E)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid,
(Z)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid ethyl
ester,
(Z)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid, or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mix-
ture of optical isomers, including a racemic mixture, or any tautomeric forms.
Other examples of compounds of the invention are:
{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-3-chloro-allyloxy]-phenyl}-acetic acid,
4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid,
{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
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{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-3-bromo-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-3-bromo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-3-iodo-allyloxy]-phenyl}-acetic acid,
{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-3-iodo-phenyl}-acetic acid,
3-{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-3-chloro-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-3-chloro-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-3-chloro-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-3-chloro-allyloxy]-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-3-chloro-phenyl}-propionic acid,
3-{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-3-chloro-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-3-chloro-phenyl}-propionic acid,
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3-{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-3-chloro-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-3-chloro-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-3-chloro-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-3-bromo-phenyl}-propionic acid,
5 3-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-3-bromo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-3-bromo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-3-bromo-allyloxy]-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-3-bromo-phenyl}-propionic acid,
3-{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-3-bromo-phenyl}-propionic acid,
10 3-{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-3-bromo-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-3-bromo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-3-bromo-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-3-bromo-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-fluoro-phenyl)-allyloxy]-3-iodo-phenyl}-propionic acid,
15 3-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-3-iodo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-iodo-phenyl)-allyloxy]-3-iodo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-trifluoromethyl-phenyl)-3-iodo-allyloxy]-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-cyano-phenyl)-allyloxy]-3-iodo-phenyl}-propionic acid,
3-{4-[3,3-Bis-biphenyl)-4-yl-allyloxy]-3-iodo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-furan-2-yl-phenyl)-allyloxy]-3-iodo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-furan-3-yl-phenyl)-allyloxy]-3-iodo-phenyl}-propionic acid,
3-{4-[3,3-Bis-(4-thiophen-2-yl-phenyl)-allyloxy]-3-iodo-phenyl}-propionic
acid,
3-{4-[3,3-Bis-(4-thiophen-3-yl-phenyl)-allyloxy]-3-iodo-phenyl}-propionic
acid, or
a salt thereof with a pharmaceutically acceptable acid or base, or any optical
isomer or mix-
ture of optical isomers, including a racemic mixture, or any tautomeric forms.
The present invention also encompasses pharmaceutically acceptable salts of
the
present compounds. Such salts include pharmaceutically acceptable acid
addition salts,
pharmaceutically acceptable base addition salts, pharmaceutically acceptable
metal salts,
ammonium and alkylated ammonium salts. Acid addition salts include salts of
inorganic acids
as well as organic acids. Representative examples of suitable inorganic acids
include hydro-
chloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the
like. Representative
examples of suitable organic acids include formic, acetic, trichloroacetic,
trifluoroacetic,
propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, malefic,
malic, malonic, mandelic,
oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic,
tartaric, ascorbic,
pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,
aspartic, stearic,
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palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-
toluenesulfonic acids,
sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates,
hydroxynaph-
thoates, glycerophosphates, ketoglutarates and the like. Further examples of
pharmaceuti-
cally acceptable inorganic or organic acid addition salts include the
pharmaceutically accept-
s able salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated
herein by reference. Ex-
amples of metal salts include lithium, sodium, potassium, magnesium, zinc,
calcium salts and
the like. Examples of amines and organic amines include ammonium, methylamine,
di-
methylamine, trimethylamine, ethylamine, diethylamine, propylamine,
butylamine, tetrame-
thylamine, ethanolamine, diethanolamine, triethanolamine, meglumine,
ethylenediamine,
choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-
glucamine,
guanidine and the like. Examples of cationic amino acids include lysine,
arginine, histidine
and the like.
The pharmaceutically acceptable salts are prepared by reacting the compound of
formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium
methoxide, so-
dium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and
the like, in
solvents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol
etc. Mixture of
solvents may be used. Organic bases like lysine, arginine, diethanolamine,
choline, guandine
and their derivatives etc.. may also be used. Alternatively, acid addition
salts wherever appli-
cable are prepared by treatment with acids such as hydrochloric acid,
hydrobromic acid, ni-
tric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid,
methanesulfonic acid, acetic
acid, citric acid, malefic acid salicylic acid, hydroxynaphthoic acid,
ascorbic acid, palmitic acid,
succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like
in solvents like
ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents
may also be
used.
The stereoisomers of the compounds forming part of this invention may be
prepared
by using reactants in their single enantiomeric form in the process wherever
possible or by
conducting the reaction in the presence of reagents or catalysts in their
single enantiomer
form or by resolving the mixture of stereoisomers by conventional methods.
Some of the
preferred methods include use of microbial resolution, enzymatic resolution,
resolving the
diastereomeric salts formed with chiral acids such as mandelic acid,
camphorsulfonic acid,
tartaric acid, lactic acid, and the like wherever applicable or chiral bases
such as brucine,
(R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the
like. Com-
monly used methods are compiled by Jaques et al in "Enantiomers, Racemates and
Resolu-
tion" (Wiley Interscience, 1981). More specifically the compound of formula I
may be con-
vetted to a 1:1 mixture of diastereomeric amides by treating with chiral
amines, aminoacids,
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aminoalcohols derived from aminoacids; conventional reaction conditions may be
employed
to convert acid into an amide; the dia-stereomers may be separated either by
fractional crys-
tallization or chromatography and the stereoisomers of compound of formula I
may be pre-
pared by hydrolysing the pure diastereomeric amide.
Various polymorphs of compound of general formula I forming part of this
invention
may be prepared by crystallization of compound of formula I under different
conditions. For
example, using different solvents commonly used or their mixtures for
recrystallization; crys-
tallizations at different temperatures; various modes of cooling, ranging from
very fast to very
slow cooling during crystallizations. Polymorphs may also be obtained by
heating or melting
the compound followed by gradual or fast cooling. The presence of polymorphs
may be de-
termined by solid probe nmr spectroscopy, it spectroscopy, differential
scanning calorimetry,
powder X-ray diffraction or such other techniques.
The invention also encompasses prodrugs of the present compounds, which on ad-
ministration undergo chemical conversion by metabolic processes before
becoming active
pharmacological substances. In general, such prodrugs will be functional
derivatives of the
present compounds, which are readily convertible in vivo into the required
compound of the
formula (I). Conventional procedures for the selection and preparation of
suitable prodrug
derivatives are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier,
1985.
The invention also encompasses active metabolites of the present compounds.
The invention also relates to pharmaceutical compositions comprising, as an
active
ingredient, at least one compound of the formula I or any optical or geometric
isomer or
tautomeric form thereof including mixtures of these or a pharmaceutically
acceptable salt
thereof together with one or more pharmaceutically acceptable carriers or
diluents.
Furthermore, the invention relates to the use of compounds of the general
formula I
or their tautomeric forms, their stereoisomers, their polymorphs, their
pharmaceutically ac-
ceptable salts or pharmaceutically acceptable solvates thereof for the
preparation of a phar-
maceutical composition for the treatment and/or prevention of conditions
mediated by nu-
clear receptors, in particular the Peroxisome Proliferator-Activated Receptors
(PPAR) such
as the conditions mentioned above.
In another aspect, the present invention relates to a method of treating
and/or
preventing Type I or Type II diabetes.
In a still further aspect, the present invention relates to the use of one or
more
compounds of the general formula I or pharmaceutically acceptable salts
thereof for the
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preparation of a pharmaceutical composition for the treatment and/or
prevention of Type I or
Type II diabetes.
In a still further aspect, the present compounds are useful for the treatment
and/or
prevention of IGT.
In a still further aspect, the present compounds are useful for the treatment
and/or
prevention of Type 2 diabetes.
In a still further aspect, the present compounds are useful for the delaying
or pre-
vention of the progression from IGT to Type 2 diabetes.
In a still further aspect, the present compounds are useful for the delaying
or pre-
vention of the progression from non-insulin requiring Type 2 diabetes to
insulin requiring
Type 2 diabetes.
In another aspect, the present compounds reduce blood glucose and triglyceride
levels and are accordingly useful for the treatment and/or prevention of
ailments and disor-
ders such as diabetes and/or obesity.
In still another aspect, the present compounds are useful for the treatment
and/or
prophylaxis of insulin resistance (Type 2 diabetes), impaired glucose
tolerance, dyslipidemia,
disorders related to Syndrome X such as hypertension, obesity, insulin
resistance, hypergly-
caemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial
ischemia and
other cardiovascular disorders.
In still another aspect, the present compounds are effective in decreasing
apoptosis
in mammalian cells such as beta cells of Islets of Langerhans.
In still another aspect, the present compounds are useful for the treatment of
certain
renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic
syndrome, hyper-
tensive nephrosclerosis.
In still another aspect, the present compounds may also be useful for
improving
cognitive functions in dementia, treating diabetic complications, psoriasis,
polycystic ovarian
syndrome (PCOS) and prevention and treatment of bone loss, e.g. osteoporosis.
The present compounds may also be administered in combination with one or more
further pharmacologically active substances eg., selected from antiobesity
agents, antidiabet-
ics, antihypertensive agents, agents for the treatment andlor prevention of
complications re-
sulting from or associated with diabetes and agents for the treatment and/or
prevention of
complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be
adminis-
tered in combination with one or more antiobesity agents or appetite
regulating agents.
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Such agents may be selected from the group consisting of CART (cocaine am-
phetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists,
MC4 (melano-
cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists,
CRF (corticotro-
pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding
protein) an-
y tagonists, urocortin agonists, (33 agonists, MSH (melanocyte-stimulating
hormone) agonists,
MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin)
agonists, se-
rotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake
inhibitors, mixed sero-
tonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin
agonists, galanin
antagonists, growth hormone, growth hormone releasing compounds, TRH
(thyreotropin re-
leasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators,
leptin ago-
nists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR
(retinoid X recep-
tor) modulators or TR (3 agonists.
In one embodiment of the invention the antiobesity agent is leptin.
In another embodiment the antiobesity agent is dexamphetamine or amphetamine.
In another embodiment the antiobesity agent is fenfluramine or
dexfenfluramine.
In still another embodiment the antiobesity agent is sibutramine.
In a further embodiment the antiobesity agent is orlistat.
In another embodiment the antiobesity agent is mazindol or phentermine.
Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1)
derivatives
such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is
incorporated herein
by reference as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise sulphonylureas,
bigua-
nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as
those disclosed in
WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1
agonists, po-
tassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861
to
Novo Nordisk A/S which are incorporated herein by reference, DPP-IV
(dipeptidyl peptidase-
IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of
gluconeogenesis and/or
glycogenolysis, glucose uptake modulators, compounds modifying the lipid
metabolism such
as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors
(statins), com-
pounds lowering food intake, RXR agonists and agents acting on the ATP-
dependent potas-
slum channel of the ~i-cells.
In one embodiment of the invention the present compounds are administered in
combination with insulin.
In a further embodiment the present compounds are administered in combination
with a sulphonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide.
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In another embodiment the present compounds are administered in combination
with a biguanide eg. metformin.
In yet another embodiment the present compounds are administered in
combination
with a meglitinide eg. repaglinide or senaglinide.
5 In a further embodiment the present compounds are administered in
combination
with an a-glucosidase inhibitor eg. miglitol or acarbose.
In another embodiment the present compounds are administered in combination
with an agent acting on the ATP-dependent potassium channel of the [3-cells
eg. tolbutamide,
glibenclamide, glipizide, glicazide or repaglinide.
10 Furthermore, the present compounds may be administered in combination with
nateglinide.
In still another embodiment the present compounds are administered in
combination
with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine,
colestipol, clofi-
brate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or
dextrothyroxine.
15 In a further embodiment the present compounds are administered in
combination
with more than one of the above-mentioned compounds eg. in combination with a
sulphony-
lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin,
insulin and a
sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
Furthermore, the present compounds may be administered in combination with one
20 or more antihypertensive agents. Examples of antihypertensive agents are ~i-
blockers such
as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE
(angiotensin con-
verting enzyme) inhibitors such as benazepril, captopril, enalapril,
fosinopril, lisinopril,
quinapril and ramipril, calcium channel blockers such as nifedipine,
felodipine, nicardipine,
isradipine, nimodipine, diltiazem and verapamil, and a-blockers such as
doxazosin, urapidil,
prazosin and terazosin. Further reference can be made to Remington: The
Science and
Practice of Pharmacy, 19t" Edition, Gennaro, Ed., Mack Publishing Co., Easton,
PA, 1995.
It should be understood that any suitable combination of the compounds
according
to the invention with one or more of the above-mentioned compounds and
optionally one or
more further pharmacologically active substances are considered to be within
the scope of
the present invention.
The present invention also relates to a process for the preparation of the
above said
novel compounds, their derivatives, their analogs, their tautomeric forms,
their stereoisom-
ers, their polymorphs, their pharmaceutically acceptable salts or
pharmaceutically acceptable
solvates.
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PHARMACEUTICAL COMPOSITIONS
The compounds of the invention may be administered alone or in combination
with
pharmaceutically acceptable carriers or excipients, in either single or
multiple doses. The
pharmaceutical compositions according to the invention may be formulated with
phar-
maceutically acceptable carriers or diluents as well as any other known
adjuvants and ex-
cipients in accordance with conventional techniques such as those disclosed in
Remington:
The Science and Practice of Pharmacy, 19t" Edition, Gennaro, Ed., Mack
Publishing Co.,
Easton, PA, 1995. The compositions may appear in conventional forms, for
example capsules,
tablets, aerosols, solutions, suspensions or topical applications.
Typical compositions include a compound of formula I or a pharmaceutically
acceptable acid addition salt thereof, associated with a pharmaceutically
acceptable
excipient which may be a carrier or a diluent or be diluted by a carrier, or
enclosed within a
carrier which can be in the form of a capsule, sachet, paper or other
container. In making the
compositions, conventional techniques for the preparation of pharmaceutical
compositions
may be used. For example, the active compound will usually be mixed with a
carrier, or
diluted by a carrier, or enclosed within a carrier which may be in the form of
a ampoule,
capsule, sachet, paper, or other container. When the carrier serves as a
diluent, it may be
solid, semi-solid, or liquid material which acts as a vehicle, excipient, or
medium for the
active compound. The active compound can be adsorbed on a granular solid
container for
example in a sachet. Some examples of suitable carriers are water, salt
solutions, alcohols,
polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive
oil, gelatine, lactose,
terra albs, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin,
agar, pectin,
acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty
acids, fatty acid amines,
fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene,
hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or
diluent may include
any sustained release material known in the art, such as glyceryl monostearate
or glyceryl
distearate, alone or mixed with a wax. The formulations may also include
wetting agents,
emulsifying and suspending agents, preserving agents, sweetening agents or
flavouring
agents. The formulations of the invention may be formulated so as to provide
quick,
sustained, or delayed release of the active ingredient after administration to
the patient by
employing procedures well known in the art.
The pharmaceutical compositions can be sterilized and mixed, if desired, with
auxil-
iary agents, emulsifiers, salt for influencing osmotic pressure, buffers
and/or colouring sub-
stances and the like, which do not deleteriously react with the active
compounds.
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The route of administration may be any route, which effectively transports the
active
compound to the appropriate or desired site of action, such as oral, nasal,
pulmonary, trans-
dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous,
intraurethral, intramuscu-
lar, intranasal, ophthalmic solution or an ointment, the oral route being
preferred.
If a solid carrier is used for oral administration, the preparation may be
tabletted,
placed in a hard gelatin capsule in powder or pellet form or it can be in the
form of a troche or
lozenge. If a liquid carrier is used, the preparation may be in the form of a
syrup, emulsion, soft
gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous
liquid suspension
or solution.
For nasal administration, the preparation may contain a compound of formula 1
dissolved or suspended in a liquid carrier, in particular an aqueous carrier,
for aerosol
application. The carrier may contain additives such as solubilizing agents,
e.g. propylene glycol,
surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or
cyclodextrin, or
preservatives such as parabenes.
For parenteral application, particularly suitable are injectable solutions or
suspen-
sions, preferably aqueous solutions with the active compound dissolved in
polyhydroxylated
castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or
binder or
the like are particularly suitable for oral application. Preferable carriers
for tablets, dragees,
or capsules include lactose, corn starch, and/or potato starch. A syrup or
elixir can be used in
cases where a sweetened vehicle can be employed.
A typical tablet which may be prepared by conventional tabletting techniques
may
contain:
Core:
Active compound (as free compound or salt thereof) 5 mg
Colloidal silicon dioxide (Aerosil) 1.5 mg
Cellulose, microcryst. (Avicel) 70 mg
Modified cellulose gum (Ac-Di-Sol) 7.5 mg
Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg
*Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizes for film coating.
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If desired, the pharmaceutical composition of the invention may comprise the
compound of formula (I) in combination with further pharmacologically active
substances
such as those described in the foregoing.
The compounds of the invention may be administered to a mammal, especially a
human in need of such treatment, prevention, elimination, alleviation or
amelioration of
diseases related to the regulation of blood sugar.
Such mammals include also animals, both domestic animals, e.g. household pets,
and non-domestic animals such as wildlife.
The compounds of the invention are effective over a wide dosage range. A
typical
oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight
per day,
preferably from about 0.01 to about 50 mg/kg body weight per day, and more
preferred from
about 0.05 to about 10 mg/kg body weight per day administered in one or more
dosages
such as 1 to 3 dosages. The exact dosage will depend upon the frequency and
mode of ad-
ministration, the sex, age, weight and general condition of the subject
treated, the nature and
severity of the condition treated and any concomitant diseases to be treated
and other fac-
tors evident to those skilled in the art.
The formulations may conveniently be presented in unit dosage form by methods
known to those skilled in the art. A typical unit dosage form for oral
administration one or
more times per day such as 1 to 3 times per day may contain of from 0.05 to
about 1000 mg,
preferably from about 0.1 to about 500 mg, and more preferred from about 0.5
mg to about
200 mg.
Any novel feature or combination of features described herein is considered
essential to this invention.
The present invention is further illustrated in the following representative
examples
which are, however, not intended to limit the scope of the invention in any
way.
EXAMPLES
The compounds used as starting materials are either known compounds or com-
pounds which can readily be prepared by methods known per se. The structures
of the com
pounds are confirmed by either elemental analysis (MA) nuclear magnetic
resonance (NMR),
mass spectrometry (MS) or optical rotation. NMR shifts (5) are given in parts
per million
(ppm) and only selected peaks are given. mp is melting point and is given in
°C. Column
chromatography was carried out using the technique described by W.C. Still et
al, J. Org.
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Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art 9385). The optical
rotation was
measured on a Advanced Laser Polarimeter.
The abbreviations as used in the examples have the following meaning:
THF: tetrahydrofuran
DMSO: dimethylsulfoxide
CDCI3: deutorated chloroform
DMF: N,N-dimethylformamide
min: minutes
h: hours
General procedure (A)
Stets A:
Reacting a compound of formula II
X\ /Y
~O
(II)
wherein X and Y are defined as above, through a Wittig-like process with for
example
(Et0)~PO(CHR~)COOR6 (wherein Rs is an alkyl group), in the presence of a base
such as
sodium hydride, EtONa and the like to give a compound of formula III
X Y
O
O
R6 (III)
wherein X, Y, R~ and R6 are defined as above
St- ep B:
Reducing the compound of formula III, wherein X, Y, R~ and R6 are defined as
above with a suitable reagent such as diisobutylaluminium hydride, to give a
compound of
formula IV
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X Y
R~
OH
(IV)
wherein X, Y and R~ are defined as above, and
5 Step C:
Reacting the compound of formula IV, wherein X, Y and R~ are defined as above,
(except that when X or Y is substituted with hydroxy, amino, C~.6-alkylamino
or C2_s-
dialkylamino these functionalities have to be protected) with a compound of
formula V
H
I CV)
z
~Ar
I
Q\ /O
O~R
wherein Z, Ar, Q and R2 are defined as above, except that Rz is not hydrogen
under Mitsun-
obu conditions, using a reagent such as
triphenylphosphine/diethylazodicarboxylate and the
like to obtain a compound of formula I, wherein X, Y, Z, Ar, Q, R~ and R~ are
defined as
above, except that RZ is not hydrogen.
General procedure (B)
St_ ep A:
Converting the -OH functionality in the compound of formula IV, wherein X, Y
and R~
are defined as above, to an appropriate leaving group (L) such as p-
toluenesulfonate,
methanesulfonate, halogen (for example by methods according to: Houben-Weyl,
Methoden
der organischen Chemie, Alkohole III, 6/1 b, Thieme-Verlag 1984, 4th Ed., pp.
927-939;
Comprehensive Organic Transformations. A guide to functional group
preparations, VCH
Publishers 1989, 1 St Ed., pp. 353-363 and J. Org. Chem. ,Vol. 36 (20), 3044-
3045, 1971 ),
triflate and the like, to give a compound of formula VI
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26
X Y
R~
L
(VI)
wherein X, Y, R~ and L are defined as above.
Step B:
Reacting the compound of formula VI wherein L is a leaving group such as p-
toluenesulfonate, methanesulfonate, halogen, triflate and the like and wherein
X, Y and R~
are defined as above with a compound of formula V wherein Z, Ar, Q and R2 are
defined as
above, except that Rz is not hydrogen to give a compound of formula I wherein
X, Y, Z, Ar, Q,
R~ and Ra are defined as above, except that R2 is not hydrogen.
General procedure (C)
Step A:
By chemical or enzymatic saponification of a compound of formula I wherein X,
Y, Z,
Ar, Q, R~ and R2 are defined as above, except that R2 is not hydrogen to give
a compound of
formula I wherein X, Y, Z, Ar, Q, R~ and R2 are defined as above, except that
R2 is hydrogen.
Example 1 (General procedure (A))
3-(3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester
Br
O
~CH3
St_ ea A:
A solution of triethyl phosphonoacetate (26.8 g, 120.0 mmol) in dry THF (100
mL)
was added at 0°C over a period of 25 min. to a stirred suspension of
sodium hydride (60% in
oil, 4.8 g, 120.0 mmol) in dry THF (100 ml). After stirring at 0°C for
30 min. a solution of 4,4'-
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dibromobenzophenone (20.4 g, 60.0 mmol) in dry THF (200 ml) was added and the
mixture
slowly warmed to room temperature, and stirring continued for 48 h. The
reaction mixture
was diluted with1 N hydrochloric acid (400 ml) and ethyl acetate (100 ml). The
organic phase
was separated, and the aqueous phase further extracted with ethyl acetate (2 x
300 ml). The
combined organic phases were washed with water (300 ml x 3), dried (MgS04),
filtered and
concentrated in vacuo. The product was purified by column chromatography on
silica gel
(15% ethyl acetate in n-heptane eluent) to give 24.5 g (99%) 3,3-bis-(4-
bromophenyl)-acrylic
acid ethyl ester as an off-white amorphous solid.
'H NMR (CDCL3): 81.15 (3H, t), 4.05 (2H, q), 6.34 (1H, s), 7.10 (4H, dd), 7.48
(4H, dd).
Step B:
A 1 M solution of DIBAL-H in toluene (150 ml, 150 mmol) was added dropwise, at
-
70°C over 30 min, to a stirred solution of 3,3-bis-(4-bromophenyl)-
acrylic acid ethyl ester
(24.5 g, 59.7 mmol) in dry THF (400 ml) and stirred for 30 min. The mixture
was warmed to
room temperature, and stirred for 1.5 h. The mixture was poured into 1 N HCI
(700 ml) with
vigorous stirring and the product extracted with ethyl acetate (3 x 200 ml).
The combined or-
ganic extracts were washed with brine, dried (MgS04), and evaporated to give
the crude
product as an off-white solid, which was purified by column chromatography on
silica gel
(15% ethyl acetate in n-heptane eluent). The purified product was diluted in
boiling heptane,
filtered and the filtrate cooled, giving 15.8 g (72%) 3,3-bis-(4-
bromophenyl)prop-2-en-1-of as
an crystalline solid.
' H NMR (CDCL3): ~ 1.45 (1 H, t), 4.18 (2H, t), 6.23 (1 H, t), 7.06 (4H, dd),
7.45 (4H, dd).
St- ep C:
1 ) To an ice-cooled solution of 3-(3-hydroxyphenyl)propionic acid (20.0 g,
120
mmol) in ethanol was dropwise added thionyl chloride (8.8 ml, 120 mmol). The
mixture was
stirred at room temperature over night, concentrated in vacuo and submitted to
flash chroma-
tography (10% ethyl acetate in toluene eluent) to give 23.3 g of 3-(3-hydroxy-
phenyl)-
propionic acid ethyl ester.
'H NMR (CDCL3): 81.25 (3H, t), 2.60 (2H, t), 2.88 (2H, t), 4.13 (2H, q), 6.65-
6.75 (3H, m),
7.05-7.15 (1 H, m).
2) Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (567 mg, 2.25
mmol) was added at 0-5°C to a stirred solution of tributylphosphine
(455 mg, 2.25 mmol), 3-
(3-hydroxy-phenyl)-propionic acid ethyl este (291 mg, 1.5 mmol) and 3,3-bis-(4-
bromophenyl)prop-2-en-1-of (552 mg, 1.5 mmol) in dry THF (15 ml), the mixture
warmed to
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28
room temperature, and stirred for 48 h. The reaction mixture was concentrated
in vacuo, and
added water and ethyl acetate (30 ml each). The aqueous layer was collected
and further
extracted with ethyl acetate (2 x 30 ml). The organic layers were combined,
washed with wa-
ter, dried (MgSO4) and evaporated. The crude product was then purified by
column chroma-
tography on silica (toluene eluent) to give 756 mg (93%) of the title
compound.
'H NMR (CDCL3): S 1.23 (3H, t), 2.57 (2H, t), 2.88 (2H, t), 4.10 (2H, q), 4.52
(2H, d), 6.30
(1 H, t), 6.62-6.70 (2H, m), 6.77 (1 H, d), 7.03-7.18 (5H, m), 7.48 (2H, d),
7.52 (2H, d).
Example 2 (General procedure (C))
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid
OH
St, ep A:
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester
(example
1 ) (755 mg, 1.4 mmol) was hydrolysed in 1 N NaOH (5.6 ml) and ethanol (15 ml)
for 16 h at
room temperature. Water (5 ml) was added and ethanol removed by concentratio
in vacuo.
The mixture was neutralised with 6N HCI. The crude product was extracted with
ethyl acetate
(x 3) The organic layers were combined, dried (MgS04) and evaporated. The
residue was
dissolved in toluene and the title compound precipitated with petroleum ether,
to give 430 mg
of the title compound.
'H NMR (MeOD): X2.55 (2H, t), 2.85 (2H, t), 4.55 (2H, d), 6.35 (1H, t), 6.60-
6.73 (2H, m),
6.78 (1 H, d), 7.08-7.18 (5H, m), 7.45 (2H, d), 7.58 (2H, d).
Example 3 (General procedure (A))
3-{3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid ethyl ester
Br "-
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Br Br
O ~ O
O
Step A-B:
3,3-Bis-(4-bromophenyl)prop-2-en-1-of was prepared as described in example 1,
step A-B.
Step C:
1 ) To an ice-cooled solution of 3-(3-hydroxyphenyl)-acetic acid (21.0 g, 138
mmol) in
ethanol was dropwise added thionyl chloride (10.1 ml. 138 mmol). The mixture
was stirred at
room temperature over night, concentrated in vacuo and submitted to flash
chromatography
(10% ethyl acetate in toluene eluent) to give 23.8 g of 3-(3-hydroxy-phenyl)-
acetic acid ethyl
ester.
'H NMR (CDCL3): s 1.27 (3H, t), 3.55 (2H, s), 4.15 (2H, q), 6.11 (1 H, s),
6.68-6.85 (3H, m),
7.15 (1 H, t).
2) Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (567 mg, 2.25
mmol) was added at 0-5°C to a stirred solution of tributylphosphine
(455 mg, 2.25 mmol), 3-
(3-hydroxy-phenyl)-acetic acid ethyl este (270 mg, 1.5 mmol) and 3,3-bis-(4-
bromophenyl)prop-2-en-1-of (552 mg, 1.5 mmol) in dry THF (15 ml), the mixture
warmed to
room temperature, and stirred for 48 h. The reaction mixture was concentrated
in vacuo, and
added water and ethyl acetate (30 ml each). The aqueous layer was collected
and further
extracted with ethyl acetate (2 x 30 ml). The organic layers were combined,
washed with wa-
ter, dried (MgS04) and evaporated. The crude product was then purified by
column chroma-
tography on silica (toluene eluent) to give 701 mg (88%) of the title
compound.
'H NMR (CDCL3): 81.23 (3H, t), 3.53 (2H, s), 4.13 (2H, q), 4.52 (2H, d), 6.32
(1H, t), 6.70-
6.78 (2H, m), 6.87 (1 H, d), 7.05-7.13 (5H, m), 7.20 (2H, t), 7.42 (2H, d),
7.52 (2H, d).
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Example 4 (General procedure (C))
3-~3-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid
Br "°
5 St-ep A:
The title compound was prepared from 3-{3-[3,3-bis-(4-bromo-phenyl)-allyloxy]-
phenyl)-acetic acid ethyl ester (example 3) (701 mg, 1.3 mmol) by a procedure
analogous to
that described in example 2.
'H NMR (CDCL3): X3.55 (2H, s), 4.53 (2H, d), 6.30 (1H, t), 6.75 (2H, bs), 6.84
(1H, d), 7.10
10 (4H, t), 7.20 (1 H, t), 7.40 (2H, d), 7.52 (2H, d).
Example 5 (General procedure (A))
3-{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl)-propionic acid ethyl ester
Br Br
O
O
O
15 Step A-B:
3,3-Bis-(4-bromophenyl)prop-2-en-1-of was prepared as described in example 1
step A-B.
St- ep C:
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1 ) To an ice-cooled solution of 3-(p-hydroxyphenyl)-propionic acid (8.3 g,
50.0
mmol) in ethanol (100 mL) was dropwise added thionyl chloride (3.7 mL, 50.7
mmol). The
mixture was stirred at room temperature over night, concentrated in vacuo and
the residue
purified by kugelrohr distillation, to give 9.6 g (99%) of 3-(4-hydroxy-
phenyl)-propionic acid
ethyl ester as a colourless oil.
'H NMR (CDCL3): 81.21 (3H, t), 2.58 (2H, t), 2.86 (2H, t), 4.12 (2H, q), 6.75
(2H, d), 6.90
(1 H, bs), 7.01 (2H, d).
2) Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0
mmol)
was added at 0-5°C to a stirred solution of tributylphosphine (404 mg,
2.0 mmol), 3-(4-
hydroxy-phenyl)-propionic acid ethyl ester (388 mg, 2.0 mmol) and 3,3-bis-(4-
bromophenyl)prop-2-en-1-of (736 mg, 2.0 mmol) in dry THF (50 ml), the mixture
warmed to
room temperature, and stirred for 4 h. The reaction mixture was concentrated
in vacuo, and
added water and ethyl acetate (75 ml each). The aqueous layer was collected
and further
extracted with ethyl acetate (2 x 75 ml). The organic layers were combined,
washed with wa-
ter, dried (MgSO~) and evaporated. The crude product was then purified by
column chroma-
tography on silica (25 % ethylacetane in heptane eluent) to give 1.0 g (92%)
of the title com-
pound.
'H NMR (CDCL3): 8 1.23 (3H, t), 2.58 (2H, t), 2.88 (2H, t), 4.12 (2H, q), 4.52
(2H, d), 6.32
(1 H, t), 6.76 (2H, d), 7.04-7.15 (6H, m), 7.42 (2H, d), 7.53 (2H, d).
Example 6 (General procedure (C))
3-{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic acid
Br Br
i
OH
O
St_ ep A:
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To a solution of 3-{4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-phenyl}-propionic
acid ethyl
ester (example 5) (1.0 g, 2.0 mmol) in toluene (20 mL) and ethanol (50 mL) was
added 1 N
NaOH (10.0 mL) and the reaction mixture was stirred for 16 h at room
temperature. The re-
action mixture was concentrated in vacuo and 1 N HCI added. The product was
extracted
with ethyl acetate (x 3). The organic layers were combined, washed with water,
dried
(MgS04), filtered and concentrated in vacuo. The residue was recrystalised
from warm etha-
nol (100 mL), witch was concentrated to 60 mL, and cooled, to give 600 mg (56
%) of the title
compound.
'H NMR (CDCI3): 82.65 (2H, t), 2.90 (2H, t), 4.53 (2H, d), 6.32 (1H, t), 6.76
(2H, d), 7.03-7.15
(6H, m), 7.42 (2H, d), 5.52 (2H, d).
Example 7 (General procedure (A))
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid methyl ester
Br Br
O
O
Step A-B:
3,3-Bis-(4-bromophenyl)prop-2-en-1-of was prepared as described in example 1
step A-B.
St_ ea C:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (504 mg, 2.0
mmol)
was added at 0-5°C to a stirred solution of tributylphosphine (404 mg,
2.0 mmol), methyl 4-
hydroxyphenylacetate (250 mg, 1.5 mmol) and 3,3-bis-(4-bromophenyl)prop-2-en-1-
of (552
mg, 1.5 mmol) in dry THF (10 ml), the mixture stirred for 1 h, filtered and
concentrated in
vacuo. The crude product was then purified by column chromatography on silica
(toluene
eluent). The purified product was suspended in petroleum ether, filtered to
give 480 mg
(62%) of the title compound.
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'H NMR (CDCL3): X3.55 (2H, s), 3.68 (3H, s), 4.52 (2H, d), 6.32 (1H, t), 6.78
(2H, d), 7.03-
7.20 (6H, m), 7.42 (2H, d), 7.53 (2H, d).
Example 8 (General procedure (C))
(4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid
Br Br
O
OH
Step A
To a solution of {4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-phenyl}-acetic acid
ethyl ester
(example 7) (473 mg, 0.9 mmol) in THF (5 mL) and ethanol (3 mL) was added 1 N
NaOH (3
mL) and the reaction mixture was stirred at 60°C for 1 h and at room
temperature over night.
The title compound as an sodium salt, was isolated by filtration and washed
with ethanol to
give 375 mg (81 %).
'H NMR (MeOD): 63.40 (2H, s), 4.53 (2H, d), 6.35 (1H, t), 6.73 (2H, d), 7.08-
7.25 (6H, m),
7:47 (2H, d), 5.57 (2H, d).
Example 9 (General procedure (A))
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid ethyl
ester
Br Br
O ~ O
O
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34
Step A-B:
3,3-Bis-(4-bromophenyl)prop-2-en-1-of was prepared as described in example 1
step A-B.
Step C:
1) To an ice-cooled solution of 3-chloro-4-hydroxyphenylacetic acid (10.0 g,
53.0
mmol) in ethanol was dropwise added thionyl chloride (3.9 ml, 53.5 mmol). The
mixture was
stirred at room temperature for 48 h, concentrated in vacuo and submitted to
flash chroma-
tography (graduated from toluene to 5% ethyl acetate in toluene eluent) to
give 11.0 g of 3-
chloro-4-hydroxyphenylacetic acid ethyl ester.
H NMR (CDCL3): s 1.27 (3H, t), 3.53 (2H, s), 4.15 (2H, q), 5.65 (1 H, s), 6.95
(1 H, d), 7.08
(1 H, dd), 7.26 (1 H, d).
2) A solution of tributylphosphine (955 ~I, 3.0 mmol), 3- chloro-4-
hydroxyphenylacetic acid ethyl ester (472 mg, 2.2 mmol) and 3,3-bis-(4-
bromophenyl)prop-2-
en-1-of (736 mg, 2.0 mmol) in dry THF (15 ml) was stirred at 0-5°C for
30 min, under a at-
mosphere of nitrogen. Azodicarboxylic dipiperidide (756 mg, 3.0 mmol) was
added the mix-
ture stirred at 0-5°C for 2 h, and at room temperature over night. The
reaction mixture was
filtered and the filtrate concentrated in vacuo. The crude product was then
purified by column
chromatography on silica (eluent graduated from heptane to toluene) to give
1.0 g (89%) of
the title compound.
H NMR (CDCL3): ~ 1.25 (3H, t), 3.52 (2H, s), 4.14 (2H, q), 4.58 (2H, d), 6.34
(1 H, t), 6.72
(1 H, d), 7.03-7.14 (5H, m), 7.30 (1 H, d), 7.42 (2H, d), 7.53 (2H, d).
Example 10 (General procedure (C))
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl}-acetic acid
Bra ~Br
/ \
I
CI
° \ O
I/
OH
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Step A:
To a solution of {4-[3,3-bis-(4-bromo-phenyl)-allyloxy]-3-chloro-phenyl)-
acetic acid
ethyl ester (example 9) (1.0 g, 1.8 mmol) in THF (8 ml) and ethanol (5 ml) was
added 1 N
NaOH (4.0 ml) and the reaction mixture was stirred for 1 h at room
temperature. The reaction
5 mixture was concentrated in vacuo. The residue was suspended in water and
817 mg (82%)
of the title compound was isolated by filtration as the sodium salt.
'H NMR (MeOD): X3.37 (2H, s), 4.57 (2H, d), 6.40 (1 H, t), 6.79 (1 H, d), 7.07-
7.20 (5H, m),
7.35 (1 H, d), 7.45 (2H, d), 7.58 (2H, d).
Example 11 (General procedure (A))
10 (E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid methyl
ester
Br
O
O
St, ep A:
Sodium (5.29 g, 230 mmol) was added to ethanol (200 ml) at 20°C and the
mixture
15 stirred until the metal had fully reacted. Triethyl phosphonoacetate (30.7
ml, 153 mmol) was
added, the mixture stirred for 20 min, then a solution of 4-bromobenzophenone
(20.0 g, 76.6
mmol) was added and the reaction mixture heated to 70°C under reflux
for 17 h. The solution
was cooled, the ethanol evaporated and the residue partitioned between 4 N HCI
and ethyl
acetate. The aqueous layer was collected and further extracted with ethyl
acetate (2 x 200
20 ml). The organic layers were combined, washed with brine, dried (MgS04) and
evaporated.
This was purified by column chromatography on silica gel to give:
(~)-3-(4-bromophenyl)-3-phenylacrylicacid ethyl ester as a white crystalline
compound; 11.1
g. 'H NMR (300 MHz, CDCI3) ~ 1.17 (3H, t), 4.07 (2H, q), 6.37 (1 H, s), 7.08
(2H, d), 7.20-
7.42 (5H, m), 7.50 (2H, d); and
25 (E)-3-(4-bromophenyl)-3-phenylacrylicacid ethyl ester as a clear oil; 12.0
g. NMR (300 MHz,
CDCI3) ~: 1.10 (3H, t), 4.05 (2H, q), 6.34 (1 H, s), 7.10-7.22 (4H, m), 7.34-
7.48 (5H, m).
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Step B:
A 1.2 M solution of DIBAL-H in toluene (45 ml, 42 mmol) was added dropwise, at-
15°C over 20 min, to a stirred solution of (E)-3-(4-bromophenyl)-3-
phenylacrylicacid ethyl es-
ter (6.0 g, 18.1 mmol) in dry THF (80 ml), and the mixture stirred for 30 min.
Rochelles salt
and water was carefully added, and the resulting mixture extracted with ethyl
acetate (x2).
The combined organic extracts were washed with brine, dried (MgS04), and
evaporated to
give 5.2 g of (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol.
'H NMR (300 MHz, CDC13) ~ 1.40 (1 H, br s), 4.22 (2H, d), 6.23 (1 H, t), 7.06-
7.18 (4H, m),
7.32-7.45 (5H, m).
Stets C:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5°C to
a stirred so-
lution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-
hydroxyphenylacetate (332
mg, 2.0 mmol) and (E)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-of (578 mg, 2.0
mmol) in
dry THF (25 ml), the mixture was stirred for 1 h. The mixture was filtered and
concentrated I
vacuo. The residue was purified by flash chromatography on silica gel (toluene
as eluent) to
give 710 mg (81 %) of the title compound.
'H NMR (300 MHz, CDCI3) S 3.54 (2H, s), 3.67 (3H, s), 4.55 (2H, d), 6.30 (1H,
t), 6.78 (2H,
d), 7.10-7.22 (6H, m), 7.35-7.43 (5H, m).
Example 12 (General procedure (C))
(E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid
Br
O ~ O
OH
St- ep A:
To a solution of (E)-(4-[3-(4-bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic
acid
ethyl ester (example 11) (700 mg, 1.6 mmol) in THF (5 m) and ethanol (5 ml)
was added 1 N
NaOH (5.0 ml) and the reaction mixture was stirred for 1 h at 60°C for
1 h and at room tem-
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37
perature over night. The reaction mixture was added water and the organic
solvent evapo-
rated. 1 N HCI was added to pH ~1-2 and the product extracted with dichloro-
methane/isopropanol (19:1). The combined organic phases were dried (MgS04),
filtered and
concentrated in vacuo. The residue was suspended in toluene/petroleum ether
(1:1 ) and 490
mg (70%) of the title compound was isolated by filtration.
'H NMR (CDCI3): X3.57 (2H, s), 4.5 (2H, d), 6.30 (1H, t), 6.79 (2H, d), 7.08-
7.22 (6H, m),
7.35-7.45 (5H, m).
Example 13 (General procedure (A))
(Z)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-phenyl}-acetic acid methyl ester
Br
O
\ Oi
Step A:
(Z)-3-(4-bromophenyl)-3-phenylacrylicacid ethyl ester was prepared as
described in
example 11 step A.
St_ ep B:
A 1.2 M solution of DIBAL-H in toluene (84 ml, 100 mmol) was added dropwise,
at -
15°C over 20 min, to a stirred solution of (Z)-3-(4-bromophenyl)-3-
phenylacrylicacid ethyl es-
ter (11.1 g, 33.5 mmol) in dry THF (150 ml), and the mixture stirred for 30
min. Rochelles salt
and water was carefully added, and the resulting mixture extracted with ethyl
acetate (x2).
The combined organic extracts were washed with brine, dried (MgS04), and
evaporated to
give 9.3 g of (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-ol.
'H NMR (300 MHz, CDCI3) ~ 1.40 (1 H, br s), 4.22 (2H, d), 6.23 (1 H, t), 7.06-
7.18 (4H, m),
7.32-7.45 (5H, m).
St_ ea C:
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Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5°C to
a stirred so-
lution of tributylphosphine (0.94 ml, 786 mg, 3.0 mmol), methyl 4-
hydroxyphenylacetate (332
mg, 2.0 mmol) and (Z)-3-(4-bromo-phenyl)-3-phenyl-prop-2-en-1-of (578 mg, 2.0
mmol) in
dry THF (25 ml), the mixture was stirred for 1 h. The mixture was filtered and
concentrated I
vacuo. The residue was purified by flash chromatography on silica gel (toluene
as eluent) to
give 650 mg (74%) of the title compound.
'H NMR (300 MHz, CDCI3) ~ 3.55 (2H, s), 3.68 (3H, s), 4.54 (2H, d), 6.33 (1H,
t), 6.80 (2H,
d), 7.10 (2H, d), 7.16 (2H, d), 7.20-7.32 (5H, m), 7.53 (2H, d).
Example 14 (General procedure (A))
(E)-{4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-3-chloro-phenyl}-acetic acid
ethyl ester
Br
;I
O ~ O
O~
Step A-B:
(E)-3-(4-Bromo-phenyl)-3-phenyl-prop-2-en-1-of was prepared as described in ex-
ample 11 step a-b.
St-- ep C:
1 ) To an ice-cooled solution of 3-chloro-4-hydroxyphenyl-acetic acid (10.0 g,
53
mmol) in ethanol was dropwise added thionyl chloride (3.9 mL. 53.5 mmol). The
mixture was
stirred at room temperature over night, concentrated in vacuo and submitted to
flash chroma-
tography (eluent: graduated from 10 % ethyl acetate in toluene to toluen) to
give 11 g of 3-
chloro-4-hydroxyphenyl-acetic acid ethyl ester.
' H NMR (CDCL3): ~ 1.25 (3H, t), 3.52 (2H, s), 4.15 (2H, q), 5.75 (1 H, s),
6.93 (1 H, d), 7.05
(1 H, d), 7.25 (1 H, s).
2) Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (756 mg, 3.0
mmol)
was added at 0-5°C to a stirred solution of tributylphosphine (786 mg,
3.0 mmol), 3-chloro-4-
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hydroxyphenyl-acetic acid ethyl ester (537 mg, 2.5 mmol) and (E)-3-(4-bromo-
phenyl)-3-
phenyl-prop-2-en-1-of (578 mg, 2.0 mmol) in dry THF (15 ml), the mixture was
stirred for 2 h.
The reaction mixture was filtered and concentrated in vacuo. The residue was
purified by
flash chromatography on silica (eluent: toluen) to give 640 mg (66%) of the
title compound.
'H NMR (CDCL3): s 1.25 (3H, t), 3.50 (2H, s), 4.14 (2H, q), 4.53 (2H, d), 6.33
(1 H, t), 6.70
(1 H, d), 7.03 (1 H, dd), 7.13 (2H, d), 7.15-7.22 (2H, m), 7.30 (1 H, d), 7.35-
7.45 (5H, m).
Example 15 (General procedure (C))
(E)-(4-[3-(4-Bromo-phenyl)-3-phenyl-allyloxy]-3-chloro-phenyl}-acetic acid
Br
v v OH
Step A
The title compound was prepared from (E)-{4-[3-(4-bromo-phenyl)-3-phenyl-
allyloxy]-3-chloro-phenyl}-acetic acid ethyl ester (example 14) (640 mg, 1.3
mmol) by a pro-
cedure analogous to that described in example 12.
'H NMR (CDCL3): X3.53 (2H, s), 4.63 (2H, d), 6.33 (1 H, t), 6.68 (1 H, d),
7.03 (1 H, dd), 7.08-
7.22 (4H, m), 7.30 (1 H, d), 7.35-7.45 (5H, m).
Example 16 (General procedure (A))
(E)-(4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester
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/ \
\ /
O ~ O
/
O
Step A:
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester
was pre-
pared from 2-acetylfluorene and triethylphosphonoacetate by a procedure
analogous to that
5 described in example 11-A.
'H NMR (CDCL3): X1.32 (3H, t), 2.63 (3H, s), 3.90 (2H, s), 4.23 (2H, q), 6.22
(2H, d), 7.28-
7.42 (4H, m), 7.54 (4H, dt), 7.68 (2H, d), 7.78 (4H, t).
St-ea B:
10 A 1 M solution of DIBAL-H in toluene (15 ml, 15 mmol) was added dropwise,
at -
70°C over 30 min, to a stirred solution of (E)-{4-[3-(9H-fluoren-2-yl)-
but-2-enyloxy]-phenyl}-
acetic acid methyl ester (2.0 g, 7.2 mmol) in dry THF (100 ml) and stirred for
30 min. The
mixture was warmed to room temperature, and stirred for 1.5 h. The mixture
quenched with
methanol (2 mL), added 1 N HCI (30 ml) and the product extracted with ethyl
acetate (3 x 50
15 ml). The combined organic extracts were washed with brine, dried (MgS04),
and evaporated
to give the crude (E)-3-(9H-fluoren-2-yl)-but-2-en-1-ol.
'H NMR (CDCL3): X2.13 (3H, s), 3.90 (2H, s), 4.40 (2H, s), 6.05 (1H, t), 7.22-
7.42 (2H, m),
7.45 (1 H, d), 7.54 (1 H, d), 7.60 (1 H, s), 7.75 (2H, dd)
20 St- ep C:
Under a atmosphere of nitrogen, methyl 4-hydroxyphenylacetate (183 mg, 1.1
mmol) was added to a stirred cooled solution of azodicarboxylic dipiperidide
(378 mg, 1.5
mmol), tributylphosphine (304 mg, 1.5 mmol) and (E)-3-(9H-fluoren-2-yl)-but-2-
en-1-of (236
mg, 1.0 mmol) in dry benzene (30 ml), the mixture warmed to room temperature,
and stirred
25 for 17 h. The reaction mixture was diluted with water (100 ml) and ethyl
acetate (100 ml
each). The aqueous layer was collected and further extracted with ethyl
acetate (2 x 50 ml).
The organic layers were combined, washed with brine, dried (MgS04) and
evaporated. The
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crude product was then purified by column chromatography on silica (eluent: 15
% ethyl ace-
tate in toluene) to give 240 mg (62%) of the title compound.
'H NMR (CDCL3): 8 2.19 (3H, s), 3.58 (2H, s), 3.69 (3H, s), 3.90 (2H, s), 4.76
(2H, d), 6.11
(1 H, t), 6.92 (2H, d), 7.21 (2H, d), 7.30 (1 H, d), 7.37 (1 H, t), 7.45 (1 H,
d), 7.54 (1 H, d), 7.62
(1 H, s), 7.73 (2H, dd).
Example 17 (General procedure (C))
(E)-f4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid
O ~ O
OH
Step A:
(E)-~4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl)-acetic acid ethyl ester
(example
16) (193 mg, 0.5 mmol) was suspended in 1 N NaOH (5.0 mL) and methanol (5 mL)
and
stirred for 16 h at room temperature. A 2"d portion and 1 N NaOH was added and
stirring con-
tinued for 24 h. The mixture was concentrated to 10 mL volume then diluted
with 1 N HCI (50
mL) and ethyl acetate (150 mL). The aqueous layer was separated and extracted
with ethyl
acetate (50 mL) The organic layers were combined, dried (NaS04) and
evaporated. The
residue was recrystallised from ethyl acetate (50 ml) to give 140 mg (75 %) of
the title com-
pound as an pale yellow powder.
'H NMR (DMSO): X2.17 (3H, s), 3.49 (2H, s), 3.93 (2H, s), 4.78 (2H, d), 6.11
(1H, s), 6.94
(2H, d), 7.18 (2H, d), 7.31 (1 H, dt), 7.38 (1 H, t), 7.50 (1 H, d), 7.58 (1
H, d), 7.70 (1 H, s), 7.87
(2H, t).
Example 18 (General procedure (A))
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester
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42
O \
0
Step A-B:
(E)-3-(9H-Fluoren-2-yl)-but-2-en-1-of was prepared as described in example 16
step
A-B.
Step C:
The title compound was prepared from 3-(4-hydroxy-phenyl)-propionic acid ethyl
es-
ter (example 5, step C-1) (213 mg, 1.1 mmol) and (E)-3-(9H-fluoren-2-yl)-but-2-
en-1-of (235
mg, 1.0 mmol) by a procedure analogous to that described in example 16-step C.
'H NMR (CDCL3): 81.25 (3H, t), 2.18 (3H, s), 2.60 (2H, t), 2.90 (2H, t), 3.90
(2H, s), 4.12
(2H, q), 4.75 (2H, d), 6.10 (1 H, t), 6.89 (2H, d), 7.13 (2H, d), 7.30 (1 H,
d), 7.38 (1 H, t), 7.45
(1 H, d), 7.53 (1 H, d), 7.63 (1 H, s), 7.75 (2H, dd).
Example 19 (General procedure (C))
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid
\ /
O \
off
0
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St-ep A:
(E)-{4-[3-(9H-Fluoren-2-yl)-but-2-enyloxy]-phenyl}-propionic acid ethyl ester
(exam-
ple 18) (220 mg, 0.53 mmol) was suspended in 1 N NaOH (5.5 ml) and methanol
(20 ml) and
stirred for 24 h at room temperature. The mixture was diluted with 1 N HCI (50
ml) and ethyl
acetate (50 mL). The aqueous layer was separated and extracted with ethyl
acetate (50 ml)
The organic layers were combined, washed with brine, dried (MgSO4) and
evaporated. The
residue was recrystallised from boiling ethanol (20 ml) to give 150 mg (73 %)
of the title
compound.
'H NMR (DMSO): 82.16 (3H, s), 2.76 (2H, t), 3.93 (2H, s), 4.76 (2H, d), 6.10
(1 H, t), 6.91
(2H, d), 7.14 (2H, d), 7.28-7.40 (2H, m), 7.50 (1 H, d), 7.58 (2H, d), 7.69 (1
H, s), 7.87 (2H, t).
Example 20 (General procedure (A))
(E)-{4-[3-(4-Phenoxy-phenyl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester
O
/
Step A-C:
O ~ O
O
The title compound was prepared from 4-phenoxyacetophenone (12.0 g, 0.056 mol)
by a sequence analogous to that described in example 22 step A-C, to give 168
mg (44%) of
the title compound
'H NMR (CDCL3): X2.12 (3H, s), 3.57 (2H, s), 3.68 (3H, s), 4.72 (2H, d), 6.02
(1 H, t), 6.9-7.5
(13H, m).
Example 21 (General procedure (C))
(E)-{4-[3-(4-Phenoxy-phenyl)-but-2-enyloxy]-phenyl}-acetic acid
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O
/
Step A:
O
/
OH
(E)-{4-[3-(4-Phenoxy-phenyl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester
(ex-
ample 20 (150 mg, 0.4 mmol) was suspended in 1 N NaOH (1 mL) and ethanol (5
ml) and
stirred for 24 h at room temperature. The mixture was diluted with 1 N HCI (1
mL) and ethyl
acetate (10 mL). The aqueous layer was separated and extracted with ethyl
acetate (20 mL)
The organic layers were combined, washed with brine, dried (MgS04) and
evaporated to give
116 mg (80 %) of the title compound.
'H NMR (DMSO): 82.10 (3H, s), 3.57 (2H, s), 4.74 (2H, d), 6.01 (1H, t), 6.9-
7.2 (9H, m),
7.35-7.5 (4H, m).
Example 22 (General procedure (A))
(E)-{3-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl
ester
Br
/ O
St_ ep A:
(~-3-(4'-Bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester was prepared from 4-
(4-
bromophenyl)acetophenone (12.0 g, 0.044 mol), sodium (1.25 g, 0.052 mol) and
triethyl
phosphonoacetate (11.73 g, 0.052 mol) by a procedure analogous to that
described in ex-
ample 11 step A, yielding 11.97 g (80%).
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'H NMR (300 MHz, CDC13) 8: 1.32 (3H, t), 2.61 (3H, d), 4.23 (2H, q), 6.19 (1H,
d), 7.40-7.58
(8H, m).
Step B:
5 (E)-3-(4'-bromo-biphenyl-4-yl)-but-2-en-1-of was prepared from (E~-3-(4'-
bromo-
biphenyl-4-yl)-but-2-enoic acid ethyl ester (3.45 g, 10.0 mmol) and DIBAL-H
(1M in toluene,
40 mL, 40 mmol) by a procedure analogous to that described in example 11 step
B, yielding
1.68 g (55%).
'H NMR (300MHz, CDCI3) 8: 2.14 (3H, d), 4.4 (2H, t), 6.05 (1 H, dt), 7.45-7.55
(8H, m).
Step C:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (353 mg, 1.4
mmol)
was added at 0-5 °C to a stirred solution of tributylphosphine (0.4 mL,
1.4 mmol), ethyl 3-
hydroxyphenylacetate (120 mg, 0.7 mmol) and (E)- 3-(4'-bromo-biphenyl-4-yl)-
but-2-en-1-of
(200 mg, 0.7 mmol) in dry THF (10 ml), the mixture stirred for 16 h, filtered
and concentrated
in vacuo. The crude product was then purified by column chromatography on
silica (eluent:
% ethyl acetate in heptane) to give 168 mg (44%) of the title compound.
'H NMR (CDCL3): X1.25 (3H, t), 2.17 (3H, s), 3.59 (2H, s), 4.14 (2H, q) 4.77
(2H, d), 6.11
(1 H, t), 6.85-8.90 (3H, m), 7.23 (1 H, m), 7.45-7.57 (8H, m).
20 Example 23 (General procedure (C))
(E)-{3-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid
Br
St_ ep A:
\ \
O \ OH
O
(E)-{3-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl
ester
(example 22) (150 mg, 0.32 mmol) was suspended in 1 N NaOH (0.82 mL) and
ethanol (5
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46
mL) and stirred for 24 h at room temperature. The mixture was diluted with 1 N
HCI (0.82 mL)
and ethyl acetate (10 mL). The aqueous layer was separated and extracted with
ethyl ace-
tate (20 mL) The organic layers were combined, washed with brine, dried
(MgS04) and
evaporated to give 138 mg (98 %) of the title compound.
'H NMR (DMSO): 82.13 (3H, s), 3.54 (2H, s), 4.78 (2H, d), 6.12 (1 H, t), 6.83-
6.9 (3H, m),
7.23 (1 H, m), 7.56-7.68 (8H, m).
Example 24 (General procedure (A))
(E)-~4-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl
ester
Br
O
O
Step C:
Under an atmosphere of nitrogen, azodicarboxylic dipiperidide (353 mg, 1.4
mmol)
was added at 0-5 °C to a stirred solution of tributylphosphine (0.4 mL,
1.4 mmol), methyl 4-
hydroxyphenylacetate (110 mg, 0.7 mmol) and (E)- 4-(4'-Bromo-biphenyl-4-yl)-
but-2-en-1-of
(example 22 step A-B)(200 mg, 0.7 mmol) in dry THF (10 mL), the mixture
stirred for 16 h,
filtered and concentrated in vacuo. The crude product was then purified by
column chroma
tography on silica (eluent: 20 % ethyl acetate in heptane) to give 264 mg
(84%) of the title
compound.
'H NMR (CDCL3): 82.12 (3H, s), 3.58 (2H, s), 3.68 (3H, s), 4.76 (2H, d), 6.12
(1H, t), 6.8-6.9
(3H, m), 7.23 (1 H, m), 7.56-7.68 (8H, m).
Example 25 (General procedure (C))
(E)-{4-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid
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Br
Stets A:
\ \
O \ O
OH
(E)-{4-[3-(4'-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl
ester (ex-
ample 24) (210 mg, 0.58 mmol) was suspended in 1 N NaOH (1.16 mL) and ethanol
(5 mL)
and stirred for 24 h at room temperature. The mixture was diluted with 1 N HCI
(1.16 mL) and
ethyl acetate (10 mL). The aqueous layer was separated and extracted with
ethyl acetate (30
L) The organic layers were combined, washed with brine, dried (MgSO4) and
evaporated to
give 141 mg (55 %) of the title compound.
'H NMR (DMSO): X2.14 (3H, s), 3.53 (2H, s), 4.78 (2H, d), 6.10 (1H, t), 6.8-
6.9 (3H, m), 7.23
(1 H, m), 7.53-7.72 (8H, m).
Example 26 (General procedure (A))
(E)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid
ethyl ester
Step A-C:
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The title compound was prepared by a method analogous to that described in ex-
ample 14, using (4-fluorophenyl)-(2-phenyl-1,3-thiazol-5-yl)-methanone as
starting material.
'H NMR (CDCL3): S 1.25 (3H, t), 3.52 (2H, s), 4.15 (2H, q), 4.53 (2H, d), 6.40
(1 H, t), 6.70
(1 H, d), 7.03-7.20 (3H, m), 7.24-7.38 (4H, m), 7.40-7.48 (3H, m), 7.93 (2H,
dd).
Example 27 (General procedure (C))
(E)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid
F
N ~ I _ I~
OH
Step A:
The title compound was prepared by a method analogous to that described in ex-
ample 2, using (E)-{3-chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-
allyloxy]-phenyl}-
acetic acid ethyl ester (example 26) as starting material.
~H NMR (MeOD): 83.50 (2H, s), 5.53 (2H, d), 6.43 (1 H, t), 6.78 (1 H, d), 7.08
(1 H, dd), 7.13-
7.23 (2H, m), 7.25-7.38 (4H, m), 7.40-7.50 (3H, m), 7.85-7.95 (2H, m).
Example 28 (General procedure (A))
(~-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl}-acetic acid
ethyl ester
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49
/ S
CI
o \
I/
Step A-C:
The title compound was prepared by a method analogous to that described in ex-
ample 14, using (4-fluorophenyl)-(2-phenyl-1,3-thiazol-5-yl)-methanone as
starting material.
'H NMR (CDCL3): ~ 1.25 (3H, t), 3.52 (2H, s), 4.15 (2H, q), 4.85 (2H, d), 6.35
(1 H, t), 6.84
(1 H, d), 7.0-7.18 (3H, m), 7.28-7.40 (4H, m), 7.40-7.48 (3H, m), 7.90-7.98
(2H, m).
Example 29 (General procedure (C))
(E)-{3-Chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-allyloxy]-
phenyl-acetic acid
/ S
\ ~ ~~~N
CI
O \ O
I/
OH
St- ep A:
The title compound was prepared by a method analogous to that described in ex-
ample 2, using (Z)-{3-chloro-4-[3-(4-fluoro-phenyl)-3-(2-phenyl-thiazol-5-yl)-
allyloxy]-phenyl}-
acetic acid ethyl ester (example 28) as starting material.
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'H NMR (MeOD): X3.53 (2H, s), 6.40 (1 H, t), 6.98 (1 H, d), 7.03-7.25 (3H, m),
7.28-7.50 (7H,
m), 7.88-7.95 (2H, m).
Example 30 (General procedure (A))
(E)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl}-acetic acid
ethyl ester
5
l S
N
CI
O ~ O
O~
Step A-C:
The title compound was prepared by a method analogous to that described in ex-
ample 14, using 1-(2-phenyl-thiazol-5-yl)-ethanone as starting material.
10 'H NMR (CDCL3): X1.25 (3H, t), 2.19 (3H, s), 3.52 (2H, s), 4.15 (2H, q),
4.78 (2H, d), 6.17
(1 H, t), 6.90 (1 H, d), 7.15 (1 H, d), 7.34 (1 H, s), 7.38-7.48 (3H, m), 7.75
(1 H, s), 7.88-7.80
(2H, m).
Example 31 (General procedure (C))
(E)-~3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl}-acetic acid
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S
N
CI
O ~ O
OH
Stets A:
The title compound was prepared by a method analogous to that described in ex-
ample 2, using (E)-{3-chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-
phenyl}-acetic acid
ethyl ester (example 30) as starting material.
'H NMR (CDCL3): X2.18 (3H, s), 3.55 (2H, s), 4.78 (2H, d), 6.15 (1H, t), 6.90
(1H, d), 7.13
(1 H, dd), 7.33 (1 H, d), 7.38-7.47 (3H, m), 7.79 (1 H, s), 7.85-7.93 (2H, m).
Example 32 (General procedure (A))
(Z)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl-acetic acid
ethyl ester
S
N
CI
O ~ O
O~
Step A-C:
The title compound was prepared by a method analogous to that described in ex-
ample 14, using 1-(2-phenyl-thiazol-5-yl)-ethanone as starting material.
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'H NMR (CDCL3): 61.25 (3H, t), 2.25 (3H, s), 3.52 (2H, s), 4.15 (2H, q), 4.80
(2H, d), 5.95
(1 H, t), 6.82 (1 H, d), 7.10 (1 H, dd), 7.32 (1 H, d), 7.40-7.50 (3H, m),
7.75 (1 H, s), 7.90-7.98
(2H, m).
Example 33 (General procedure (C))
(Z)-{3-Chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-phenyl)-acetic acid
/ S
\~
CI
I,
OH
Stea A:
The title compound was prepared by a method analogous to that described in ex-
ample 2, using (Z)-{3-chloro-4-[3-(2-phenyl-thiazol-5-yl)-but-2-enyloxy]-
phenyl}-acetic acid
ethyl ester (example 32) as starting material.
'H NMR (CDCL3): 62.25 (3H, s), 3.55 (2H, s), 4.79 (2H, d), 5.96 (1 H, t), 6.83
(1 H, d), 7.12
(1 H, dd), 7.32 (1 H, d), 7.40-7.50 (3H, m), 7.79 (1 H, s), 7.88-7.97 (2H, m).
Example 34 (General procedure (A))
(E)-~4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid ethyl
ester
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S
N
I
CI
O ~ O
I~
O
Step A-C:
The title compound was prepared by a method analogous to that described in ex-
ample 14, using (1,1'-biphenyl)-4-yl-(2-phenyl-1,3-thiazol-5-yl)-methanone as
starting mate-
rial.
'H NMR (CDCL3): ~ 1.25 (3H, t), 3.52 (2H, s), 4.15 (2H, q), 4.63 (2H, d), 6.43
(1 H, t), 6.75
(1 H, d), 7.15 (1 H, dd), 7.30 (1 H, d), 7.35-7.54 (9H, m), 7.64-7.70 (4H, m),
7.88-7.98 (2H, m).
Example 35 (General procedure (C))
(E)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl)-
acetic acid
N~
OH
St- ep A:
The title compound was prepared by a method analogous to that described in ex-
ample 2, using (E)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-
chloro-phenyl}-
acetic acid ethyl ester (example 34) as starting material.
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'H NMR (CDCL3): ~ 3.54 (2H, s), 4.63 (2H, d), 6.42 (1 H, t), 6.73 (1 H, d),
7.15 (1 H, dd), 7.32
(1 H, dd), 7.35-7.53 (9H, m), 7.62-7.79 (4H, m), 7.87-7.93 (2H, m).
Example 36 (General procedure (A))
(Z)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid ethyl
ester
Step A-C:
The title compound was prepared by a method analogous to that described in ex-
ample 14, using (1,1'-biphenyl)-4-yl-(2-phenyl-1,3-thiazol-5-yl)-methanone as
starting mate-
rial.
'H NMR (CDCL3): 81.25 (3H, t), 3.52 (2H, s), 4.15 (2H, q), 4.87 (2H, d), 6.44
(1H, t), 6.85
(1 H, d), 7.09 (1 H, dd), 7.32 (1 H, d), /.37 (1 H, d), 7.40-7.52 (8H, m),
7.53-7.65 (4H, m), 7.90-
7.98 (2H, m).
Example 37 (General procedure (C))
(Z)-(4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-chloro-phenyl}-
acetic acid
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OH
Stets A:
The title compound was prepared by a method analogous to that described in ex-
ample 2, using (Z)-{4-[3-Biphenyl-4-yl-3-(2-phenyl-thiazol-5-yl)-allyloxy]-3-
chloro-phenyl)-
5 acetic acid ethyl ester (example 36) as starting material.
'H NMR (CDCL3): 83.55 (2H, s), 4.88 (2H, d), 6.44 (1 H, t), 6.87 (1 H, d),
7.12 (1 H, dd), 7.32
(1 H, d), 7.35 (1 H, d), 7.40-7.50 (7H, m), 7.55-7.65 (4H, m), 7.82 (1 H, s),
7.90-7.97 (2H, m).
PHARMACOLOGICAL METHODS
10 In vitro PPARalpha, PPARgamma and PPARdelta activation activity
The PPAR transient transactivation assays are based on transient transfection
into
human HEK293 cells of two plasmids encoding a chimeric test protein and a
reporter protein
respectively. The chimeric test protein is a fusion of the DNA binding domain
(DBD) from the
yeast GAL4 transcription factor to the ligand binding domain (LBD) of the
human PPAR pro-
15 teins. The PPAR-LBD moiety harbored in addition to the ligand binding
pocket also the na-
tive activation domain (activating function 2 = AF2) allowing the fusion
protein to function as
a PPAR ligand dependent transcription factor. The GAL4 DBD will direct the
chimeric protein
to bind only to Gal4 enhancers (of which none existed in HEK293 cells). The
reporter plas-
mid contained a Gal4 enhancer driving the expression of the firefly luciferase
protein. After
20 transfection, HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein.
The fusion
protein will in turn bind to the Gal4 enhancer controlling the luciferase
expression, and do
nothing in the absence of ligand. Upon addition to the cells of a PPAR ligand
luciferase pro-
tein will be produced in amounts corresponding to the activation of the PPAR
protein. The
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amount of luciferase protein is measured by light emission after addition of
the appropriate
substrate.
CELL CULTURE AND TRANSFECTION
HEI<293 cells were grown in DMEM + 10% FCS. Cells were seeded in 96-well
plates the day before transfection to give a confluency of 50-80 % at
transfection. A total of
0,8 ~,g DNA containing 0,64 p.g pM1a/yLBD, 0,1 ~,g pCMVaGaI, 0,08 p,g
pGL2(Gal4)5 and
0,02 wg pADVANTAGE was transfected per well using FuGene transfection reagent
accord-
ing to the manufacturers instructions (Roche). Cells were allowed to express
protein for 48 h
followed by addition of compound.
Plasmids: Human PPAR a, y and s was obtained by PCR amplification using cDNA
synthe-
sized by reverse transcription of mRNA from human liver, adipose tissue and
plancenta re-
spectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. The ligand
binding
domain (LBD) of each PPAR isoform was generated by PCR (PPARa: as 167 - C-
terminus;
PPARy: as 165 - C-terminus; PPARB: as 128 - C-terminus) and fused to the DNA
binding
domain (DBD) of the yeast transcription factor GAL4 by subcloning fragments in
frame into
the vector pM1 (Sadowski et al. (1992), Gene 118, 93'~ generating the plasmids
pM1aLBD,
pM1yLBD and pM1s. Ensuing fusions were verified by sequencing. The reporter
was con-
structed by inserting an oligonucleotide encoding five repeats of the GAL4
recognition se-
quence (5 x CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988), Nucleic Acids Res.
16,
8792) into the vector pGL2 promotor (Promega) generating the plasmid
pGL2(GAL4)5.
pCMV(3Gal was purchased from Clontech and pADVANTAGE was purchased from
Promega.
IN VITRO TRANSACTIVATION ASSAY
Compounds: All compounds were dissolved in DMSO and diluted 1:1000 upon
addition to
the cells. Compounds were tested in quadruple in concentrations ranging from
0.001 to 300
pM. Cells were treated with compound for 24 h followed by luciferase assay.
Each compound
was tested in at least two separate experiments.
Luciferase assay: Medium including test compound was aspirated and 100 ~,I PBS
incl.
1 mM Mg++ and Ca++ was added to each well. The luciferase assay was performed
using
the LucLite kit according to the manufacturers instructions (Packard
Instruments). Light
emission was quantified by counting on a Packard LumiCounter. To measure ~3-
galactosidase activity 25 ~,I supernatant from each transfection lysate was
transferred to a
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new microplate. ~i-galactosidase assays were performed in the microwell plates
using a kit
from Promega and read in a Labsystems Ascent Multiscan reader. The ~i-
galactosidase data
were used to normalize (transfection efficiency, cell growth etc.) the
luciferase data.
STATISTICAL METHODS
The activity of a compound is calculated as fold induction compared to an
untreated
sample. For each compound the efficacy (maximal activity) is given as a
relative activity
compared to to Wy14,643 for PPARoc, Rosiglitazone for PPARy and Carbacyclin
for PPARB.
The EC50 is the concentration giving 50% of maximal observed activity. EC50
values were
calculated via non-linear regression using GraphPad PRISM 3.02 (GraphPad
Software, San
Diego, Ca). The results were expressed as means ~ SD.
