Note: Descriptions are shown in the official language in which they were submitted.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
NEW COMPOUNDS, THEIR PREPARATION AND USE
FIELD OF INVENTION
The present invention relates to novel compounds, pharmaceutical compositions
containing
them, methods for preparing the compounds and their use as medicaments. More
specifi-
cally, compounds of the invention can be utilised in the treatment and/or
prevention of condi-
tions mediated by nuclear receptors, in particular the Peroxisome Proliferator-
Activated Re-
ceptors (PPAR).
BACKGROUND OF THE INVENT10N
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 impaired glu-
cose tolerance, insulin resistance, hypertriglyceridaemia andlor obesity).
The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately
display moderately
effective triglyceride-lowering activities although they are neither potent
nor efficacious
enough to be a single therapy of choice for the dyslipidaemia often observed
in Type 2 dia-
betic or metabolic syndrome patients. The thiazolidinediones also potently
lower circulating
glucose levels of Type 2 diabetic animal models and humans. However, the
ttbrate 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.
Thiazolidinediones, 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
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
2
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
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
2o rodents and humans. This effect is, at least partially, based on a PPARa-
mediated transcrip-
tional regulation of the major HDL apolipoproteins, apo A-l and apo A-II. The
hypotriglyceridemic action of fibrates and fatty acids also involves PPARa and
can be
summarised as follows: (I) an increased fipo(ysis 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 ~-
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
hypoiipidemic
effect of fibrates.
A number of compounds have been reported to be useful in the treatment of
hyperglycemia,
hyperlipidemia and hypercholesterolemia (U.S. Pat. 5,306,726, PCT Publications
nos.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
3
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 and WO 99/16758).
SUMMARY OF THE INVENTION
10
Glucose lowering as a single approach does not overcome the macrovascular
complications
associated with Type 2 diabetes and metabolic syndrome. Novel treatments of
Type 2 dia-
betes and metabolic syndrome must therefore aim at lowering both the overt
hypertriglyceri-
daemia associated with these syndromes as well as alleviation of
hyperglycaemia.
The clinical activity of fibrates and thiazolidinediones indicates that
research for compounds
displaying combined PPARa and PPARy activation should lead to the discovery of
effica-
cious glucose and triglyceride lowering drugs that have great potential in the
treatment of
Type 2 diabetes and the metabolic syndrome (i.e. impaired glucose tolerance,
insulin resis-
tance, hypertriglyceridaemia and/or obesity).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to compounds of the general formula
(I):
Y
CH2)~ R~ O
R2
(Q)m Ar ~OR4
R3
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
4
wherein X is hydrogen or
X is C,_,Z-alkyl, C2_,2-alkenyl, C2_,2-alkynyl, aryl, heteroaryl, aralkyl,
heteroaralkyl or heterocy-
ciyi each of which is optionally substituted with one or more substituents
selected from haio-
gen, perhalomethyl, hydroxy, C»-alkyl, C2~-alkenyl, C2.~-alkynyl, hydroxy, C,~-
alkoxy, C,.~-
alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl,
heteroaralkyl, heteroary-
loxy, heteroaralkoxy, C~~-alkylthio, cyano, amino, C~~-aikylamino, C,~-
dialkyiamino, carboxy
or C~~-alkylester; and
Y is hydrogen or
Y is C~_,2-alkyl, C2.,2-alkenyl, C2_~z-alkynyl, C~,2-alkenynyl, aryl,
heteroaryl, aralkyl or het-
eroaralkyl each of which is optionally substituted with one or more
substituents selected from
halogen, C,~-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy
or C,~-
alkylester; and
Z is hydrogen, halogen, hydroxy or
Z is C~~-alkyl or C,~-alkoxy each of which is optionally substituted with one
or more substitu-
ents selected from C»-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and
Q is O, S or NRS, wherein R5 is hydrogen, C~~-alkyl, C2.~-alkenyl, C2~-
alkynyl, C~-alkenynyl,
aralkyl or heteroaralkyl and wherein R5 is optionally substituted with one or
more substituents
selected from halogen, hydroxy, C,~-alkoxy, amino or carboxy; and
Ar is arylene, heteroarylene or a divalent heterocyclic group each of which
can be optionally
substituted with one or more substituents selected from C,~-alkyl, aryl or
C,.~-alkoxy each of
which can be optionally substituted with halogen, hydroxy, carboxy or C»-
alkylester; and
R~ is hydrogen, hydroxy or halogen; or R, forms a bond together with R2; and
Rz is hydrogen or C~.~-alkyl; or R2 forms a bond together with Ri; and
R3 is hydrogen, C,~-alkyl, CZ~-alkenyl, CZ~-alkynyl, C~-alkenynyl, aryl,
aralkyl, C~~-
alkoxyC~.~-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups
optionally substituted
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
with one or more substituents selected from halogen, perhalomethyl, hydroxy,
cyano, car-
boxy or C~~alkylester; and
R4 is hydrogen, C,~-alkyl, Cz~-alkenyl, Cz~-alkynyl, C~-alkenynyl or aryl;
5
n is an integer ranging from 0 to 3; and
m is an integer ranging from 0 to 1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate
thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers
including a race-
mic mixture, or polymorphs. ~ .
in a preferred embodiment, the present invention is concerned with compounds
of formula (I)
Y
CH2)~ R~ O
R2
(Q)m Ar ~OR4
R3
wherein X is hydrogen or
X is C~_,z-alkyl, C2_~2-alkenyl, Cz_~z-alkynyl, aryl, heteroaryl, aralkyl,
heteroaralkyl or heterocy-
clyl each of which is optionally substituted with one or more substituents
selected from halo-
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
6
gen, perhalomethyl, hydroxy, C»-alkyl, C2~-alkenyl, CZ~-alkynyl, hydroxy, C~~-
alkoxy, C1~-
alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl,
heteroaralkyl, heteroary
loxy, heteroaralkoxy, C~~-alkylthio, cyano, amino, G~.~-alkylamino, C~~-
dialkylamino, carboxy
or C~~-alkylester; and
Y is hydrogen or
Y is C~_T2-alkyl, C2_,2-alkenyl, CZ_,2-alkynyl, C~,2-alkenynyl, aryl,
heteroaryi, araikyl or het-
eroaralkyl each of which is optionally substituted with one or more
substituents selected from
halogen, C,.~-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy
or C~~-
alkylester; and
Z is hydrogen, halogen, hydroxy or
Z is Cite-alkyl or C,~-alkoxy each of which is optionally substituted with one
or more substitu-
ents selected from C~~-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and
Q is O, S or NR5, wherein R5 is hydrogen, C~~-alkyl, C2~-alkenyl, C2~-alkynyl,
C~-alkenynyl,
aralkyl or heteroaralkyl and wherein R5 is optionally substituted with one or
more substituents
selected from halogen, hydroxy, C~_s-alkoxy, amino or carboxy; and
Ar is arylene, heteroarylene or a divalent heterocyclic group each of which
can be optionally
substituted with one or more substituents selected from C~~-alkyl, aryl or C,~-
alkoxy each of
which can be optionally substituted with halogen, hydroxy, carboxy or C1~-
alkylester; and
R, is hydrogen, hydroxy or halogen; or R~ forms a bond together with R2; and
RZ is hydrogen or C~.~-alkyl; or R2 forms a bond together with Ri; and
R3 is hydrogen, C~.~-alkyl, C2~-alkenyl, C2.~-alkynyl, C~-alkenynyl, aryl,
aralkyl, C~.~-
alkoxyCl~-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups
optionally substituted
with one or more substituents selected from halogen, perhalomethyl, hydroxy,
cyano, car-
3o boxy or C»alkylester; and
R4 is hydrogen, C,.~-alkyl, CZ.~-alkenyl, C2~-alkynyl, C~-alkenynyl or aryl;
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
7
n is an integer ranging from 1 to 3; and
mist;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate
thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers
including a
racemic mixture, or polymorphs.
fn another preferred embodiment, the present invention is concerned with
compounds of
formula f
Y
CH2)~ R~ O
(Q)m Ar ~OR4
R3
wherein X is hydrogen, C,_,Z-alkyl, CZ_,2-alkenyl, C2_~2-alkynyl, aryl,
heteroaryl, aralkyl, het-
eroaralkyl or heterocyclyl optionally substituted with one or more
substituents selected from
halogen, perhalomethyl, hydroxy, C,.~-alkyl, C2~-alkenyl, C2~-alkynyl,
hydroxy, C~~-alkoxy,
C~~-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl,
heteroaralkyl,
heteroaryloxy, heteroaralkoxy, C~~-alkylthio, cyano, amino, C,~-alkylamino,
C~~-
dialkylamino, carboxy or C~~-alkylester; and
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
Y is hydrogen, C,_,2-alkyl, CZ_,2-alkenyl, C2_~2-alkynyl, C~,2-alkenynyl,
aryl, heteroaryl, aralkyl
or heteroaralkyl optionally substituted with one or more substituents selected
from halogen,
C~~-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C,.~-
alkylester; and
Z is hydrogen, halogen, hydroxy, C~~-alkyl or C~~-alkoxy optionally
substituted with one or
more substituents selected from C~~-alkoxy, halogen, hydroxy, carboxy, amino
or cyano; and
Q is O, S or NRS, wherein R5 is hydrogen, C~_6-alkyl, C2~-alkenyl, CZ~-
alkynyl, C~-alkenynyl,
aralkyl or heteroaralkyl and wherein R5 is optionally substituted with one or
more substituents
selected from halogen, hydroxy, C~~-alkoxy, amino or carboxy; and
Ar is aryfene, heteroarylene or a divalent heterocyclic group each of which
can be optionally
substituted with one or more substituents selected from C,.~-alkyl, aryl or
C~~-alkoxy each of
which can be optionally substituted with halogen, hydroxy, carboxy or C,~-
afkyfester; and
R, is hydrogen, hydroxy or halogen; or Ri forms a bond together with R2; and
R2 is hydrogen or C~_6-alkyl; or R2 forms a bond together with R~; and
R3 is hydrogen, C,~-alkyl, C2.~-alkenyl, C2~-alkynyl, C~-alkenynyl, aryl,
aralkyl, C~.~-
alkoxyC,~-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups
optionally substituted
with one or more substituents selected from halogen, perhalomethyl, hydroxy,
cyano, car-
boxy or C~~-alkylester; and
R4 is hydrogen, C,~-alkyl, C2.~-alkenyl, C2~-alkynyl, C~-alkenynyl or aryl;
n is an integer ranging from 0 to 3; and
m is an integer ranging from 0 to 1;
or a pharmaceutically acceptable salt thereof, or a pharmaceutically
acceptable solvate
thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers
including a race-
mic mixture, or polymorphs.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
9
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula 1 wherein X is aryl, heteroaryl or heterocyclyl optionally substituted
with one or more
substituents selected from halogen, perhalomethyl, C,~-alkoxy, C1~-alkylthio,
aryl, aryloxy,
arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or
heteroaralkoxy.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein X is aryl, heteroaryl or heterocyclyl each of which is
optionally substituted with
one or more substituents selected from halogen, perhalomethyl, C»-alkoxy, C,~-
alkylthio,
aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl,
heteroaryloxy or
1o heteroaralkoxy.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein X is aryl optionally substituted with one or more substituents
selected from
halogen, perhalomethyl, C~~-alkoxy, C~~-alkylthio, aryl, aryloxy, arylthio,
aralkyl, aralkoxy,
heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
15 In another preferred embodiment, the present invention is concerned with
compounds of for
mula I wherein X is phenyl or naphthyl each of which is optionally substituted
with one or
more substituents selected from halogen or perhalomethyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula 1 wherein X is phenyl optionally substituted with one or more
substituents selected
20 from halogen.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein X is phenyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein X is heteroaryl optionally substituted with one or more
substituents se-
25 lected from halogen, perhalomethyl, C,~-alkoxy, C~.~-alkylthio, aryl,
aryloxy, arylthio, aralkyl,
aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein X is heterocyclyl optionally substituted with one or more
substituents se-
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
lected from halogen, perhalomethyl, C»-alkoxy, C~~-alkylthio, aryl, aryloxy,
arylthio, aralkyl,
aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Y is hydrogen, Ci_,z-alkyl or aryl.
5 In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Y is hydrogen or methyl.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Y is hydrogen.
10 In another preferred embodiment, the 'present invention is concerned with
compounds of for-
mula I wherein Z is hydrogen or C1.~-alkoxy.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Z is hydrogen.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Q is O.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Ar is arylene optionally substituted with ane or more
substituents selected
from C,~-alkyl or C~~-alkoxy each of which can be optionally substituted with
carboxy.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein Ar is phenylene.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein R~ is hydrogen or R~ forms a bond together with R2.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein R, is hydrogen.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
11
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula 1 wherein R2 is hydrogen or R2 forms a bond together with R~.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein R2 is hydrogen.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein R3 is C,~-alkyl.
in another preferred embodiment, the present invention is concerned with
compounds of for-
mula 1 wherein R3 is C,_Z-alkyl.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein R~ is hydrogen.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein n is 1.
In another preferred embodiment, the present invention is concerned with
compounds of for-
mula I wherein m is 1.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein alkyl is methyl or ethyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein alkenyl is vinyl or 1-propenyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein alkynyl is 1-propynyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula ! wherein alkenynyl is 1-pentene-4-yne.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
12
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein alkoxy is methoxy, ethoxy, isopropoxy or cyclopropoxy.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein aryl is phenyl or naphthyl optionally substituted with
halogen.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein arylene is phenylene.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein halogen is chlorine.
In another preferred embodiment, the present invention is concerned with
compounds of
formula 1 wherein perhaiomethyl is trifluoromethyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein heteroaryl is furan, pyrrole, pyridine, indole or
benzofuran.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein heteroarylene is furan, pyrrole, pyridine, indole or
benzofuran.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein aralkyl is benzyl.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein aryloxy is phenoxy.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein aralkoxy is benzyloxy.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein n is an integer ranging from 1 to 3 and m is 1.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
13
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein the substituents Z and Y are arranged in a trans-
configuration.
In another preferred embodiment, the present invention is concerned with
compounds of
formula I wherein the substituents Z and Y are arranged in a cis-
configuration.
Preferred compounds of the invention are:
(E~-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid
ethyl ester,
(,E~-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid,
(z7-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid ethyl
ester, _.
(Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid,
(E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid ethyl
ester,
(E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers, including a racemic mixture, or any tautomeric
forms.
Also preferred compounds of the invention are:
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate,
(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-
propionic acid,
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate,
(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-
propionic acid,
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-
phenyl]-propionate,
(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
14
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-
phenyl]-propionate,
(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynylo3cy)-phenyl]-
propionic acid;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers, including a racemic mixture, or any tautomeric
forms.
Also preferred compounds of the invention are:
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate,
(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-riaphthyl)-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid,
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate,
(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyi)-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid,
Ethyl (E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate,
(E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid,
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate,
(Z)-(S)-2-ethoxy-3-j4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-
2o propionic acid;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers,. including a racemic mixture, or any tautomeric
forms.
Also preferred compounds of the invention are:
(Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid
ethyl ester,
(Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid,
(E)-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid
ethyl ester;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers, including a racemic mixture, or any tautomeric
forms.
Also preferred compounds of the invention are:
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
(E~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxyJ-phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-
ethoxy-propionic acid,
10 (~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4.-
ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
15 (E~-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4.-
ynyloxy]-phenyl}-2-
ethoxy-propionic acid,
(E~-(S)-3-{4-(5-(3,5-Bis-(2,2,2-trif(uoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4.-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4.-ynyloxy]-phenyl}-2-
ethoxy-propionic
acid,
(E~-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
phenyl}-2-
ethoxy-propionic acid,
(E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-
ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
16
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl pent-2-en-4-
ynyloxy]-
phenyl}-2-ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(~ ,3-Bis-(2,2,2-triouoroethoxy)-phenyl)-3-methyl-pent-2-en-4.-
ynyioxy]-phenyl}-
2-ethoxy-propionic acid,
(>~-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-propionic
acid,
(~-{S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyfoxy]-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynylo~cy]-phenyl}-2-
etho~cy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-
phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4.-
ynyloxy]-phenyl}-
2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-chloro-
phenyl}-2-ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
17
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-
chloro-phenyl}-
2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(E7-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3, 5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyfoxy]-3-chloro-
phenyl}-2-
90 ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid, .
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
15 (~-(S)-3-{4-[5-(3,5-Bis-{2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-
ynyfoxy]-3-chloro-
phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{A.-[5-{3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-chloro-phenyl}-
2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
20 ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-ethoxy-
propionic acid,
25 (~-(S)-3-{4-(5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-chloro-
phenyl}-2-ethoxy-propionic acid,
(,E~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-
3-methyl-2-
ethoxy-propionic acid,
(E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
30 ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
(L~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
18
(l~-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Dibroma-phenyl)-3-methyl-pent-2-en-4.-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(E'-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-chloro-
phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chforo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyioxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
2o propionic acid,
(E~-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-[5-(1, 3-Bis-trifluoromethyl-phenyl)-pent-2-en-4.-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(E')-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-phenyl}-
2-ethoxy-propionic acid,
(E')-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
19
(~-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-[5-(3,5-Bis-triouoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyfoxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-j5-(3,5-Bis-(2,2,2-trifiuoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-phenyl}-
2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-( 1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4.-ynyloxy]-3-bromo-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-
methyl-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4.-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid,
(i~-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
(E~-(S)-3-~4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-j5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(!~-{S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
10 bromo-phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-triffuoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid, _
(~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
15 (~-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(E~-(S)-3-{4-j5-( 1, 3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-j5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
20 propionic acid,
(~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(L~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-2-
ethoxy-propionic acid,
(E~-(S)-3- f4-[5-(3, 5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
3o acid,
(E)-(S)-3-~4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(~-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
21
(E~-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(!~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyfoxy]-3-
iodo-phenyl}-2-
ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxyJ-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-( 1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxyJ-3-iodo-phenyl}-3-
methyl-2-
ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4.-
ynyloxyJ-3-
iodo-phenyl}-2-ethoxy-propionic acid,
(~-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-iodo-
phenyl}-2-ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(,E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxyl-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(E~-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
22
(,~-(S)-3-{4-[5-(3, 5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-
ethoxy-propionic acid,
(~-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(E')-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-
4-ynyloxy]-3-
iodo-phenyl}-2-ethoxy-propionic acid,
(E~-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-iodo-
phenyl}-2-ethoxy-propionic acid;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers, including a racemic mixture, or any tautomeric
forms.
Also preferred compounds of the invention are:
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,.
(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxyj-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-
2-ethoxy-
2o propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4.-ynyloxy]-phenyl}-
2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-
ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
23
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{~4-[5-( 1, 3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-
2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl pent-2-en-4-
ynyloxy]-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynylo~cy]-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
2o propionic acid;
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-phenyl}-
2-ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
24
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-( .S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-propionic
acid, ,
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4.-ynyloxy]-3-chloro-phenyl}-
2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyioxy]-
3-chloro-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-chloro-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-chloro-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-chloro-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyi)-3-methyl-pent-2-en-4-ynyloxy]-3-chforo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-triouoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-chloro-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-
methyl-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
10 ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
15 (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-
chloro-phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-ethoxy-
20 propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-chloro-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-
phenyl}-2-
ethoxy-propionic acid,
25 (Z)-(S)-3-{~.-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-
chloro-phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-.pent-2-en-
4-ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
chloro-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
26
(Z)-(S)-3-{4-[5-( 1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloacy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4.-ynyloxy]-
3-bromo-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4.-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-ethoxy-
propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
27
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-( 1, 3-Di methoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-
3-methyl-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-( 1, 3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-
4-ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-bromo-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid, ,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
bromo-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
28
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
1 o acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyfoxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
(Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
acid,
15 (Z)-(S)-3-{4-j5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-
iodo-phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-
ethoxy-propionic
20 acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4.-ynyloxy]-
3-iodo-phenyl}-2-
ethoxy-propionic acid,
25 (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
30 propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-
methyl-2-
ethoxy-propionic acid,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
29
(Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
iodo-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-iodo-
phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{A~-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-
3-iodo-phenyl}-
2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-
ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-
phenyl}-2-ethoxy-
propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy]-3-
iodo-phenyl}-2-ethoxy-propionic acid,
(Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-
ynyloxy)-3-iodo-
phenyl}-2-ethoxy-propionic acid;
or a salt thereof with a pharmaceutically acceptable acid or base, or any
optical isomer or
mixture of optical isomers, including a racemic mixture, or any tautomeric
forms.
In the above structural formulas and throughout the present specification, the
following terms
have the indicated meaning:
The term "C,.,2-alkyl" as used herein, alone or in combination is intended to
include those alkyl
groups of the designated length in either a linear or branched or cyclic
configuration represents
e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl and the like.
Typical C~_,Z-alkyl groups include, but are not limited to, methyl, ethyl, n-
propyl, iso-propyl,
butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl,
cyclopropyl, cyclob-
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
utyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like,
especially preferred is
methyl and ethyl.
The term "C2_~Z-alkenyl" as used herein, represents an olefinicalfy
unsaturated branched or
straight group having from 2 to the specified number of carbon atoms and at
least one dou-
ble bond. Examples of such groups include, but are not iimited to, vinyl, 1-
propenyi, 2-
propenyl, allyl, iso-proppenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl
and the like, espe-
cially preferred is vinyl and 1-propenyl
10 The term "C2_,2-alkynyl" as used herein, represent an unsaturated branched
or straight group
having from 2 to the specified number of carbon atoms and at least one triple
bond. Exam-
ples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-
butynyl, 2-
butynyl, 1-pentynyl, 2-pentynyl and the like especially preferred is 1-
propynyl.
15 The term "C~,2-alkenynyl" as used herein, represent an unsaturated branched
or straight hy-
drocarbon 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-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the like,
especially pre-
ferred is 1-pentene-4-yne.
The term "C~~-alkoxy" as used herein, alone or in combination is intended to
include those C»-
alkyl groups of the designated length in either a linear or branched or cyclic
configuration linked
thorugh 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 especially
preferred is methoxy and ethoxy. Examples of branched alkoxy are isopropoxy,
sec-butoxy,
tert-butoxy, isopentoxy, isohexoxy and the like especially preferred is
isopropoxy. Examples of
cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy
and the like,
especially preferred is cyclopropoxy.
The term "C,~-alkylthio" as used herein, alone or in combination, refers to a
straight or
branched or cyclic monovalent substituent comprising a C~~-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.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
31
Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio,
cyclopentylthio, cyclohexylthio
and the like.
The term "C,~-alkylamino" as used herein, alone or in combination, refers to a
straight or
branched or cyclic monovalent substituent comprising a C~.~-alkyl group linked
through amino
having a free valence bond from the nitrogen atom e.g. methylamino,
ethylamino,
propylamino, butylamino, pentylamino and the like. Examples of cyclic
alkylamino are
cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the
like.
The term "C~.~-alkoxyC~.~-alkyl" as used herein, alone or in combination,
refers to a C~~-alkyl
as defined herein whereto is attached a C~~-alkoxy as defined herein, e.g.
methoxymethyl,
ethoxymethyl, methoxyethyl, ethoxyefhyl and the like.
The term "aryl" is intended to include aromatic rings, such as carbocyclic
aromatic rings
selected from the group consisting of phenyl, naphthyl, (1-naphthyf or 2-
naphthyl) and the like
optionally substituted with halogen, amino, hydroxy, C»-alkyl, C,.~-alkoxy,
C~.~-alkylester or
carboxy and the like, especially preferred is phenyl and naphtyl optionally
substituted with
halogen.
2o The term "arylene" is intended to include divalent aromatic rings, suhch as
carbocyclic aromatic
rings selected from the group consisting of phenylene, naphthylene and the
like optionally
substituted with halogen, amino, hydroxy, C~~-alkyl, C~~-alkoxy, C~~-
alkylester or carboxy and
the like, especially preferred is phenylene.
The term "halogen" means fluorine, chlorine, bromine or iodine especially
preferred is
chlorine
The term "perhalomethyl" means trifluoromethyl, trichloromethyl,
tribromomethyl or
triiodomethyl, especially preferred is trifluoromethyl.
The term "C~~-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-
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
32
ethyl-N-methyiamino, 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 5-6 membered monocyclic aromatic system or a 9-10
membered
bicyclic aromatic system containing one or more heteroatoms selected from
nitrogen, oxygen
and sulfur, e.g. furan, thiophene, pyrrole, imidazole, pyrazole, triazole,
pyridine, pyrazine,
pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole,
thiadiazole, quinoline,
isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran,
pteridine and
purine and the like especially preferred is furan, pyrrole, pyridine, indole
and benzofuran.
The term "heteroarylene" as used herein, alone or in combination, refers to a
divalent group
comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered
bicyclic
aromatic system containing one or more heteroatoms selected from nitrogen,
oxygen and
sulfur, e.g. furan, thiophene, pyrrole, imidazole, pyrazole, triazole,
pyridine, pyrazine,
pyrimidine, pyridazine, isothiazole, isoxazole; oxazole, oxadiazole,
thiadiazole, quinoline,
isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran,
pteridine and
purine and the like, especially preferred is furan, pyrrole, pyridine, indole
and benzofuran.
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. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine,
pyridazine, isothi-
azole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline,
quinazoline,
quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine linked to
oxygen, 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,
especially
preferred is benzyl.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
33
The term "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy, 2-
naphthyloxy and the
like especially preferred is phenoxy. The term "aralkoxy" as used herein
refers to a Ci~-
alkoxy group substituted with an aromatic carbohydride, such as benzyloxy,
phenethoxy, 3-
phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy and the like, especially
preferred is
benzyloxy.
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 heteroarylalkyi 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~~-alkyl, halogen, hydroxy or
C~.~-alkoxy; e.g.
phenylthio, (4-methylphenyl)- thin, (2-chlorophenyl)thio and the like.
As used herein, the phrase "heterocyclyl" means a monovalent saturated or
unsaturated non
aromatic group being monocyclic and containing one or more, such as from one
to four car-
bon atom(s), and from one to four N, O or S atoms) or a combination thereof.
The phrase
"heterocyclyl" includes, but is not limited to, 5-membered heterocycles having
one hetero
atom (e.g. pyrrolidine, pyrroline and the like); 5-membered heterocycles
having two heteroa-
toms in 1,2 or 1,3 positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane,
imidazolidine, imi-
dazoline, 4-oxazolone and the like); 5-membered heterocycles having three
heteroatoms
(e.g. tetrahydrofurazan and the like); 5-membered~heterocycles having four
heteroatoms; 6-
membered heterocycles with one heteroatom (e.g. piperidine and the like); 6-
membered het-
erocycles with two heteroatoms (e.g. piperazine, morpholine and the like); 6-
membered het-
erocycles with three heteroatoms; and 6-membered heterocycles with four
heteroatoms, and
the like.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
34
As used herein, the phrase "a divalent heterocyclic group" means a divalent
saturated or un-
saturated system being monocyclic and containing one or more, such as from one
to four
carbon atom(s), and one to four N, O or S atoms) or a combination thereof. The
phrase a
divalent heterocyclic group includes, but is not limited to, 5-membered
heterocycles having
one hetero atom (e.g. pyrrolidine, pyrroline and the like); 5-membered
heterocycies having
finro heteroatoms in 1,2 or 1,3 positions (e.g. pyrazoline, pyrazolidine, 1,2-
oxathiolane, imida-
zolidine, imidazoline, 4-oxazolone and the like); 5-membered heterocycles
having three het-
eroatoms (e.g. tetrahydrofurazan and the like); 5-membered heterocycles having
four het-
eroatoms; 6-membered heterocycles with one heteroatom (e.g. piperidine and the
like); 6-
membered heterocycles with two heteroatoms (e.g. piperazine, morpholine and
the like); 6-
membered heterocycles with three he~teroatoms; and 6-membered heterocycles
with four
heteroatoms, and the like.
As used herein the term "treatment" includes treatment, prevention and
management of such
condition.
Certain of the above defined terms may occur more than once in the above
formula (I), and
upon such occurrence each term shall be defined independently of the other.
The present invention also encompasses pharmaceutically acceptable salts of
the present
compounds. Such salts include pharmaceutically acceptable acid addition salts,
pharmaceu-
tically 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
hydrochloric, hy-
drobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
Representative exam-
ples 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, palmitic,
EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic
acids, sul-
phates, nitrates, phosphates, perchlorates, borates, acetates, benzoates,
hydroxynaphtho-
ates, glycerophosphates, ketoglutarates and the like. Further examples of
pharmaceutically
acceptable inorganic or organic acid addition salts include the
pharmaceutically acceptable
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by
reference. Exam-
ples of metal salts include lithium, sodium, potassium, magnesium salts and
the like. Exam-
ples of ammonium and alkylated ammonium salts include ammonium,
methylammonium, di-
methylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium,
diethyl-
ammoni~m, butylammonium, tetramethyfammonium salts and the Pike. Examples of
organic
bases include lysine, arginine, guanidine, diethanofamine, choline 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,
sodium hy-
10 Bride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the
like, in sol-
vents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.
Mixture of sol-.
vents 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-
15 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.
24
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 re-
solving the mixture of stereoisomers by conventional methods. Some of the
preferred meth-
25 ods include use of microbial resolution, enzymatic resolution, resolving
the diastereomeric
salts formed with chiral acids such as mandelic acid, camphorsulfonic acid,
tartaric acid, lac-
tic acid, and the like wherever applicable or chiral bases such as brucine,
(R)- or (S)-
phenylethylamine, cinchona alkaloids and their derivatives and the like.
Commonly used
methods are compiled by Jaques et al in "Enantiomers, Racemates and
Resolution" (Wiley
30 Interscience, 1981 ). More specifically the compound of formula I may be
converted to a 1':1
mixture of diastereomeric amides by treating with chiral amines, aminoacids,
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
crystallization or
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
36
chromatography and the stereoisomers of compound of formula I may be prepared
by hydro-
lysing the pure diastereomeric amide.
Various polymorphs of compound of general formula 4 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; crystallizations
at different temperatures; various modes of cooling, ranging from very fast to
very slow cool-
ing during crystallizations. Polymorphs may also be obtained by heating or
melting the com-
pound followed by gradual or fast cooling. The presence of polymorphs may be
determined
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
administra-
tion undergo chemical conversion by metabolic processes before becoming active
pharma-
cological 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.
Furthermore, the present compounds of formula I can be utilised in the
treatment and/or pre-
vention of conditions mediated by nuclear receptors, in particular the
Peroxisome Prolifera-
tor-Activated Receptors (PPAR).
In a further 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
preparation of a
medicament 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.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
37
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 prevention of
the progression from IGT to Type 2 diabetes.
In a stiA further aspect, the present compounds are useful for the delaying or
prevention of
the progression from non-insulin requiring Type 2 diabetes to insulin
requiring Type 2 diabe
tes.
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
disorders 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,
hyperglycaemia,
atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia
and other car-
2o diovascular disorders.
In still another aspect, the present compounds are effective in decreasing
apoptosis in mam-
malian 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,
hypertensive
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 invention also relates to pharmaceutical compositions comprising, as an
active ingredi-
ent, at least one compound of the formula I or any optical or geometric isomer
or tautomeric
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
38
form thereof including mixtures of these or a pharmaceutically acceptable salt
thereof to-
gether 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 acceptable
salts or pharmaceutically acceptable solvates thereof for the preparation of a
pharmaceutical
composition for the treatment and/or prevention of conditions mediated by
nuclear receptors,
in particular the Peroxisome Proliferator-Activated Receptors (PPAR) such as
the conditions
mentioned above.
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
stereoisomers, their
polymorphs, their pharmaceutically acceptable salts or pharmaceutically
acceptable solvates.
The method comprises:
a)
Reacting a compound of formula II (prepared for example according to methods
described in:
Chem. Commun., 718-719, 1967; Org. Syntheses, Coll. Vol 3, 731-733, 1955; Org.
Synthe-
ses, Coll. Vol 1V, 801-803, 1963.
X
Y
O
wherein X and Y are defined as above, through a Wittig-like process with for
example
(Et0)2P0(CHZ)(CH2)tCOORs (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 111
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
39
X
Y
z CH2)c
O 'O
I
R6
(11l)
wherein X, Y, Z and Rs are defined as above, and wherein t is 0-2, and
b)
reducing a compound of formula III, wherein X, Y, Z, Rs and t are defined as
above with a
suitable reagent such as diisobutylaluminium hydride to give a compound of
formula IV
X
Y
z CH2)c
OH
(IV)
wherein X, Y, Z and t are defined as above, and
c)
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
reacting a compound of formula IV, wherein X, Y, Z and t are defined as above,
with a com-
pound of formula V
5
R~ O
R2
H-(Q)m Ar ~pR
4
R
(V)
wherein Q, Ar, R~, R2, R3, R4 and m are defined as above, except that m is not
0, under Mit-
sunobu conditions, using a reagent such as
triphenylphosphine/diethylazodicarboxylate and
the like to obtain a compound of formula I, wherein X, Y, Z, Q, Ar, Ri, R2,
R3, Rø, n and m are
defined as above; except that R4 is not H,: n and m are not 0, or
d)
by converting the -OH functionality in a compound of formula IV, wherein X, Y,
Z and t are
defined as above, to an appropriate leaving group (L) such as p-
toluenesulfonate, methane-
sulfonate, halogen (for example by methods according to: Houben-Weyl, Methoden
der or-
ganischen Chemie, Alkohole III, 6/1 b, Thieme-Verlag 1984, 4th Ed., pp. 927-
939; Compre-
hensive 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
X
Y
l
z CH2)t
L
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
41
(VI)
Wherein L, X, Y, Z and t are defined as above, or
e)
reacting a compound of formula Vl
wherein L is a leaving group such as p-toluenesulfonate, methanesulfonate,
halogen, triflate
and the like and wherein X, Y, Z and t are defined as above with a compound of
formula V
R~ O
R2
H-(Q)rt,Ar ~OR4
OR3
(V)
wherein Q, Ar, R~, R2, R3, Rd and m are defined as above except that m is not
0, to give a
compound of formula I wherein X, Y, Z, Q, Ar, R,, R2, R3, R4, n and m are
defined as above
except that R4 is not H, n and m are not 0, or
by chemical or enzymatic saponification of a compound of formula I
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
42
X
Y
R
Z ~CH2)~ ~ R2 O
(Q~r wOR4
OR3
wherein X, Y, Z, Q, Ar, R,, R2, R3, R~., n and m are defined as above except
that R~. is not H,
to obtain a compound of formula I, wherein X, Y, Z, Q, Ar, R~, RZ, R3, R4, n
and m are de-
fined as above except that R4 is H.
Alternative methods for the synthesis of a compound of formula I, a compound
of formula I II,
a compound of formula !V and a compound of formula VI are:
9)
reacting a compound~of formula Vil
X\
(VII)
wherein X is defined as above with a compound of formula Vlll
Y
O O
I
R6
(VIII)
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
43
under Pd catalysed cross-coupling conditions (for example as described in:
Tetrahedron Lett,
39 (36), 6445-6448,1998), to give a compound of formula III wherein X, Y and
R6 are defined
as above, and wherein t is 0, and Z is hydrogen.
h)
reacting a compound of formula VIl with a compound of formula 1X
I
Y
O' ~ O
_. I
R6
(IX)
according to a method analogous to that described in Tetrahedron Lett, 39
(37), 6719-6720,
1998, to give a compound of formula III wherein X, Y, Z and R6 are defined as
above, and
wherein t is 0.
Trans-cis or cis-trans isomerization of compounds I, Ilf, 1V, and VI (Arai et
al., Chem. Rev.,
93, pp 23-39, 1993; J. March, Advanced Organic Chemistry, 4~" Ed., J. Wiley &
Sons, New
York 1992, pp. 218, 245, 745).
PHARMACOLOGICAL METHODS
In vitro PPAR alpha and PPAR gamma activation activity.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
44
Principle
The PPAR gene transcription activation assays were 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 was a fusion of the DNA binding domain
(DBD) from
the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the
human PPAR
proteins. The PPAR LBD harbored in addition to the ligand binding pocket also
the native
activation domain (activating function 2 = AF2) allowing the fusion protein to
function as a
PPAR ligand dependent transcription factor. The GAL4 DBD will force the fusion
protein to
bind only to Gal4 enhancers (of which none existed in HEK293 cells). The
reporter plasmid
contained a Gal4 enhancer driving the expression of the firefly luciferase
protein. After trans-
fection, HEK293 cells expressed the ~AL4-DBD-PPAR-LBD fusion protein. The
fusion pro-
tein will in turn bind to the Gal4 enhancer controlling the luciferase
expression, and do noth-
ing in the absence of ligand. Upon addition to the cells of a PPAR ligand,
luciferase protein
will be produced in amounts corresponding to the activation of the PPAR
protein. The
amount of luciferase protein is measured by light emission after addition of
the appropriate
substrate.
Methods
In vitro transactivation assays.
Cell culture and transfection: HEK293 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 p,g DNA containing 0,64 p,g pM1a/yLBD, 0,1 lag
pCMV~iGal, 0,08
lug pGL2Ga14DBD and 0,02 p,g pADVANTAGE was transfected per well using. FuGene
trans-
fection reagent according to the manufacturers instructions (Roche). Cells
were allowed to
express protein for 48 h followed by addition of compound.
Plasmids: Human PPAR a and ~y was obtained by PCR amplification using cDNA
synthesized
by reverse transcription of mRNA from liver and adipose tissue respectively.
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-
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
terminus) and fused to the DNA binding domain (DBD) of the yeast transcription
factor GAL4
by subcloning fragments in frame into the vector pM1 generating the plasmids
pM1ocLBD and
pM1~yLBD. Ensuing fusions were verified by sequencing. The reporter was
constructed by
inserting an oligonucleotide encoding five repeats of the GAL4 recognition
sequence (5 x
5 CGGAGTACTGTCCTCCG(AG)) into the vector pGL2 promotor (Promega) generating
the
plasmid pGL2(GAL4)5. pCMV~iGal was purchased from Clontech and pADVANTAGE was
purchased from Promega.
Luciferase assay: Medium including test compound was aspirated and 100 p,1 PBS
incl. 1 mM
10 Mg++ and Ca++ was added to each well. The luciferase assay was performed
using the Lu-
cLite kit according to the manufacturers instructions (Packard Instruments).
Light emission
was quantified by counting SPC mode on ~a Packard Instruments top-counter. To
measure (3-
galactosidase activity 25 ~,I supernatant from each transfection lysate was
transferred to a
new microplate. [3-galactosidase assays were performed in the microwell plates
using a kit
15 from Promega and read in a microplate reader. The [3-galactosidase data
were used to nor-
malize (transfection efficiency, cell growth etc.) the luciferase data.
Compounds: All compounds were dissolved in DMSO and diluted 1:1000 upon
addition to
the cells. Compounds were tested in quadruple in five concentrations ranging
form 0.01 to 30
20 ,uM. Cells were treated with compound for 24-h followed by luciferase
assay. Each compound
was tested in three separate experiments. ECSO values were calculated via non-
linear regres-
sion using GraphPad PRISM 3.02 (GraphPad Software, San Diego, CA).The results
were
expressed as means.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
46
Table 1.
In vitro PPAR alpha and PPAR gamma activation of examples according to the
present in-
vention.
In vitro activation
PPAR a PPAR y
Example no ECSO, IaM % maxa ECso, wM % maxi
6 0.20 217 0.7 108
8 0.06 ' 139 0.31 126
12 0.05 195 0.34 105
18 0.16 181 2.67 91
20 0.04 154 1.42 112
Compounds were tested in at least three separate experiments in five
concentrations ranging
from 0.01 to 30 wM. ECSO's were not calculated for compounds producing
transactivation lo-
wer than 25% at 30 wM. aFold activation relative to maximum activation
obtained with
Wy14643 (approx. 20 fold corresponded to 100%) and with brosiglitazone
(approx. 120 fold
corresponded to 100%).
PHARMACEUTICAL COMPOSITIONS
In another aspect, the present invention includes within its scope
pharmaceutical compositions
comprising, as an active ingredient, at least one of the compounds of the
general formula I or a
pharmaceutically acceptable salt thereof together with a pharmaceutically
acceptable carrier or
diluent.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
47
The present compounds may also be administered in combination with one or more
further
pharmacologically active substances eg., selected from antiobesity agents,
antidiabetics, an-
tihypertensive agents, agents for the treatment and/or prevention of
complications resulting
from or associated with diabetes and agents for the treatment and/or
prevention of complica-
tions and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be
administered in
combination with one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine
amphetamine
regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4
(melanocortin 4)
agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF
(corticotropin releas-
ing factor) agonists, CRF BP (corticotropin releasing factor binding protein)
antagonists, uro-
cortin agonists, ~i3 agonists, MSH (melanocyte-stimulating hormone) agonists,
MCH
(melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin)
agonists, serotonin
re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed
serotonin and
noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin
antago-
nists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin
releasing
hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin
agonists, DA
agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR (retinoid X
receptor)
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.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
48
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 refer-
ence as well as orally active hypoglycaemic agents.
The orally active hypoglycaemic agents preferably comprise sulphonylureas,
biguanides,
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, potas-
sium 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-lV)
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 antifipidemic agents as HMG CoA inhibitors
(statins), com-
pounds lowering food intake, RXR agonists and agents acting on the ATP-
dependent potas-
sium channel of the ~3-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 sul-
2o phonylurea eg. tolbutamide; glibenclamide,.glipizide or glicazide.
In another embodiment the present compounds are administered in combination
with a bi-
guanide eg. metformin.
In yet another embodiment the present compounds are administered in
combination with a
meglitinide eg. repaglinide or senaglinide.
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 ~i-cells eg.
tolbutamide, gliben-
clamide, glipizide, glicazide or repaglinide.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
49
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, clofibrate,
gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or
dextrothyroxine.
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
sulphonylurea 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 iiiay be administered in combination with
one or more
antihypertensive agents. Examples of antihypertensive agents are (3-blockers
such as alpre-
nolol, atenolol, timolol, pindolol, propranolol and metoproloi, ACE
(angiotensin converting en-
zyme) inhibitors such as benazepril, captopril, enalapril, fosinopril,
lisinopril, quinaprif and
ramipril, calcium channel blockers such as nifedipine, felodipine,
nicardipine, isradipine, ni-
modipine, 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 Phar-
macy, 19~' Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
25
It should be understood that any suitable combination of the compounds
according to the in-
vention with one or more of the above-mentioned compounds and optionally one
or more fur-
ther pharmacologically active substances are considered to be within the scope
of the pre-
sent invention.
Pharmaceutical compositions containing a compound of the present invention may
be prepared
by conventional techniques, e.g. as described in Remington: The Science and
Practise of
Pharmacy, 19~' Ed., 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,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
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
5 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 alba, sucrose,
cyclodextrin, amylose, magnesium stearate, talc, gelatin; agar, pectin,
acacia, stearic acid or
10 lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid
amines, fatty acid
monoglycerides and diglycerides, pentaerythritol fatty acid esters,
polyoxyethylene,
hydroxymethylcellulose and polyvinylpjirrolidone. 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,
15 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.
20 The pharmaceutical compositions can be sterilized and mixed, if desired,
with auxiliary
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.
The route of administration may be any route, which effectively transports the
active com-
25 pound to the appropriate or desired site of action, such as oral, nasal,
pulmonary, transdermal
or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral,
intramuscular, in-
tranasal, 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
30 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.
r%w,
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
51
For nasal administration, the preparation may contain a compound of formula I
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
suspensions, pref-
erably 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 cap-
sules 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. g mg
*Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
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.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
52
The compounds of the invention are effective over a wide dosage range. For
example, in the
treatment of adult humans, dosages from about 0.05 to abouta 100 mg,
preferably from about
0.1 to about 100 mg, per day may be used. A most preferable dosage is about
0.1 mg to
about 70 mg per day. In choosing a regimen for patients it may frequently be
necessary to
begin with a dosage of from about 2 to about 70 mg per day and when the
condition is under
control to reduce the dosage as low as from about 0.1 to about 10 mg per day.
The exact
dosage will depend upon the mode of administration, on the therapy desired,
form in which
administered, the subject to be treated and the body weight of the subject to
be treated; and
the preference and experience of the physician or veterinarian in charge.
°
Generally, the compounds of the present invention are dispensed in unit dosage
form
comprising from about 0.1 to about 100 mg of active ingredient together with a
pharmaceutically
acceptable carrier per unit dosage.
Usually, dosage forms suitable for oral, nasal, pulmonary or transdermal
administration
comprise from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to
about 50 mg
of the compounds of formula I admixed with°a pharmaceutically
acceptable carrier or diluent.
Any novel feature or combination of features described herein is considered
essential to this
invention.
EXAMPLES
The process for preparing compounds of formula I, and preparations containing
them, is
further illustrated in the following examples, which however, are not to be
construed as
limiting.
The structures of the compounds are confirmed by either elemental analysis
(MA) nuclear
magnetic resonance (NMR), mass spectrometry (MS) or optical rotation. NMR
shifts (8) 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. Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art
9385).
The optical rotation was measured on a Advanced Laser Polarimeter.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
53
Compounds used as starting materials are either known compounds or compounds
which
can readily be prepared by methods known per se.
Abbrevations:
THF: tetrahydrofuran
DMSO: dimethylsulfoxide
MTBE: fertbutylmethylether
CDCf3: deutorated chloroform
DMF: N,N-dimethylformamide
min: minutes
h: hours
EXAMPLE 1
O O~
O
(~-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid
ethyl ester
Method 1
a)
A solution of triethyl phosphonoacetate (25.8 g, 115 mmol) in toluene (100 mL)
was added at
0°C to a stirred suspension of sodium hydride (60% in oil, 3.12 g, 130
mmol) in toluene (300
mL) and the mixture stirred at 0°C for 30 min. A solution of 3-
phenylpropargyl aldehyde (Org.
Syntheses, Coll. Vol 3, 731-733, 1955) (10.0 g, 77 mmol) in dry THF (15 mL)
was added, the
mixture slowly warmed to room temperature, and stirring continued for 16 h.
The reaction
mixture_was quenched with ethanol (25 mL) and water (300 mL), the organic
phase sepa-
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
54
rated, and the aqueous phase extracted with dichloromethane (300 mL). The
combined or-
ganic phases were concentrated in vacuo, and submitted to flash column
chromatography,
petroleum etheritoluene (1:1 ) graduated to petroleum etheritoluene (1:9) as
eluent, to give
(1.21 g, 8°l°) of (~-5-phenyl-pent-2-en-4-ynoic acid ethyl
ester.
'H NMR (CDCI3, 300 MHz) 8: 1.30 (t, 3H), 4.25 {q, 2H), 6.30 (d, 1H, Jtans= 15
Hz), 6.98 (d,
1 H, J~"S = 15 Hz), 7.30-7:40 (m, 3H), 7.45-7.50 (m, 2H).
b)
Diisobutylaluminium hydride (1.0 M solution in toluene, 42 mL, 42 mmol) was
added, under a
nitrogen atmosphere at -70°C, to a stirred solution of (~-5-phenyl-pent-
2-en-4-ynoic acid
ethyl ester (1.2 g, 5.99 mmol) in dry THF (105 mL). After stirring for 1.5 h,
the reaction mix-
ture was quenched with methanol (5 mL) followed by saturated aqueous
Rochelle's salt (90
mL) and 1 N sodium hydroxide (40 mL). The organic phase was separated, and the
aqueous
phase extracted with ethyl acetate (250 mL, 2x). The combined organic phases
were dried
(MgS04), filtered and concentrated in vacuo to give 948 mg (100%) of (~-5-
phenyl-pent-2-
en-4.-yn-1-ol.
~H NMR (CDCI3, 300 MHz) 8: 2.20 (bs, 1 H), 4.25 (d, 2H), 5.95 (dt, 1 H, Jtmns
= 15 Hz), 6.35
(dt, 1 H, J~"S = 15 Hz), 7.23-7.35 (m, 3H), 7.35-7.48 (m, 2H).
2o c)
(~-5-Phenyl-pent-2-en-4-yn-1-of (328 mg, 2.07 mmol), tributylphosphine (606
mg, 3.0 mmol)
and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester {Tetrahedron
Letters, Vol.
35, No. 19, 3139-3142, 1994) (495 mg, 2.07 mmol) were successively dissolved
in dry ben-
zene (30 mL) under a nitrogen atmosphere and the solution cooled to
0°C. Solid 1,1'-
(azodicarbonyl) dipiperidine (756 mg, 3.0 mmol) Was added, the mixture stirred
for 10 min.,
then warmed to room temperature and stirred for 16 h. The reaction mixture was
filtered and
the filtrate concentrated in vacuo. The product was purified by flash column
chromatography
eluting with toluene graduated to tolueneiethyl acetate (19:1 ) to give 450 mg
{57%) of the
title compound.
'H NMR (CDCI3, 300 MHz) 8: 1.18 (t, 3H), 1.25 (t, 3H), 2.95 (d, 2H), 3.30-3.42
(m, 1H), 3.55-
3.67 (m, 1 H), 3.98 (t, 1 H), 4.15 (q, 2H), 4.60 (d, 2H), 6.15 (dt, 1 H, J~"S
=15 Hz), 6.48 (dt, 1 H,
Jt~ns = 15 Hz), 6.85 (d, 2H), 7.15 (d, 2H), 7.28-7.35 (m, 3H), 7.40-7.46 (m,
2H).
= 30° ~ 4°
~a~;o
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
Method 2
a)
5 To a mixture of (~-5-phenyl-pent-2-en-4-yn-1-ol. (Method 1 b) (4.9 g; 31.0
mmol) and triethyl-
amine (3.8 g; 38.0 mmol) in, dry dichloromethane (200 mL) was added
methanesulfonyl chlo-
ride (3.8 g, 33 mmol) dropwise. Stirring was continued at room temperature
overnight. The'
reaction mixture was concentrated in vacuo and the residue washed with hep-
taneJdichloromethane (x2) to give 4.5 g (82 %) crude (E)-(5-chloro-pent-3-en-1-
ynyl)-
10 benzene.
'H NMR (CDC13, 300 MHz) 8: 4.13 (d, 2H)), 6.0 (d, 1 H, J;,~ns = 15 HZ), 6.29
(dt, 1 H, Jtans = 15
Hz), 7.28-7.35 (m, 3H), 7.40-7.48 (m, 2H).
b)
15 To a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-benzene (177 mg, 1.0 mmol)
and (S)-2-
ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in
acetone (15
mL) was added potassium carbonate (700 mg, 5.0 mmol) and potassium iodide (17
mg, 0.1
mmol). The mixture was heated o reflux over night with stirring. Water was
added and the
product extracted with tent-butyl~methyl ether (x3) The combined organic
phases were dried
20 (MgS04), filtered and concentrated in vacuo; to: give the title compound as
a crude product.
Method 3
a)
25 A solution of (~-5-phenyl-pent-2-en-4-yn-1-of (Method 1 b) (980 mg, 6.2
mmol) in dry toluene
(20 mL) was cooled on ice and phosphorus tribromide (0.59 mL, 6.2 mmol) added
slowly.
After 16 h at 5°C the mixture was diluted with ethyl acetate and washed
with water (x3). The
organic phase was concentrated in vacuo and the residue extracted with heptane
(x3). The
combined heptane phases were concentrated in vacuo to give 900 mg of crude (~-
(5-
30 bromo-pent-3-en-1-ynyl)-benzene. (According to NMR the product contained ~5
% of the (~-
isomer).
' H NMR (CDCI3, 300 MHz) 8: 4.02 (d, 1 H), 4.25 (d, 0.05 H), 5.82 (d, 0.05 H,
J~;S = 8 Hz), 5.95
(d, 1 H, J~"S = 16 Hz), 6.18 (dt, 0.05 H, J~;S = 8 Hz), 6.35 (dt, 1 H, Jfans =
16 Hz), 7.26-7.35 (m,
3H), 7.35-7.48 (m, 2H).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
56
EXAMPLE 2
i
H
H
O ~ O OH
(E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en=4-ynyloxy)-phenyl]-propionic acid
Aqueous sodium hydroxide (1 N, 5 mL, 5.0 mmol) was added to a stirred solution
of (~-(S)-2-
ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester
(example 1 )
(450 mg, 1.18 mmol) in ethanol (5 mL) and the resulting mixture stirred at
room temperature
for 16 h. The ethanol was evaporated in vacuo and the mixture acidified to pH
1 with 1 N hy-
drochloric acid. The product was extracted into ethyl acetate (30 mL x 2), and
the combined
organic phases dried (MgS04), filtered and evaporated to give 225 mg
(54°!°) of the title com-
pound as white crystals.
'H NMR (CDCI3, 300 MHz) 8: 1.20 (t, 3H), 2.97 (dd,1H), 3.10 (dd, 1H), 3.42-
3.65 (m, 2H),
4.05:. (d.d~,1 H), 4.63 (dd, 2H), 6.08 (dt, 1 H, Jtans = 15 HZ), 6.39 (dt, 1
H, J~"S = 15 HZ), 6.85 (d,
2H), 7.15 (d, 2H), 7.30-7.35 (m, 3H), 7.40-7.48 (m, 2H).
[ ~ = 23° ~ 3°
a ,o
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
57
EXAMPLE 3
(Z)-(S)-2-Ethoxy-3-(4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid ethyl
ester
1,1'-(azodicarbonyl) dipiperidine (0.504 g, 2.0 mmol) was added at 0°C
to a stirred solution of
tributylphosphine (0.493 mL, 2.0 mmol), (Z)-3-methyl-5-phenyl-pent-2-en-4-yn-1-
of (0.172 g,
1.0 mmol) (J. Org. Chem. 1999, 64 (21 ), 7687-7692), and (S)-ethyl 2-ethoxy-3-
(4-hydroxy-
phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL), the mixture
allowed to warm
to room temperature, and stirring continued for 24 h. The resulting mixture
was evaporated in
vacuo, and the residue purified by flash column chromatography on silica gel
(20% ethyl ace-
tate in n-heptane eluent) to give (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-
pent-2-en-4-
ynyloxy)-phenyl]-propionic acid ethyl ester as an oil; 0.267 g (68%).
'H NMR (300 MHz, CDCI3) s: 1.1-1.25 (6H, m), 2.0 (3H,. d), 2.93 (2H, d), 3.25-
3.38 (1 H, m),
3.51-3.62 (1 H, m), 3.97 (1 H, t), 4.13 (2H, q), 4.80 (2H, dd), 5.95 (1 H,
dt), 6.86 (2H, d), 7.15
(2H, d), 7.25-7.35 (3H, m), 7.40-7.43 (2H, m).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
5$
EXAMPLE 4
(Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid
Sodium hydroxide (1 N, 1.25 mL, 1.25 mmol) was added to a solution of (Z)-(S)-
2-ethoxy-3-
[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester
(example 3)
(0.246 g, 0.627 mmol) in ethanol (20 mL) and the mixture stirred at
70°C for 2.5 h. After cool-
ing to room temperature the resulting mixture was partitioned between water
(50 mL) and
ethyl acetate (50 mL). The aqueous phase was collected, acidified with 1 N
hydrochloric acid
(5 mL) and extracted into ethyl acetate (100 mL). The organic phase was washed
with brine,
dried (Na2S04) and evaporated to give (E)-(S)-3-[ 4-( 3-biphenyl-4-yl-but-2-
enyloxy)-phenyl ]-
2-ethoxy-propionic acid as an oil; 0.150 g (66%).
'H NMR (300 MHz, CDCI3) 8: 1.05 (3H, t), 1.92 (3H, d), 2.8 (1 H, dd), 2.92 (1
H, dd), 3.2-3.3
(1 H, m), 3.4-3.5 (1 H, m), 3.9 (1 H, dd), 4.7 (2H, dd), 5.85 (1 H, dt), 6.8
(2H, d), 7.1 (2H, d),
7.2-7.25 (3H, m), 7.3-7.4 (2H, m), 8.9 (1 H, br s).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
59
EXAMPLE 5
I
i w
0
l~ o~
0
(E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid ethyl
ester
The title compound was prepared from of (E)-3-methyl-5-phenyl-pent-2-en-4-yn-1-
of (0.172
g, 1.0 mmol), (J. Med. Chem. 1998, 47(14), 2524-2536), tributylphosphine
(0.370 mL, 1.5
mmol), 1,1'-(azodicarbonyl) dipiperidine (0.378 g, 1.5 mmol) and (S)-ethyl 2-
ethoxy-3-(4-
hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL) by a
procedure
analogous to that described in example 3, yielding 0.276 g (68%) of (E)-(S)-2-
ethoxy-3-[4-(3-
methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester.
'H NMR (300 MHz, CDCI3) 8: 1.1-1.25 (6H, m), 1.98 (3H, d), 2.95 (2H, d), 3.29-
3.4 (1 H, m),
3.53-3.65 (1 H, m), 3.95 (1 H, t), 4.15 (2H, q), 4.60 (2H, dd), 6.15 (1 H,
dt), 6.8 (2H, d), 7.15
(2H, d), 7.20-7.3 (3H, m), 7.35-7.45 (2H, m).
EXAMPLE 6
i
i o
/ OH
O
(E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid
The title compound was prepared from (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-
pent-2-en-4-
ynyloxy)-phenyl]-propionic acid ethyl ester (example 5) (0.270 g,0.698 mmol )
and sodium
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
hydroxide (1 N, 1.4 mL, 1.4 mmol) by a procedure analogous to that described
in example 4
yielding 0.100 g (39%) of (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-
ynyloxy)-
phenyl]-propionic acid.
' H NMR (300 MHz, CDCI3) 8: 1.18 (3H, t), 1.98 (3H, d), 2.9 (1 H, dd), 2.05 (1
H, dd), 3.4-3.5
5 (1 H, m), 3.55-3.65 (1 H, m), 4.05 (1 H, dd), 4.62 (2H, dd), 6.15 (1 H, m),
6.8 (2H, d), 7.15 (2H,
d), 7.3 ( 3H, m), 7.43 (2H, m).
EXAMPLE 7
CI , ~% \ O ~ O O~,/
~ i
O
CI
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate
Method 1
a)
To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220
mL) was
added PdCl2(PPh3)2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), cop-
per(I)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction
mixture was
stirred at room temperature for 48 hours, filtered and evaporated. The residue
was purified
by column chromatography using methylene chloride:hexanes (1:1) as eluent. The
desired 4-
(3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield.
'H NMR (300 MHz, CDCI3) 8: 2.46 (s, 3H), 7.45 (s, 3H).
b)
To a solution of sodium (163 mg, 6.8 mmol) in ethanol (6 mL) at -10 °C
was added triethyl
phosphonoacetate (1.37 mL, 6.8 mmol) and the reaction mixture was stirred for
5 minutes. A
solution of 4-(3,5-dichloro-phenyl)-3-butyn-2-one (214 mg, 5.7 mmol) in
ethanol (4 mL) was
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
61
added and the reaction mixture stirred overnight at room temperature and
evaporated. The
residue was treated with water (10 mL) and extracted with 3x30 mL ethyl
acetate. The dried
organic phases were evaporated to give a mixture of (E~- and (Z)-3-methyl-5-
(3,5-dichloro-
phenyl)-pent-2-en-4-ynoic acid ethyl esters. The mixture was separated by
column chroma-
tography using hexanes:methylene chloride (10:1 ) as eluent, giving pure (E~
in 130 mg, and
pure (Z) in 160 mg yields.
(E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester:'H NMR
(300 MHz,
CDCI3} 8: 1.29 (t, 3H), 2.36 (s, 3H), 4.20 (q, 2H), 6.16 (m, 1 H), 7.34 (s,
3H).
(Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester:'H NMR
(300 MHz,
CDCi3) 8: 1.29 (t, 3H), 2.12 (s, 3H), 2.25 (q, 2H), 6.09 (m, 1 H), 7.34 (m, 1
H), 7.40 (m, 2H).
c)
To a solution of (~-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid
ethyl ester (130
mg, 0.46 mmol) in THF (0.5 mL) was added dropwise diisobutylaluminium hydride
(1.0 M so-
lution in toluene, 2.1 mL, 2.1 mmol) at -20 °C. The reaction mixture
was stirred for 2 hours at
-20 °C, whereafter saturated ammonium chloride was added. The mixture
was treated with
ethyl acetate and decalite and filtered. The filtrate was evaporated to give
crude (~-3-
methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-of in 113 mg yield.
'H NMR (300 MHz, CDCI3) 8: 1.85 (s, 3H), 2.00 (br.s, 1 H), 4.20 (d, 2H), 6.04
(m, 1 H), 7.20 (s,
3H).
d)
To a solution of (~-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-of (113
mg, 0.46
mmol) in THF (10 mL) was added triphenylphosphine (218 mg, 0.71 mmol) at 0
°C. To the
mixture was added diethyl azodicarboxylate (0.109 mL, 0.71 mmol) and (S)-2-
ethoxy-3-(4-
hydroxy-phenyl)-propionic acid ethyl ester (169 mg, 0.71 mmol) and the
reaction mixture was
stirred at 0 °C for 2 h and then at room temperature overnight. Water
(15 mL) was added and
the mixture was extracted with methylene chloride (3x30 mL). The combined and
dried or-
ganic phases were evaporated and the residue purified by column chromatography
using
methylene chloride as efuent to give the title compound in 35 mg yield.
'H NMR (300 MHz, CDCl3) 8: 1.16 (t, 3H), 1.23 (t, 3H), 1.98 (s, 3H), 2.97 (d,
2H), 3.42-3.30
(m, 1 H), 3.65-3.55 (m, 1 H), 3.97 (t, 1 H), 4.16 (q, 2H), 4.62 (d, 2H), 6.20
(m, 1 H), 8.83 (d, 2H),
7.16 (d, 2H), 7.37 (m, 3H).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
62
Method 2
a)
A solution of 1-bromo-3,5-dichloro-benzene (904 mg, 4.0 mmol), PdCl2(PPh3)~
(96 mg, 0.08
mmol), 2-methyl-3-butyn-2-of (672 mg, 8.0 mmol) and Cul (4 mg, 0.02 mmol) in
diethylamine
(16 mL) was stirred at room temperature for 50 h. The reaction mixture was
evaporated and
the residue purified by column chromatography using methylene chloride as
eluent. The de-
sired product 3-(2,5-dichlorophenyl)-2-methyl-3-butyn-2-of was isolated in 910
mg (99%)
yield.
''H NMR (300 MHz, CDCI3) 8: 1.62 (6H, s), 7.30 (3H, s).
b)
To a solution of 3-(2,5-dichlorophenyl)-2-methyl-3-butyn-2-of (840 mg, 3.46
mmol) in dry
toluene (15 mL) was added sodium hydroxide pellets (45 mg) at room
temperature. The re-
action mixture was heated and a mixture of toluene and formed acetone was
distilled of. The
reaction mixture was washed with aqueous potassium carbonate (1 M, 2.5 mL),
water (2.5
mL) and brine (2.5 mL). The organic phase was dried and evaporated to give the
desired
product 1,3-dichloro-phenyl acetylene in 537 mg (91%) yield.
'H NMR (300 MHz, CDCI3) 8: 3.15 (1H, s), 7.37 (3H, s).
C)
To a solution of 1,3-dichloro-phenyl acetylene (6.07 g, 35.5 mmol) in dry THF
(60 mL) was
added palladium acetate (186 mg, 0.68 mmol), ethyl 2-butynoate (5.97 g, 53.2
mmol) and tris
(2,6-dimethoxyphenyl)phosphine (316 mg, 0.68 mmol) at room temperature. The
reaction
mixture was stirred for 18 h and filtered. The filtrate was washed with water
(10 mL), and the
water phase was extracted with ether (10 mL). The combined organic phases were
dried and
evaporated. The residue was purified by column chromatography using
heptane:THF (20:1 )
as eluent. (~-3-Methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl
ester was iso-
lated in 4.65 g (46%) yield.
d)
The title compound was prepared from (E~-3-methyl-5-(3,5-dichloro-phenyl)-pent-
2-en-4-
ynoic acid ethyl ester according to the procedure described in method 1,c-d.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
63
EXAMPLE 8
~ O ~ O OH
CI
O
CI
(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-
propionic acid _,
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate was hydrolysed as described in Example 2 to give the title
compound.
'H NMR (300 MHz, CDCI3) 8: 1.12 (t, 3H), 1.95 (s, 3H), 3.12-2.85 (m, 2 H),
3.48-3.32 (m,
1 H), 3.65- 3.53 (m, 1 H), 4.03 (m, 1 H), 4.59 (d, 2H), 6.17 (t, 1 H), 6.80
(d, 2H), 7.15 (d, 2H),
7.30 (s, 3H).
EXAMPLE 9
' o~/
c1 i ~/ ~° ' o
1 1~ o
'
c1
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
64
a)
(2)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-of was made from (Z)-3-
methyl-5-(3,5-
dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (160 mg) (example 7b)
using the condi-
tions described in example 7c. Yield 140 mg.
'H NMR (300 MHz, CDCI3) s: 1.88 (s, 3H), 1.92 ( br. s, 1 H), 4.33 (d, 2H),
5.90 (t, 1 H), 7.21
(s, 3H).
b)
The title compound was prepared from (Z)-3-methyl-5-(3,5-dichToro-phenyl)-pent-
2-en-4-yn-
1-0l (140 mg) using the conditions described in example 7d. Yield 172 mg.
'H NMR (300 MHz, CDCI3) 8: 1.17 (t, 3H), 1.25 (t, 3H), 2.00 (s, 3H), 2.95 (d,
2H), 3.42-3.28
(m, 1 H), 3.67-3.55 (m, 1 H), 3.98 (t, 1 H), 4.16 (q, 2H), 4.77 (d, 2H), 6.02
(t, 1 H), 6.86 (d, 2H),
7.28 (d, 2H), 7.32 (s, 3H).
EXAMPLE 10
OH
CI / // ~O 1 O
O
CI
(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-
propionic acid
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate was hydrolysed as described in Example 2 to give the title
compound. Yield 164
mg.
'H NMR (300 MHz, CDCI3) b: 1.18 (t, 3H), 2.01 (s, 3H), 3.10-2.90 (m, 2H), 3.46-
3.33 (m, 1H),
3.67-3.55 (m, 1 H), 4.04 (m, 1 H), 4.75 (d, 2H), 6.02 (t, 1 H), 6.87 (d, 2H),
7.18 (d, 2H), 7.33 (s,
3H).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
EXAMPLE 11
F ~ 0 0 0~
F
F / ~ ~ / O
5 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-
4-ynyloxy)-
phenyl]-propionate
The title compound was made as described in example 7a-d using 3-
trifluoromethyl-1-iodo-
benzene instead of 1,3-dichloro-5-iodo-benzene in example 7a.
10 'H NMR (300 MHz, CDCI3) 8: 1.18 (t, 3H), 1.24 (t, 3H), 2.00 (s, 3H), 2.96
(d, 2H), 3.42-3.31
(m, 1 H), 3.66-3.55 (m, 1 H), 3.98 (t, 1 H), 4.27 (q, 2H), 4.65 (d, 2H), 6.23
(1 H), 6.84 (d, 2H),
7.18 (d, 2H), 7.71-7.38 (m, 5H).
15 EXAMPLE 12
F \
F / v 'O~~\\%/~Ofi
F /
(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
20 propionic acid
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-
phenyl]-propionate was hydrolysed as described in Example 2 to give the title
compound.
'H NMR (300 MHz, CDCI3) 8: 1.19 (t, 3H), 1.98 (s, 3H), 3.12-2.90 (m, 2H), 3.48-
3.36 (m, 1H),
25 3.69-3.56 (m, 1 H), 4.50 (m, 1 H), 4.64 (d, 2H), 6.21 (t, 1 H), 6.85 (d,
2H), 7.18 (d, 2H), 7.70-
7.49 (m, 5H).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
66
EXAMPLE 13
o-../
1 p
F O
F / \ \ /
F
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-
phenyl]-propionate
The title compound was synthesised from .(Z)-3-methyl-5-(3-trifluromethyl-
phenyl)-pent-2-en-
4-yn-1-of which was derived from the reaction sequence described in example 11
using the
conditions described in example 7c-d.
'H NMR (300 MHz, CDCI3) 8: 1.18 (t, 3H), 2.23 (t, 3H), 2.03 (s, 3H), 2.96 (d,
2H), 3.42-3.30
(m, 1 H), 3.66-3.55 (m, 1 H), 3.96 (t, 1 H), 4.15 (q, 2H), 4.82 (d, 2H), 6.03
(t, 1 H), 6.87 (d, 2H),
7.17 (d, 2H), 7.70-7.43 (m, 5H).
EXAMPLE 14
OH
F ~~ ~O O
w
/ 1 1 O
w /
(Z)-{S)-2-ethoxy-3-[4-(3-methyl-5-(3-triouoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionic acid
Ethyi (Z)-(S)-2-ethoxy-3-[4-{3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-
ynyloxy)-
phenyl]-propionate was hydrolysed as described in Example 2 to give the title
compound.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
67
'H NMR (300 MHz, CDC13) 8: 1.16 (t, 3H), 2.02 (s, 3H), 3.10-2.92 (m, 2H), 3.47-
3.36 (m, 1 H),
3.68-3.57 (m, 1 H), 4.03 (m, 1 H), 4.80 (d, 2H), 6.02 (t, 1 H), 6.89 (d, 2H),
7.18 (d, 2H), 7.72-
7.42 (m, 5H).
EXAMPLE 15
/ 1
0 0,/
/ ~ W / o ~ J o
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4.-ynyloxy)-
phenyl]-propionate
The title compound was made as described in example 7a-d using 1-
iodonaphthalene in-
stead of 1,3-dichloro-5-iodo-benzene in example 7a.
'H NMR (300 MHz, CDCI3) 8: 1.18 (t, 3H), 1.24 (t, 3H), 2.08 (s, 3H), 2.96 (d,
2H), 3.42-3.30
(m, 1 H), 3.66-3.53 (m, 1 H), 3.98 (t, 1 H), 4.15 (q, 2H), 4.65 (d, 2H), 6.30
(m, 1 H), 6.86 (d, 2H),
7.18 (d, 2H), 7.86-7.38 (m, 6H), 8.33 (d, 1 H).
EXAMPLE 16
OH
O
O
~ O
(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid
Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate
was hydrolysed as described in Example 2 to give the title compound.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
68
'H NMR (300 MHz, CDCl3) 8: 1.19 (t, 3H), 1.98 (s, 3H), 3.12-2.90 (m, 2H), 3.48-
3.36 (m, 1 H),
3.69-3.56 (m, 1 H), 4.05 (m, 1 H), 4.66 (d, 2H), 6.30 (t, 1 H), 6.85 (d, 2H),
7.18 (d, 2H), 7.90-
7.45 (m, 6H), 8.44 (d, 1 H).
EXAMPLE 17
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate
The title compound was synthesised from (Z)-3-methyl-5-(1-naphthyl)-pent-2-en-
4-yn-1-of
isolated in example 15 using the conditions described in example 7c-d.
'H NMR (300 MHz, CDCl3) 8: 1.18 (t, 3H), 1.23 (t, 3H), 2.14 (s, 3H), 2.97 (d,
2H), 3.42-3.30
(m, 1 H), 3.66-3.53 (m, 1 H), 3.98 (t, 1 H), 4.15 (q, 2H), 4.95 (d, 2H), 6.06
(m, 1 H), 6.94 (d,. 2H),
7.18 (d, 2H), T.86-7.40 (m, 6H), 8.30 (m, 1 H).
EXAMPLE 18
O OH
O
o
i
(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate
was hydrolysed as described in Example 2 to give the title compound.
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
69
'H NMR (300 MHz, CDC13) S: 1.04 (t, 3H), 2.02 (s, 3H), 3.00-2.80 (m, 2H), 3.34-
3.22 (m, 1H),
3.57-3.46 (m, 1 H), 3.94 (m, 1 H), 4.83 (d, 2H), 5.94 (t, 1 H), 6.84 (d, 2H),
7.08 (d, 2H), 7.75-
7.26 (m, 6H), 8.20 (m, 1 H), 9.2 (br.s, 1 H).
EXAMPLE 19
CI ~ ~ ~V ~O ~ O O~
0
c1
Ethyl (E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate
a)
To a solution of 1,3-dichloro-5-iodo-benzene (5.44 g, 20 mmol) in diethylamine
(75 mL) was
added PdCl2(PPh3)2 (280 mg, 0.4 mmol), trimethylsilylacetylene (2.36 g, 24.0
mmol) and
copper(I)iodide (20 mg, 0.1 mmol). The reaction mixture was stirred at room
temperature for
24 h, filtered and evaporated. The residue was purified by column
chromatography using
heptane:ethyl acetate (8:2) as eluent. The desired (3,5-dichloro-
phenylethynyl)-trimethyl-
silane product was isolated in 4.85 g yield.
'H NMR (300 MHz, CDCI3) s: 0.09 (s, 9H), 7.15 (m, 3H).
b)
To a solution of (3,5-dichloro-phenylethynyl)-trimethylsilane (4.85 g, 19.9
mmol) in methanol
(50 mL) was added 1 M potassium hydroxide (30 mL). The reaction mixture was
stirred 1 h at
room temperature and evaporated. The residue was treated with water (10 mL)
and ex-
tracted with 3x40 mL diethyl ether. The tried organic phases were evaporated
to give the de-
sired 1,3-dichloro-5-ethynyl-benzene product in 2.3 g yield.
'H NMR (300 MHz, CDCI3) b: 2.13 (s, 1H), 7.38 (s, 3H).
c)
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in
triethylamine (32.4 mL)
was added PdClz(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid
ethyl ester
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
(1.84 g, 8.1 mmol) and copper(I)iodide (7.7 mg, 0.04 mmol). The reaction
mixture was stirred
for 2 h at 50°C, whereafter the reaction mixture was cooled to room
temperature, water (30
mL) added and the mixture extracted with diethyl ether (3x20 mL). The combined
and dried
organic phases were evaporated to give crude (E)-5-(3,5-dichloro-phenyl)-pent-
2-en-4-ynoic
5 acid ethyl ester in 1.1 g yield.
'H NMR (300 MHz, CDCl3) &: 1.32 (t, 3H), 4.22 (q, 2H), 6.32 (d, 1 H, J = 16
Hz), 6.92 (d, 1 H,
J = 16 Hz), 7.37 (s, 3H).
d)
1o To a solution of diisobutylaluminium hydride (1.0 M solution in toluene, 20
mL, 20 mmol) at-
78 °C was slowly added (~-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic
acid ethyl ester (1.1 g,
4.08 mmol). The reaction mixture was~stirred for 2 h at -78 °C, where
after the reaction mix-
ture was poured into hydrocloride acid (6N, 50mL ) and extracted with diethyl
ether (3X40
mL) The combined and dried organic phases were evaporated to give crude (E)-5-
(3,5-
15 dichloro-phenyl)-pent-2-en-4-yn-1-of in 750 mg yield.
H NMR (300 MHz, CDCI3) s: 4.3 (dd, 2H), 5.95 (dt, 1 H,J = 5 and 16 Hz), 6.4
(dt, 1 H, J
=5and16 Hz), 7.30 (s, 3H).
e)
20 The title compound was prepared from (E)-5-(3,5-dichloro-phenyl)-pent-2-en-
4-yn-1-of (454
mg, 2 mmol) using the conditions described in example 7d. Yield 125 mg yield.
'H NMR (300 MHz, CDCI3) 8: 1.14 {t, 3H), 1.22 (t, 3H), 2.95 (d, 2H), 3.30-3.42
(m, 1H), 3.55-
3.6.7 (m, 1 H), 3.95 (t, 1 H), 4.16 (q, 2H), 4.6 (dd, 2H, J = 1.5 ands Hz),
6.05 (dt, 1 H, J =
1.5and 16 Hz), 6.35 (dt, 1 H, J = Sand 16 Hz), 6.83 (d, 2H), 7.15 (d, 2H),
7.36 (m, 3H).
EXAMPLE 20
\ O \ O OH
CI
O
CI
(E)-(S)-2-Ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-
propionic acid
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
71
Ethyl (E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-propionate
was hydrolysed as described in Example 2 to give the title compound.
'H NMR (300 MHz, CDCl3) b: 1.19 (t, 3H), 2.88-3.12 (m, 2 H), 3.37-3.50 (m,
1H), 3.65- 3.70
(m, 1 H), 4.05 (m, 1 H), 4.70 (dd, 2H, J = 1.5 and 5 Hz), 6.1 (dt, 1 H, J =
1.5 and 't6 Hz), 6.45
(dt, 1 H, J = 5 and 16 Hz), 6.85 (d, 2H), 7.18 (d, 2H), 7.30 {s, 3H).
EXAMPLE 21
ci /~ - 'o ~ o
ci
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate
a)
(Z)-5-(3,5-DichlOro-phenyl)-pent-2-en-4-ynoic acid ethyl ester was made from
cis-3-iodo
acrylic acid ethyl ester {Can J Chem, 72 (8), 1816-1819, 1994). (4 g) using
the conditions
described in example 19 c. Yield 4.62 g.
' H NMR (300 MHz, CDC13) 8: 1.4 (t, 3H), 4.3 (q, 2H), 6.2 (d, 1 H, J = 11 Hz),
6.34 (d, 1 H, J =
11 Hz), 7.32 (s, 1 H) 7.4 (s, 2H).
b)
(Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-of was made from (Z)-5-(3,5-
dichloro-phenyl)-
pent-2-en-4-ynoic acid ethyl ester (4.6 g) using the conditions described in
example 19 d.
Yield 3.63 g.
'H NMR (300 MHz, CDC13) 8: 4.4 (dd, 2H, J = 1.5 and 6.5 Hz), 5.75 (dt, 1 H, J
=1.5 and 11
Hz), 6.21 (dt, 1 H, J = 6.5 and 11 Hz), 7.3 (s, 3H).
c)
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
72
The title compound was from (Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-of
(300 mg, 1.32
mmol) using the conditions described in example 19 e. Yield 180 mg yield.
'H NMR (300 MHz, CDCl3) 8: 1.12 (t, 3H), 1.2 (t, 3H), 2.9 (d, 2H), 3.26-3.44
(m, 1 H), 3.51
3.69 (m, 1 H), 3.94 (t, 1 H), 4.14 (q, 2H), 4.85 (dd, 2H, J = 1.8 and 6.3 Hz),
5.87 (dt, 1 H, J =
1.8 and 11 Hz), 6.25 (dt, 1 H, J = 6.3. and 11 Hz), 6.82 (d, 2H), 7.15 (d,
2H), 7.33 (m, 3H).
EXAMPLE 22
0 off
ci / 1 _ o
. . 1 , o
c~
(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-
phenyl]-
propionic acid
Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-
ynyloxy)-phenyl]-
propionate was hydrolysed as described in Example 2 to give the title
compound. Yield 100
mg.
'H NMR (300 MHz, DMSO-D6) 8: 1.16 (t, 3H), 2.85-3.05 (m, 2H), 3.3-3.45 (m,
1H), 3.6-3.7
(m, 1 H), 4.06 (m, 1 H), 4.9 (dd, 2H, J = 1.8 and 6.2 Hz), 6.1 (dt, 1 H, J =
1.8 and 11 Hz), 6.45
(dt, 1 H, J = 6.2 and 11 Hz), 6.93 (d, 2H), 7.20 (d, 2H), 7.65 (d, 2H), 7.71
(d,1 H).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
73
EXAMPLE 23
(Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4.-ynyloxy)-phenyl]-propionic acid
ethyl ester
a)
(Z)-5-phenyl-pent-2-en-4.-ynoic acid ethyl ester Was made from cis-3-iodo
acrylic acid ethyl
ester (2 g) and phenylacetylene using the conditions described in example 19
c. Yield 1.24 g.
'H NMR (300 MHz, CDCI3) 8: 1.3 (t, 3H), 4.25 (q, 2H), 6.12 (d, 1 H, J~;S =
11.3 Hz), 6.35 (d,
1 H, JC;S = 11.3 Hz), 7.36 (m, 3H) 7.53 (m, 2H).
b)
(Z)-5-phenyl-pent-2-en-4-yn-1-of was made from (Z)-5-phenyl-pent-2-en-4-ynoic
acid ethyl
ester (1.0 g) using the conditions described in example 19 d. Yield 0.7 g.
' H NMR (300 MHz, CDCI3) 8: 4.5 (dd, 2H, J = 1.5 and 6.5 Hz), 5.80 (dt, 1 H, J
=1.5 and 10.5
Hz), 6.14 (dt, 1 H, J = 6.4 and 10.5 Hz), 7.31 (m, 3H), 7.43 (m, 2H).
c)
The title compound was prepared from (Z)-5-phenyl-pent-2-en-4-yn-1-of (200 mg,
1.3 mmol)
using the conditions described in example 19 e. Yield 380 mg.
'H NMR (300 MHz, CDCI3) 8: 1.2 (dt, 6H), 2.98 (d, 2H), 3.3-3.41 (m, 1 H), 3.53-
3.68 (m, 1 H),
3.95 (t, 1 H), 4.18 (q, 2H), 4.9 (dd, 2H, J = 1.6 and 6.4 Hz), 5.95 (dt, 1 H,
J = 1.6 and 11 Hz),
6.2 (dt, 1 H, J = 6.4 and 11 Hz), 6.89 (d, 2H), 7.17 (d, 2H), 7.35 (m, 3H) ),
7.47 (m, 2H).
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
74
EXAMPLE 24
0 off
1 0
1, o
(Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid
Ethyl (Z)-(S)-2-ethoxy-3-[4-(phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionate
was hydrolysed
as described in Example 2 to give the title compound. Yield 264 mg.'H NMR (300
MHz,
DMSO-Ds) 8: 1.15 (t, 3H), 2.8-3.0 (m, 2H)x 3.3-3.4 (m, 1 H), 3.5-3.65 (m, 1
H), 3.96 (m, 1 H),
4.89 (dd, 2H, J = 1.6 and 6.3 Hz), 6.08 (dt, 1 H, J = 1.6 and 11 Hz), 6.3 (dt,
1 H, J =6.3 and 11
Hz), 6.9 (d, 2H), 7.20 (d, 2H), 7.4 (m, 3H), 7.5 (m, 2H).
EXAMPLE 25
H
H O
O \ O
I
/ O\
(E~-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid
ethyl ester
a)
NaH 60% in paraffin oil (1.18g, 29.5 mmol) was added to a solution of diethoxy-
phosphoryl-
ethoxy-ethylacetate (7.46g, 27.8mmol)) in dry THI= (40 mL) at 0 °C. 3-
Benzyloxybenzaldehyde (ALDRICH) (5.0 g, 23.6 mmol) dissolved in dry THF (20
mL) was
added dropwise keeping the temperature below 10 °C. The reaction
mixture was allowed to
reach room temperature followed by the addition of water. The product was
extracted into
CA 02396372 2002-07-04
WO 01/55086 PCT/DKO1/00057
MTBE, and the combined organic phases dried (Na2S0ø), filtered and evaporated
to give 7.6
g (99°l°) of {E,~-3-(3-benzyloxyphenyl)-2-ethoxyacrySic aced
ethyS ester as a yellow oil.
'H NMR (CDCI3, 400 MHz) 8: 1.09 (t), 1.34 (t), 1.37 (t), 3.92 (q), 3.98 (q),
4.12 (q), 4.30 (q),
5.04 (s), 5.09 (s), 6.95 (s), 7.26 (s), 7.2-7.5 (m).
5
b)
(E,L7-3-(3-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (6.8 g) dissolved
in ethyl acetate
(40 mL) was hydrogenated at 10 bar using PdIC (10%) (1.08 g) until the
reaction was shown
10 to be completed by HPLC. The reaction mixture was filtered through a pad of
celite and the
solvent evaporated. The product was purified by column chromatography eluting
with ethyl
acetate/heptane 1:2 to give 3.1 g (62%) of (R,S)-2-ethoxy-3-
hydroxyphenyl)propanoic acid
ethyl ester.
'H NMR (CDCI3, 400 MHz) 8: 1.16 (t, 3H), 1.23 (t, 3H), 2.97-2.95 (m, 2H), 3.41-
3.33 (dq,
15 1 H), 3.65-3.57 (dq, 1 H), 4.02(t, 1 H), 4.17 (q, 2H), 5.33 (s, 1 H), 6.81-
6.70 (m, 3H), 7.15 (t,
1H).'3C-NMR (75 MHz, CDCI3) b 14.51, 15.36, 39,58, 61,48, 66,74, 80.52,
114.15, 116.87,
121.79, 129.81, 139.07, 156.20, 173.27. MS m/z (MH+) 239.2. Elemental
analysis: Anal.
Calcd. for C~3H~80~: C, 65.53; H, 7.61 %. Found: C, 65.98; H, 7.96.
20 c)
The title compound (120 mg, 63%) was prepared from (R,S)-2-ethoxy-3-(3-
hydroxyphenyl)propanoic acid ethyl ester (120 mg, 0.5 mmol) and (E)-5-phenyl-
pent-2-en-4-
yn-1-of (example 1, method 1 b)(79 mg, 0.5 mmol), by a procedure analogous to
that de-
scribed in example 1 (method 1 c).
