NO20023567L - Alkynyl-substituted propionic acid derivatives and their use against diabetes and obesity - Google Patents

Description

Field of the invention

The present invention relates to new compounds, pharmaceutical preparations containing them, methods for producing the compounds and their use as medicines. More specifically, compounds according to the invention can be used in the treatment and/or prophylaxis of conditions mediated by nuclear receptors, in particular the peroxisome proliferator-activated receptors (PPAR).

The background of the invention

Coronary artery disease (CAD) is the leading cause of death in patients with type II diabetes and metabolic syndrome (that is, patients who fall within the "deadly quartet" category of impaired glucose tolerance, insulin resistance, hypertriglyceridemia, and/or obesity).

The hypolipidemic fibrates and the antidiabetic thiazolidinediones each exhibit moderately effective triglyceride-lowering activities, although they are neither strong nor efficacious enough to be a single therapy of choice for the dyslipidemia commonly observed in patients with type II diabetes or the metabolic syndrome. The thiazolidinediones also strongly lower circulating glucose levels in animal models and in humans with type II diabetes. However, the fibrate class of compounds is without beneficial effects on glycemia. Studies regarding the molecular actions of these compounds indicate that the thiazolidinediones and fibrates exert their effects by activating distinct transcription factors in the peroxisome proliferator-activated receptor (PPAR) family, which results in increased and decreased expression of specific enzymes and apolipoproteins, respectively, both key elements in regulation of plasma triglyceride content. Fibrates are, on the one hand, PPARot activators that work mainly in the liver. Thiazolidinediones, on the other hand, are high-affinity ligands for PPARγ that act 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 nutrient influx and release it in the form of free fatty acids in times of nutrient deficiency. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Much evidence points to the central role of PPARγ activation in the initiation and regulation of this cell differentiation. Several highly specialized proteins are induced during adipocyte differentiation, and most of them are involved in lipid storage and metabolism. The exact connection from activation of PPARγ to changes in glucose metabolism, most notably a reduction in insulin resistance in muscle, has not yet been clarified. A possible connection is via free fatty acids, so 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 dramatically reduces the concentration of free fatty acids in plasma, 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 reduced insulin resistance as a result.

PPARot is involved in the stimulation of β-oxidation of fatty acids. In rodents, a PPARα-mediated change in the expression of genes involved in fatty acid metabolism underlies the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to the liver and kidney, which can lead to hepatocarcinogenesis in rodents. The phenomenon of peroxisome proliferation is not seen in humans. In addition to its role in peroxisome proliferation in rodents, PPARα is also involved in the control of HDL cholesterol levels in rodents and humans. This effect is based at least in part on a PPARα-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic effect of fibrates and fatty acids also involves PPARα, and can be summarized as follows: (I) an increased lipolysis and removal of residual particles due to changes in lipoprotein lipase and apo C-III levels, (II) a stimulation of cellular fatty acid uptake and the subsequent conversion to acyl-CoA derivatives by the induction of fatty acid-binding protein and acyl-CoA synthase, (III) an induction of the fatty acid Ø-oxidation reaction pathway, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a reduction in VLDL production. Both increased catabolism of triglyceride-rich particles as well as reduced excretion of VLDL particles therefore constitute mechanisms that contribute to the hypolipidaemic effect of fibrates.

A number of compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia, and hypercholesterolemia (US Patent No. 5,306,726) PCT Publication No. WO 91/19702, 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

Glucose lowering as a single procedure does not overcome the macrovascular complications associated with type II diabetes and metabolic syndrome. New treatments for type II diabetes and metabolic syndrome must therefore aim to reduce both the overt hypertriglyceridemia associated with these syndromes and relief of hyperglycaemia.

The clinical activity of fibrates and thiazolidinediones indicates that research into compounds exhibiting combined PPARα and PPARγ activation should lead to the discovery of effective glucose- and triglyceride-lowering drugs that have great potential in the treatment of type II diabetes and the metabolic syndrome (the i.e. impaired glucose tolerance, insulin resistance, hypertriglyceridemia and/or obesity).

Detailed description of the invention

The present invention therefore relates to compounds with the general formula (I):

where

X is hydrogen or

X is C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C1-6 -alkyl, C2-6-Alkenyl, C2-6-Alkynyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkylthio, Aryl, Aryloxy, Arylthio, Acyl, Aralkyl, Aralkoxy, Heteroaryl, Heteroaralkyl, Heteroaryloxy, Heteroaralkoxy, C1-6 -alkylthio, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, carboxy and C1-6-alkyl ester; and

Y is hydrogen or

Y is C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, C4-12-alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy and C 1-6 alkyl ester; and

Z is hydrogen, halogen, hydroxy or

Z is C 1-6 alkyl or C 1-6 alkoxy, each of which is optionally substituted with one or more substituents selected from C 1-6 alkoxy, halogen, hydroxy, carboxy, amino and cyan; and

Q is 0, S or NR5, where R5 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6_alkynyl, C1-6-alkenynyl, aralkyl or heteroaralkyl, and where R5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkoxy, amino and carboxy; and

Ar is arylene, heteroarylene or a divalent heterocyclic group each optionally substituted with one or more substituents selected from C 1-6 alkyl, aryl and C 1-6 alkoxy each optionally substituted with halogen, hydroxy, carboxy or C 1-6 -alkyl ester; and

R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and

R 2 is hydrogen or C 1-6 alkyl; or R 2 forms a bond together with R 1 ; and

R3 is hydrogen, C1-6-alkyl-, C2-6-alkenyl-, C2-6_alkynyl-, C1-6-alkenynyl-, aryl-, aralkyl-, C1-6-alkyl-C1-6-alkyl-, acyl-, heterocyclyl -, heteroaryl or heteroaralkyl groups which are optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyan, carboxy and C 1-6 alkyl ester; and

R 4 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 alkenynyl or aryl;

n is an integer in the range from 0 to 3; and

m is an integer in the range 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 racemic mixture, or polymorphs.

In a preferred embodiment, the present invention relates to compounds of formula (I)

where

X is hydrogen or

X is C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C1-6-alkyl, C2 -6-Alkenyl, C2-6-Alkynyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkylthio, Aryl, Aryloxy, Arylthio, Acyl, Aralkyl, Aralkoxy, Heteroaryl, Heteroaralkyl, Heteroaryloxy, Heteroarloxy, C1-6-Alkylthio, Cyan, Amino , C 1-6 -alkylamino, C 1-6 -dialkylamino, carboxy and C 1-6 -alkyl ester; and

Y is hydrogen or

Y is C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 4-12 alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl each optionally substituted with one or more substituents selected from halogen, C 1-6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy and C 1-6 alkyl ester; and

Z is hydrogen, halogen, hydroxy or

Z is C 1-6 alkyl or C 1-6 alkoxy each of which is optionally substituted with one or more substituents selected from C 1-6 alkoxy, halogen, hydroxy, carboxy, amino and cyan; and

Q is O, S or NR5, where R5 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, d-6-alkenynyl, aralkyl or heteroaralkyl, and where R5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkoxy, amino and carboxy; and

Ar is arylene, heteroarylene or a divalent heterocyclic group each optionally substituted with one or more substituents selected from C 1-6 alkyl, aryl and C 1-6 alkoxy each optionally substituted with halogen, hydroxy, carboxy or Ci -6-alkyl ester; and

R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and

R 2 is hydrogen or C 1-6 alkyl; or R 2 forms a bond together with R 1 ; and

R3 is hydrogen, C1-6-alkyl-, C2-6-alkenyl-, C2-6-alkynyl-, C4-6-alkenynyl-, aryl-, aralkyl-, C1-6-alkoxy-C1-6-alkyl-, acyl- , heterocyclyl, heteroaryl or heteroaralkyl groups which are optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyan, carboxy and C 1-6 alkyl ester; and

R 4 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkenynyl or aryl;

n is an integer in the range from 1 to 3; and

more 1;

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.

In another preferred embodiment, the present invention relates to compounds of formula (I)

where

X is hydrogen, C1-12-alkyl, C2-12-alkenyl, C2-12-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, Ci- 6-Alkyl, C2-6-Alkenyl, C2-6-Alkynyl, Hydroxy, C1-6-Alkoxy, C1-6-Alkylthio, Aryl, Aryloxy, Arylthio, Acyl, Aralkyl, Aralkoxy, Heteroaryl, Heteroaralkyl, Heteroaryloxy, Heteroaralkoxy, Ci- 6-alkylthio, cyano, amino, C1-6-alkylamino, C1-6-dialkylamino, carboxy and C1-6-alkyl ester; and

Y is hydrogen, d-12-alkyl, C2-12_alkenyl, C2-12-alkynyl, C1-12-alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C1-6- alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy and C 1-6 alkyl ester; and

Z is hydrogen, halogen, hydroxy, C 1-6 alkyl or C 1-6 alkoxy which is optionally substituted with one or more substituents selected from C 1-6 alkoxy, halogen, hydroxy, carboxy, amino and cyan; and

Q is 0, S or NR5, where R5 is hydrogen, C1-6-alkyl, C2-6_alkenyl, C2-6-alkynyl, C1-6-alkenynyl, aralkyl or heteroaralkyl, and where R5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkoxy, amino and carboxy; and

Ar is arylene, heteroarylene or a divalent heterocyclic group each optionally substituted with one or more substituents selected from C 1-6 alkyl, aryl and C 1-6 alkoxy each optionally substituted with halogen, hydroxy, carboxy or Ci -6-alkyl ester; and

R 1 is hydrogen, hydroxy or halogen; or Rx forms a bond together with R2; and

R 2 is hydrogen or C 1-6 alkyl; or R 2 forms a bond together with R 1 ; and

R3 is hydrogen, C1-6-alkyl-, C2-6-alkenyl-, C2-6-alkynyl-, C4-6-alkenynyl-, aryl-, aralkyl-, C1-6-alkoxy-C1-6-alkyl-, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyan, carboxy and C 1-6 alkyl ester; and

R 4 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 4-6 alkenynyl or aryl;

n is an integer in the range from 0 to 3; and

m is an integer in the range 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 racemic mixture, or polymorphs.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is aryl, heteroaryl or heterocyclyl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C1-6-alkoxy, C1-6-alkylthio, aryl, aryloxy , arylthio, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1-6 alkoxy, C 1-6 alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is aryl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1-6 -alkyl, C 1-6 -alkylthio, aryl, aryloxy, arylthio , aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is phenyl or naphthyl, each optionally substituted with one or more substituents selected from halogen and perhalomethyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is phenyl which is optionally substituted with one or more substituents selected from halogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is phenyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is heteroaryl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1-6 -alkyl, C 1-6 -alkylthio, aryl, aryloxy, arylthio , aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where X is heterocyclyl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1-6 -alkyl, C 1-6 -alkylthio, aryl, aryloxy, arylthio , aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Y is hydrogen, C1-12 alkyl or aryl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Y is hydrogen or methyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Y is hydrogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Z is hydrogen or C 1-6 alkoxy.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Z is hydrogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Q is 0.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Ar is the arylene which is optionally substituted with one or more substituents selected from C1-6-alkyl and C1-6-alkoxy, each of which can optionally be substituted with carboxy.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Ar is phenylene.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Ri is hydrogen or Ri forms a bond together with R2.

In another preferred embodiment, the present invention relates to compounds of formula (I) where Ri is hydrogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where R2 is hydrogen or R2 forms a bond together with Ri.

In another preferred embodiment, the present invention relates to compounds of formula (I) where R2 is hydrogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where R3 is C1-6 alkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where R 3 is C 1-2 alkyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where R4 is hydrogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where n is 1.

In another preferred embodiment, the present invention relates to compounds of formula (I) where m is 1.

In another preferred embodiment, the present invention relates to compounds of formula (I) where alkyl is methyl or ethyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where alkenyl is vinyl or 1-propenyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where alkynyl is 1-propynyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where alkenynyl is l-penten-4-yne.

In another preferred embodiment, the present invention relates to compounds of formula (I) where alkoxy is methoxy, ethoxy, isopropoxy or cyclopropoxy.

In another preferred embodiment, the present invention relates to compounds of formula (I) where aryl is phenyl or naphthyl which is optionally substituted with halogen.

In another preferred embodiment, the present invention relates to compounds of formula (I) where the aryl is phenyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where halogen is chlorine.

In another preferred embodiment, the present invention relates to compounds of formula (I) where perhalomethyl is trifluoromethyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where heteroaryl is furan, pyrrole, pyridine, indole or benzofuran.

In another preferred embodiment, the present invention relates to compounds of formula (I) where the heteroaryl is furan, pyrrole, pyridine, indole or benzofuran.

In another preferred embodiment, the present invention relates to compounds of formula (I) where aralkyl is benzyl.

In another preferred embodiment, the present invention relates to compounds of formula (I) where aryloxy is phenoxy.

In another preferred embodiment, the present invention relates to compounds of formula (I) where aralkyloxy is benzyloxy.

In another preferred embodiment, the present invention relates to compounds of formula (I) where n is an integer in the range from 1 to 3, and m is 1.

In another preferred embodiment, the present invention relates to compounds of formula (I) where the substituents Z and Y are arranged in a trans configuration.

In another preferred embodiment, the present invention relates to compounds of formula (I) where the substituents Z and Y are arranged in a cis configuration.

Preferred compounds according to the invention are: (E)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid ethyl ester, (E)-(S)-2 -ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5- phenylpent-2-ene-4-ynyloxy)phenyl]propionic acid ethyl ester, (Z)-(S)-2-ethoxy-3-[.4-(3-methyl-5-phenylpent-2-ene-4-ynyloxy)phenyl ]propionic acid, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid ethyl ester, (E)-(S)-2 -ethoxy-3-[4-(3-methyl-5-phenylpent-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 according to the invention are: ethyl-(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy) phenyl]propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, ethyl -(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (Z)- (S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, ethyl-(E)-(S) -2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (E)-(S)-2-ethoxy-3- [4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid,

ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionate,

(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy}phenylpropionic 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 according to 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-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, (Z)-(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-(5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (E)-(S)-2-ethoxy-3-[4-(5-(3,5 -dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid,

ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate,

(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)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 according to the invention are: (Z)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid ethyl ester, (Z)-(S)- 2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid, (E)-(RS)-2-ethoxy-3-[3-(5-phenylpent-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 according to the invention are: (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{ 4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3 -bis-trifluoromethylphenyl)pent-2-ene-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-ene -4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl }-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[ 5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-( 2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis -(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5- (1,3 -difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent -2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1, 3-diiodophenyl}-3-methylpent-2-en-4- yn-yloxyphenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-ene-4-ynyloxy]phenyl }-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-3-methyl-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-meth ylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl )-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4 - [5-(1,3-bis-(2,2,2 -trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3 -methylpent-2-ene-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-ene- 4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid , (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S )-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E) - (S) -3-{4- [5-(3, 5-bis-(2,2-, 2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(3,5-bis-(2,2,2-trifluoro ethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2 -en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy] -3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3- chlorophenyl}-2 -ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl}-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4- [5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2 -ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4- [5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl}-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-3-methyl-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4 - [5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2 -ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy] -3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4- [5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4- [5- (1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl}-2 -ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-(4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl}-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-3-methyl-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3- methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl}-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4- [5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl}-2 -ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid , (E)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E) -(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S) -3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3 -{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-3-methyl-2-ethoxypropionic acid, (E)-(S)-3-{4 -[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5- (1,3-bis-(2, 2, 2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3 -{4- [5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyl oxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3 -iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-( S)-3-{4-[5-(3,5-bis-(2, 2, 2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2- ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]- 3-iodophenyl}-2-ethoxypropionic 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 according to the invention are: (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid,

(Z)-(S)-3-{4- [5- (1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl}pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid,

(Z)-(S)-3-{4-(5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-3-methyl-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2, 2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-difluorophenylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-,(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy] -

3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy] -

3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-(4-[5-(1,3-Dibrdimphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-yn-, yloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-3-methyl-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3 -chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4- [5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-stoxy-propionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1, 3-bis-(2,2, 2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, . (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-3-methyl-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-(4- [5- (1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4- [5- (1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2, 2, 2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, . (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z}- (S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-.(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-3-methyl-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4- [5- (1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid,

(Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic 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 structural formulas above and throughout the present description, the following terms have the indicated meaning: The term "Ci-12-alkyl", as used here, alone or in combination, is intended to include those alkyl groups of a specified length either in a straight chain or branched or cyclic configuration constituting e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like. Typical C 1-12 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like, particularly preferred are methyl and ethyl.

The term "C2-12-alkenyl" as used herein is an olefinically unsaturated, branched or straight chain group having from two to the specified number of carbon atoms, and at least one double bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, isopropenyl, 1,3-butadiene-yl, 1-butenyl, hexenyl, pentenyl and the like, particularly preferred are vinyl and 1 -propenyl.

The term "C2-12-alkynyl", as used herein, is an unsaturated, branched or straight chain group having from two to the specified number of carbon atoms, and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like, particularly preferred is 1-propynyl.

The term "C4-12-alkenynyl" as used herein is an unsaturated, branched or straight chain hydrocarbon group having from 4 to the indicated 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, l-penten-4-yne, 3-penten-l-yne, 1,3-hexadien-5-yne and the like, particularly preferred is l-penten-4-yne .

The term "Ci-6-Alkoxy", as used herein, alone or in combination, is intended to include those C1-6_alkyl groups having the specified length in either a straight-chain or branched or cyclic configuration, bonded through an ether oxygen, and having their free valence bond from the ether oxygen. Examples of straight-chain alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like, particularly preferred are methoxy and ethoxy. Examples of branched alkoxy are isopropoxy, sec.-butoxy, tert.-butoxy, isopentoxy, isohexoxy and the like, particularly preferred is isopropoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, particularly preferred is cyclopropoxy.

The term "Ci-6-alkylthio", as used herein, alone or in combination, refers to a straight-chain or branched or cyclic, monovalent substituent comprising a Ci-6-alkyl group, bonded through a divalent sulfur atom, which has its free valence bond from the sulfur atom, and which has 1-6 carbon atoms, e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio and the like. Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

The term "Ci-6-alkylamino", as used herein, alone or in combination, refers to a straight-chain or branched or cyclic, monovalent substituent comprising a Ci-6-alkyl group linked through amino with a free valence bond from the nitrogen atom, f .ex. methylamino, ethylamino, propylamino, butylamino, pentylamino and the like. Examples of cyclic alkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like.

The term "Ci-6-Alkoxy-Ci-6-Alkyl" as used herein refers, alone or in combination, to a C1-6-alkyl as defined herein, to which is bound a C1-6-Alkoxy as defined here, e.g. methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl 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-naphthyl or 2-naphthyl) and the like, optionally substituted with halogen, amino, hydroxy, Ci-6 -alkyl, C 1-6 -alkyl, C 1-6 -alkyl ester or carboxy and the like, particularly preferred are phenyl and naphthyl which are optionally substituted with halogen.

The term "arylene" is intended to include divalent aromatic rings, such as carbocyclic, aromatic rings selected from the group consisting of phenylene, naphthylene and the like, optionally substituted with halogen, amino, hydroxy, C1-6-alkyl, C1-6-alkoxy, C1- 6-alkyl ester or carboxy and the like, particularly preferred is phenyl.

The term "halogen" means fluorine, chlorine, bromine or iodine, chlorine being particularly preferred.

The term "perhalomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl, particularly preferred is trifluoromethyl.

The term "Ci-6-dialkylamino", as used herein, refers to an amino group in which the two hydrogen atoms are independently substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms, such as dimethylamino, N-ethyl -N-methylamino, diethylamino, di-propylamino, N-(n-butyl)-N-methylamino, di(n-pentyl)amino and the like.

The term "acyl", as used here, refers to a monovalent substituent comprising a C 1-6 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 sulphur, 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, particularly preferred are furan, pyrrole, pyridine, indole and benzofuran.

The term "heteroaryl" 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 sulphur, 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, particularly preferred are furan, pyrrole, pyridine, indole and benzofuran.

The term "heteroaryloxy", as used herein, alone or in combination, refers to a heteroaryl as defined herein, bonded to an oxygen atom with its free valence bond from the oxygen atom, e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine bound 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 carbon atoms, substituted with an aromatic hydrocarbon, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthyl-methyl , 2-(1-naphthyl)ethyl and the like, particularly preferred is benzyl.

The term "aryloxy" refers, as used here, to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like, particularly preferred is phenoxy.

The term "araloxy" as used herein refers to a C 1-6 alkoxy group substituted with an aromatic hydrocarbon, such as benzyloxy, phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphthyl)ethoxy and the like, particularly preferred is benzyloxy.

The term "heteroaralkyl", as used herein, refers to a straight or branched, saturated carbon chain containing from 1 to 6 carbon atoms, 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-pyrimidinyl)ethyl and the like.

The term "heteroaralkyl", as used herein, refers to a heteroarylalkyl as defined herein, bonded to an oxygen atom with 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 attached to oxygen, and the like.

The term "arylthio", as used here, alone or in combination, refers to an aryl group bound through a divalent sulfur atom with its free valence bond from the sulfur atom, the aryl group being optionally mono- or poly-substituted with C 1-6 alkyl, halogen, hydroxy or C 1-6 alkoxy, e.g. phenylthio, (4-methylphenyl)thio, (2-chlorophenyl)thio and the like.

As used herein, the term "heterocyclyl" means a monovalent, saturated or unsaturated, non-aromatic group which is monocyclic and contains one or more, such as from 1 to 4, carbon atom(s), and 1-4 N-, 0 or S atom(s), or a combination thereof. The term "heterocyclyl" includes, but is not limited to, 5-membered heterocyclic compounds having one heteroatom (eg, pyrrolidine, pyrroline, and the like); 5-membered heterocyclic compounds having 2 heteroatoms in the 1,2- or 1,3-position (eg, pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine, imidazoline, 4-oxazolone, and the like); heterocyclic compounds having 5 members with 3 heteroatoms (eg, tetrahydrofurazan and the like); heterocyclic compounds having 5 members with 4 heteroatoms; 6-membered heterocyclic compounds with one heteroatom (eg, piperidine and the like); 6-membered heterocyclic compounds with 2 heteroatoms (eg piperazine, morpholine and

the like); 6-membered heterocyclic compounds with

3 heteroatoms; and 6-membered heterocyclic compounds with 4 heteroatoms and the like.

As used herein, the term "a divalent heterocyclic group" means a divalent, saturated or unsaturated system which is monocyclic and contains one or more, such as from 1 to 4, carbon atom(s), and 1-4 N-, 0 - or S atom(s), or a combination thereof. The term a divalent heterocyclic group includes, but is not limited to, 5-membered heterocyclic compounds having one heteroatom (eg, pyrrolidine, pyrroline, and the like); 5-membered heterocyclic compounds having 2 heteroatoms in the 1,2- or 1,3-position (eg, pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine, imidazoline, 4-oxazolone and the like); 5-membered heterocyclic compounds having 3 heteroatoms (e.g. tetrahydrofurazan and

the like); 5-membered heterocyclic compounds that have

4 heteroatoms; 6-membered heterocyclic compounds with

one heteroatom (eg, piperidine and the like); 6-membered heterocyclic compounds with 2 heteroatoms (eg, piperazine, morpholine, and the like); 6-membered heterocyclic compounds with 3 heteroatoms; and 6-membered heterocyclic compounds with 4 heteroatoms and the like.

As used herein, the term "treatment" includes

treatment, prophylaxis and management of such a condition.

Some of the expressions defined above may appear more than once in formula (I) above, and in such cases each expression must be defined independently of the others.

The present invention also includes pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitrogenous acids and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid , methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, embonic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfates, nitrates, phosphates , perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like. Additional examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts set forth in J. Pharm. Sei., 1977, 66, 2. Examples of metal salts include lithium, sodium, potassium and magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.

The pharmaceutically acceptable salts are prepared by reacting the compound of formula I with 1-4 equivalents of a base, such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents such as ether, THF, methanol, t-butanol,' dioxane, isopropanol, ethanol etc. Mixtures of solvents can be used. Organic bases such as lysine, arginine, diethanolamine, choline, guanidine and their derivatives etc. can also be used. Alternatively, acid addition salts are prepared when appropriate by treatment with such acids as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid , tartaric acid and the like, in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixtures of solvents can also be used.

The stereoisomers of the compounds forming part of this invention can be prepared by using reactants in their single enantiomeric form in the process whenever possible, or by carrying out the reaction in the presence of reagents or catalysts in their single enantiomeric form, or by dissolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include the use of microbial resolution, enzymatic resolution, resolution of the diastereomeric salts formed with chiral acids, such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like, when appropriate, or chiral bases, such as brucine (R )-or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like. Commonly used procedures are listed by Jaques et al. in "Enantiomers, Racemates and Resolution" (Wiley Inter-science, 1981). More specifically, the compound of formula I can be converted to a 1:1 mixture of diastereomeric amides by treatment with chiral amines, amino acids, amino alcohols derived from amino acids; common reaction conditions can be used to convert acid to an amide; the diastereomers can be separated either by fractional crystallization or chromatography, and the stereoisomers of the compound of formula I can be prepared by hydrolysis of the pure diastereomeric amide.

Different polymorphs of compounds of general formula I forming part of this invention can be prepared by crystallizing a compound of formula I under different conditions, e.g. by using different solvents commonly used, or their mixtures, for recrystallization; crystallizations at different temperatures; different cooling methods varying from very fast to very slow cooling during crystallization. Polymorphs can also be obtained by heating or melting the compound, followed by gradual or rapid cooling. The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or other such techniques.

The invention also includes prodrugs of the present compounds, which after administration undergo chemical conversion by means of metabolic processes before becoming active pharmacological substances. Such prodrugs will generally be functional derivatives of the present compounds, which are readily convertible in vivo to the required compound of formula (I). Common procedures for the selection and preparation of suitable prodrug derivatives are described, e.g. in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

The invention also includes active metabolites of the present compounds.

Moreover, the present compounds of formula I can be used in the treatment and/or prophylaxis of conditions mediated by means of nuclear receptors, in particular the peroxisome proliferator-activated receptors (PPAR).

In a further aspect, the present invention relates to a method for the treatment and/or prophylaxis of type I or type II diabetes.

In yet another 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 drug for the treatment and/or prophylaxis of type I or type II diabetes.

In yet another aspect, the present compounds are useful for the treatment and/or prophylaxis of IGT.

In yet another aspect, the present compounds are useful for the treatment and/or prophylaxis of type II diabetes.

In yet another aspect, the present compounds are useful for delaying or prophylaxis of the progression from IGT to type II diabetes.

In yet another aspect, the present compounds are useful for delaying or prophylaxis of the progression from non-insulin-requiring type II diabetes to insulin-requiring type II diabetes.

In another aspect, the present compounds reduce blood glucose and triglyceride levels, and are therefore useful for the treatment and/or prophylaxis of such disorders and disorders as diabetes and/or obesity.

In yet another aspect, the present compounds can be used for the treatment and/or prophylaxis of insulin resistance (type II diabetes), impaired glucose tolerance, dyslipidemia, disorders related to syndrome X, such as hypertension, obesity, insulin resistance, hyperglycemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other cardiovascular disorders.

In yet another aspect, the present compounds are effective in reducing apoptosis in mammalian cells, such as beta cells or islets of Langerhans.

In yet another aspect, the present compounds can be used to treat certain kidney diseases, including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

In yet another aspect, the present compounds may also be useful for improving cognitive functions in dementia, treatment of diabetic complications, psoriasis, polycystic ovary syndrome (PCOS) and prophylaxis and treatment of bone loss, e.g. osteoporosis.

The invention also relates to pharmaceutical preparations comprising as an active ingredient at least one compound of formula I or any optical or geometric isomer or tautomeric form thereof, including mixtures thereof, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers or thinners.

The invention also 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 preparation for the treatment and/or prophylaxis 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 method for producing the above-mentioned new compounds, their derivatives, their analogues, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.

The procedure includes:

a) reaction of a compound of formula II (prepared e.g. according to methods described in Chem. Commun., 718-719, 1967; Org. Syntheses, Coll., vol. 3, 731-733, 1955; Org. .Syntheses, Coll., vol. IV, 801-803, 1963.

where X and Y are as defined above, through a Wittig-like method, e.g. with (EtO) 2 PO (CHZ) (CH 2 ) tCOOR 6 (where R 6 is an alkyl group), in the presence of such a base as sodium hydride, EtONa and the like, whereby a compound of formula III is obtained

where X, Y, Z and R 6 are defined as above, and where t is 0-2; and b) reduction of a compound of formula III, where X, Y, Z, R 6 and t are defined as above, with a suitable reagent, such as diisobutylaluminum hydride, to give a compound of formula IV

where X, Y, Z and t are defined as above; and

c) reacting a compound of formula IV, where X, Y, Z and t are defined as above, with a compound of formula

V

where Q, Ar, R 1 , R 2 , R 3 /R 4 and m are defined as above, except that m is not 0, under Mitsunobu conditions, using such a reagent as triphenylphosphine/diethyl azodicarboxylate and the like, whereby a compound with formula I, wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R o n and m are defined as above, except that R 4 is not H, and n and m are not 0; or d) by converting the -OH group in a compound of formula IV, where X, Y, Z and t are defined as above, into a suitable leaving group (L), such as p-toluenesulfonate, methanesulfonate, halogen (f .eg by methods according to Houben-Weyl, Methoden der Organischen Chemie, Alkohole III, 6/lb, Thieme-Verlag, 1984, 4th ed., pp. 927-939; Comprehensive Organic Transformations. A guide to functional group preparations, VCH Publishers, 1989, 1st ed., pp. 353-363, and J. Org. Chem., vol. 36 (20), 3044-3045, 1971), triflate and the like, whereby one obtains a compound of formula VI wherein L, X, Y, Z and t are defined as above; or e) reacting a compound of formula VI where L is a leaving group, such as p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, and where X, Y, Z and t are defined as above, with a compound of formula V where Q, Ar, Ri, R2, R3, R4 and m are defined as above, except that m is not 0, thereby obtaining a compound of formula I, where X, Y, Z, Q, Ar, Ri, R2 , R 3 , R 4 , n and m are defined as above, except that R 4 is not H, and n and m are not 0; or f) by means of chemical or enzymatic saponification of a compound of formula I

where X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R 4 , n and m are defined as above, except that R 4 is not H, thereby obtaining a compound of formula I, wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R 4 , n and m are defined as above, except that R 4 is H.

Alternative methods for the synthesis of a compound of formula I, a compound of formula III, a compound of formula IV and a compound of formula VI are:

g) conversion of a compound of formula VII:

where X is defined as above, with a compound of formula

VIII

under Pd-catalyzed cross-linking conditions (e.g. as described in Tetrahedron Lett., 39(36), 6445-6448, 1998), whereby a compound of formula III is obtained, where X, Y and R6 are defined as above, and where t is 0, and Z is hydrogen; h) reacting a compound of formula VII with a compound of formula IX

according to a method analogous to that described in Tetrahedron Lett., 35(37), 6719-6720, 1998, whereby a compound of formula III is obtained, where X, Y, Z and R6 are defined as above, and where t is 0;

i) trans-cis or cis-trans isomerization of compounds I, III, IV 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

Principle

The PPAR gene transcription activation assays were based on transient transfection in 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) of the yeast GAL4 transcription factor to the ligand-binding domain (LBD) of the human PPAR proteins. In addition to the ligand-binding pocket, the PPAR-LBD also contained the naturally occurring activation domain (activation function 2 = AF2), which enabled the fusion protein to act as a PPAR-ligand-dependent transcription factor. The GAL4-DBD will force the fusion protein to bind only to Gal4 enhancers (none of which existed in HEK293 cells). The receptor plasmid contained a Gal4 enhancer that drives the expression of the firefly luciferase protein. After transfection, HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion protein will in turn bind to the Gal4 enhancer which controls luciferase expression and does nothing in the absence of ligand. After 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 means of 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 inoculated in 96-well plates the day before transfection, whereby a confluence of 50-80% is obtained upon transfection. A total of 0.8 µg DNA containing 0.64 µg pMlot/γ-LBD, 0.1 µg pCMVpGal, 0.08 µg pGL2Gal4DBD and 0.02 µg pADVANTAGE was transfected per well using FuGene transfection reagent according to the manufacturer's instructions (Roche). Cells were allowed to express protein for 48 h, followed by addition of compound.

Plasmids: Human PPAR-α and -γ were 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 (PPARα: aal67-C-terminus; PPARγ: aal65-C-terminus) and fused to the DNA-binding domain (DBD) of the yeast transcription factor GAL4 by means of subcloning of fragments in frame in the vector pMl, whereby the plasmids pMlaLBD and pMlyLBD were generated. Subsequent fusions were verified by sequencing. The reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x CGGAGTACTGTCCTCCG(AG)) into the vector pGL2 promoter (Promega), generating the plasmid pGL2(GAL4)5. pCMVPGal was purchased from Clontech, and pADVANTAGE was purchased from Promega.

Luciferase assay: Medium containing test compound was aerated, and 100 µl of PBS, including 1 mM Mg<++>and Ca<++>, was added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturer's instructions (Packard Instruments). Light emission was quantified by counting the SPC wave type on a Packard Instruments peak counter. To measure β-galactosidase activity, 25 µl of supernatant from each transfection lysate was transferred to a new microplate. β-galactosidase assay was performed in the microwell plates using a kit from Promega and read in a microplate reader. The β-galactosidase data were used to normalize (transfection efficiency, cell growth, etc.) the luciferase data.

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 after addition to the cells. Compounds were tested in quadruplicate at five concentrations ranging from 0.01 to 30 µM. Cells were treated with compound for 24 h, followed by luciferase assay. Each compound was tested in three separate experiments. EC 50 values were calculated via non-linear regression using GraphPad PRISM 3.02

(GraphPad Software, San Diego, CA). The results were expressed as gj mean values.

Compounds were tested in at least three separate experiments at five concentrations ranging from 0.01 to 30 µM. EC50 values were not calculated for compounds that gave transactivation lower than 25% at 30 uM.<a>Folds of activation relative to maximal activation obtained with Wyl4643 (about 20-fold corresponding to 100%) and with brosiglitazone (about 120-fold corresponded to 100%).

Pharmaceutical preparations

In another aspect, the present invention includes within its scope pharmaceutical preparations which comprise 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.

The present compounds can also be administered in combination with one or more additional pharmacologically active substances, e.g. selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment and/or prophylaxis of complications arising from or associated with diabetes, and agents for the treatment and/or prophylaxis of complications and disorders arising from or associated with obesity.

In a further aspect of the invention, the present compounds can thus be administered in combination with one or more anti-obesity agents or appetite regulating agents.

Such agents can be selected from the group consisting of agonists for CART (cocaine-amphetamine-regulated transcript), antagonists for NPY (neuropeptide Y), agonists for MC4 (melano-cortin 4), orexin antagonists, agonists for TNF (tumor necrosis factor), agonists for CRF (corticotropin-releasing factor), antagonists against CRF-BP (corticotropin-releasing factor-binding protein), urocortin agonists, (33-agonists, agonists for MSH (melanocyte-stimulating hormone), antagonists against MCH (melanocyte-concentrating hormone), agonists for CCK (cholecysto-kinin) , serotonin reuptake inhibitors, serotonin and noradrenergic reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH (thyrotropin-releasing hormone) agonists, modulators of UCP 2 or 3 (uncoupling protein 2 or 3), leptin agonists, DA agonists (bromocriptine, doprexin), lipase inhibitors/ amylase, RXR (retinoid X receptor) modulators or TRØ agonists.

In one embodiment of the invention, the antiobesity agent is leptin.

In another embodiment, the antiobesity agent is dex-amphetamine or amphetamine.

In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

In yet another embodiment, the antiobesity agent is sibutramine.

In a further embodiment, the antiobesity agent is orlistat.

In another embodiment, the antiobesity agent is mazindole or phentermine.

Suitable antidiabetic agents include insulin, derivatives of GLP-1 (glucagon-like peptide-1), such as those described in

WO 98/08871, Novo Nordisk A/S, as well as orally active hypoglycemic agents.

The orally active hypoglycemic agents preferably include sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, such glucagon antagonists as those described in WO 99/01423, Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers, such as those described in

WO 97/26265 and WO 99/03861, Novo Nordisk A/S, DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds that modify lipid metabolism, such as antihyperlipidemic agents, and antilipidemic agents such as HMG-CoA inhibitors (statins), compounds that lower food intake, RXR agonists and agents that act on the ATP-dependent potassium channel in (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 sulfonylurea, e.g. tolbutamide, glibenclamide, glipizide or glicazid.

In another embodiment, the present compounds are administered in combination with a biguanide, e.g. metformin.

In yet another embodiment, the present compounds are administered in combination with a meglitinide, e.g. repaglinide or senaglinide.

In a further embodiment, the present compounds are administered in combination with an α-glucosidase inhibitor, e.g. migi in tol. or acarbose.

In another embodiment, the present compounds are administered in combination with an agent that acts on the ATP-dependent potassium channel in the β cells, e.g. tolbutamide, glibenclamide, glipizide, glicazid or repaglinide.

Moreover, the present compounds can be administered in combination with nateglinide.

In yet another embodiment, the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent, e.g. 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, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.

The present compounds can also be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers, such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin-converting enzyme) inhibitors, such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril; calcium channel blockers, such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and vera-pamil; and α-blockers, such as doxazocin, urapidil, prazosin, and terazosin. Further, reference may be made to Remington: The Science and Practice of Pharmacy, 19th ed., Gennaro, ed., Mack Publishing Co., Easton, PA, 1995.

It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and possibly one or more further pharmacologically active substances is considered to be within the scope of the present invention.

Pharmaceutical preparations containing a compound according to the present invention can be prepared using common techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th ed., 1995. The preparations may be in conventional forms, e.g. capsules, tablets, aerosols, solutions, suspensions or topical applications.

Typical preparations comprise a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable excipient which may be a carrier or a diluent, or diluted by means of a carrier, or enclosed in a carrier which may be in the form of a capsule, small bag, paper or other container. When preparing the preparations, common techniques for the preparation of pharmaceutical preparations can be used. The active connection will e.g. usually be mixed with a carrier, or diluted with a carrier, or enclosed in a carrier which may be in the form of an ampoule, capsule, pouch, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid or liquid material acting as a carrier, an excipient or a medium for the active compound. The active compound can be adsorbed on a granular, solid container, e.g. in a small bag. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinyl pyrrolidone. Likewise, the carrier or diluent may comprise any sustained release material known in the art, such as glyceryl monostearate and glyceryl distearate, alone or mixed with a wax. The preparations may also include wetting agents, emulsifying and suspending agents, preservatives, sweeteners or flavourings. The preparations according to the invention can be formulated to provide rapid, prolonged or delayed release of the active ingredient after administration to the patient, by using methods that are well known in the art.

The pharmaceutical preparations can be sterilized and, if desired, mixed with auxiliaries, emulsifiers, salt to affect osmotic pressure, buffer substances and/or dyes and the like, which do not react in a harmful way with the active compounds.

The route of administration may be any route that effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.

If a solid carrier is used for oral administration, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or it can be in the form of a lozenge or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile, injectable liquid, such as an aqueous or non-aqueous, liquid suspension or solution.

For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, especially an aqueous carrier, for aerosol application. The carrier may contain such additives as solubilizers, e.g. propylene glycol, surfactants, absorption promoters, such as lecithin (phosphatidylcholine) or cyclodextrin, or such preservatives as parabens.

For parenteral application, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

Tablets, dragees or capsules with talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferred carriers for tablets, dragees or capsules include lactose, corn starch and/or potato starch. A syrup or elixir can be used in cases where a sweetened carrier can be used.

A typical tablet that can be prepared using conventional tableting techniques may contain:

Core:

Active connection (as free connection

The compounds according to the invention can be administered to a mammal, especially a human, in need of such treatment, prophylaxis, elimination, alleviation or improvement of a disease related to the regulation of blood sugar. Such mammals also include animals, both livestock, e.g. pets, and non-domestic animals, such as wild animals.

The compounds according to the invention are effective over a wide dosage range. For example, when treating adults, dosages from approx. 0.05 to approx.

100 mg, preferably from approx. 0.1 to approx. 100 mg, per day. A highly preferred dosage is approx. 0.1 mg to approx. 70 mg per day. When choosing a regimen for patients, it may often be necessary to start with a dosage from approx. 2 to approx. 70 mg per day, and when the condition is under control to reduce the dosage to as low a value as from approx. 0.1 to approx. 10 mg per day. The exact dosage will depend on the route of administration, the desired therapy, the form in which it is administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the attending physician or veterinarian.

In general, the compounds according to 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.

Generally, dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from approx.

0.001 mg to approx. 100 mg, preferably from approx. 0.01 mg to approx.

50 mg, of the compounds of formula I mixed with a pharmaceutically acceptable carrier or diluent.

Any new feature or any new combination of features described herein is considered essential to this invention.

Examples

The procedure for the preparation of compounds of formula I and preparations containing them is further illustrated in the following examples, which, however, should not be taken as limiting. The formulas of the compounds are confirmed either by 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 indicated. Temp. is the melting point and is indicated in °C. Column chromatography was performed 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 an "Advanced Laser Polarimeter".

<*>Compounds used as starting materials are either known compounds or compounds that can be easily prepared using methods that are known per se. ;Abbreviations:;THF: tetrahydrofuran;DMSO: dimethyl sulfoxide;MTBE: tert-butyl methyl ether;CDCI3: deuterated chloroform;DMF: N,N-dimethylformamide;min: minutes;t: hours.;Example 1; ; ( E )-( S )- 2- ethoxy- 3-[ 4-( 5- phenylpent- 2- en- 4- ynyloxy) phenyl]- propionic acid ethyl ester ; Method 1; a) A solution of triethylphosphonoacetate (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 was stirred at 0 °C for 30 min. A solution of 3-phenylpropargylaldehyde (Org. Syntheses, Coll., vol. 3, 731-733, 1955) (10.0 g, 77 mmol) in dry THF (15 mL) was added, the mixture was slowly warmed to room temperature and stirring continued for 16 h. The reaction was quenched with ethanol (25 ml) and water (300 ml), the organic phase was separated and the aqueous phase extracted with dichloromethane (300 ml). The combined organic phases were concentrated under vacuum and subjected to flash column chromatography, petroleum ether/toluene (1:1) with gradual transition to petroleum ether/toluene (1:9) as eluent, yielding 1.21 g, 8%) ( E)-5-phenylpent-2-en-4-ynoic acid ethyl ester. ;<1>H-NMR (CDCl 3, 300 MHz) δ: 1.30 (t, 3 H), 4.25 (q, 2 H), 6.30 (d, 1 H, Jtrans=15 Hz), 6.98 (d, 1 H, Jtrans<=>15 Hz), 7.30-7.40 (m, 3 H), 7.45-7.50 (m, 2 H). ;b) Diisobutylaluminum 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 (E)-5-phenylpent-2-en-4-ynoic acid- ethyl ester (1.2 g, 5.99 mmol) in dry THF (105 mL). After stirring for 1 1.5 h, the reaction 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 was extracted with ethyl acetate (250 mL, 2x). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give 948 mg (100%) of (E)-5-phenylpent-2-en-4-yn-1-ol. ;<1>H-NMR (CDCl3, 300 MHz) δ: 2.20 (bs, 1 H), 4.25 (d,;2 H), 5.95 (dt, 1 H, Jtrans<=>15 Hz), 6.35 (dt, 1 H, Jtrans<=>;15 Hz), 7.23-7.35 (m, 3 H), 7.35-7.48 (m, 2 H). c) (E)-5-phenylpent-2-en-4-yn-l-ol (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) was successively dissolved in dry benzene (30 ml) under a nitrogen atmosphere, and the solution was cooled to 0 °C. Solid 1,1'-(azodicarbonyl)dipiperidine (756 mg, 3.0 mmol) was added, the mixture was stirred for 10 min, then warmed to room temperature and stirred for 16 h. The reaction mixture was filtered and the filtrate concentrated under vacuum. The product was purified by means of flash column chromatography eluting with toluene with gradual transition to toluene/ethyl acetate (19:1), whereby 450 mg (57%) of the title compound was obtained. ;<X>H-NMR (CDCl 3 , 300 MHz) δ: 1.18 (t, 3 H) , 1.25 (t, 3 H) , 2.95 (d, 2 H) , 3, 30-3 , 42 (m, 1 H) , 3, 55-3, 67 (m, 1 H) , 3.98 (t, 1 H), 4.15 (q, 2 H) , 4.60 (d, 2 H) , 6.15 (dt, 1 H, Jtrans = ;15 Hz), 6.48 (dt, 1 H, Jtrans=15 Hz), 6.85 (d, 2 H) , 7.15 (d, ;2H), 7.28-7.35 (m, 3H), 7.40-7.46 (m, 2H). ;[a]<*>= 30° ± 4°.

Procedure 2

a) To a mixture of (E)-5-phenylpent-2-en-4-yn-l-ol (method lb) (4.9 g, 31.0 mmol) and triethylamine (3.8 g, 38, 0 mmol) in dry dichloromethane (200 ml) methanesulfonyl chloride (3.8 g, 33 mmol) was added dropwise. Stirring was continued at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue washed with heptane/dichloromethane (x 2), whereby 4.5 g (82%) of impure (E)-(5-chloropent-3-en-l-yn-yl)benzene was obtained. <1>H-NMR (CDC13, 300 MHz) δ: 4.13 (d, 2 H) ), 6.0 (d, 1 H, Jtrans=15 Hz), 6.29 (dt, 1 H, Jtrans =15 Hz), 7.28-7.35 (m, 3 H), 7.40-7.48 (m, 2 H). b) To a solution of (E)-(5-chloropent-3-en-l-ynyl)benzene (177 mg, 1.0 mmol) and (S)-2-ethoxy-3-(4-hydroxyphenyl)propion- 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 to reflux overnight with stirring. Water was added and the product extracted with tert-butyl methyl ether (x 3). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under vacuum to give the title compound as a crude product.

Procedure 3

a) A solution of (E)-5-phenylpent-2-en-4-yn-l-ol (method lb) (980 mg, 6.2 mmol) in dry toluene (20 mL) was

cooled on ice, and phosphorus tribromide (0.59 mL, 6.2 mmol) was slowly added. After 16 h at 5 °C, the mixture was diluted with ethyl acetate and washed with water (x 3). The organic phase was concentrated under vacuum and the residue extracted with ethane (x 3). The combined heptane phases were concentrated under vacuum to give 900 mg of impure (E)-(5-bromopent-3-en-l-ynyl)benzene. (According to NMR, the product contained about 5% of the (Z) isomer.)

<X>H-NMR (CDCl 3 , 300 MHz) δ : 4.02 (d, 1 H), 4.25 (d,

0.05 H), 5.82 (d, 0.05 H, Jcis = 8 Hz), 5.95 (d, 1 H, JtranS<=>

16 Hz), 6.18 (dt, 0.05 H, Jcis<=>8 Hz) , 6.35 (dt, 1 H, Jtrans<=>

16 Hz), 7.26-7.35 (m, 3 H), 7.35-7.48 (m, 2 H). Example 2

( E )-( S )- 2- ethoxy- 3-[ 4-( 5- phenylpent- 2- en- 4- ynyloxy) phenyl]- propionic acid

Aqueous sodium hydroxide (1 N, 5 mL, 5.0 mmol) was added to a stirred solution of (E)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy )phenyl]propionic acid (Example 1) (450 mg,

1.18 mmol) in ethanol (5 mL), and the resulting mixture was stirred at room temperature for 16 h. The ethanol was evaporated under vacuum and the mixture acidified to pH 1 with 1 N hydrochloric acid.

The product was extracted with ethyl acetate (30 mL x 2), and the combined organic phases were dried (MgSO 4 ), filtered and evaporated to give 225 mg (54%) of the title compound as white crystals.

<1>H-NMR (CDC13, 300 MHz) δ: 1.20 (t, 3 H), 2.97 (dd, 1 H), 3.10 (dd, 1 H), 3.42-3, 65 (m, 2 H) , 4.05 (dd, 1 H) , 4.63 (dd,

2 H), 6.08 (dt, 1 H, Jtrans=15 Hz), 6.39 (dt, 1 H, Jtrans<=>

15 Hz), 6.85 (d, 2 H), 7.15 (d, 2 H), 7.30-7.35 (m, 3 H), 7.40-7.48 (m, 2 H ).

[a] f70 = 23° ± 3°.

Example 3

( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5- phenylpent- 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- phenylpent-2-en-4-yn-l-ol (0.172 g, 1.0 mmol) (J. Org. Chem., 1999, 54(21), 7687-7692) and (S)-ethyl-2- ethoxy-3-(4-hydroxyphenyl)propionate (0.262 g,

1.1 mmol) in dry benzene (20 ml), the mixture was allowed to warm to

room temperature, and stirring was continued for 24 h. The resulting mixture was evaporated under vacuum and the residue purified by flash column chromatography on silica gel (20% ethyl acetate in n-heptane as eluent) to give (Z)-(S)-2-ethoxy -3-[4-(3-Methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid ethyl ester as oil, 0.267 g (68%).

<1>H-NMR (300 MHz, CDCl 3 ) 6 : 1.1-1.25 (6 H, m) , 2.0 (3 H,

d) , 2.93 (2 H, 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 (1H, dt) , 6.86

(2H, d), 7.15 (2H, d), 7.25-7.35 (3H, m), 7.40-7.43 (2H, m).

Example 4

( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5- phenylpent- 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-phenylpent-2-ene) -4-ynyloxy)phenyl]propionic acid ethyl ester (Example 3)

(0.246 g, 0.627 mmol) in ethanol (20 mL), and the mixture was stirred at 70 °C for 2.5 h. After cooling 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 (Na 2 SO 4 ) and evaporated,

yielding (E)-(S)-3-[4-(3-biphenyl-4-ylbut-2-enyloxy)-phenyl]-2-ethoxypropionic acid as an oil, 0.150 g (66%).

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.05 (3 H, t) , 1.92 (3 H, 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 (2 H, dd ), 5.85 (1 H, dt) , 6.8 (2 H, d) , 7.1 (2 H, d) , 7.2-7.25 (3 H, m) , 7.3- 7.4 (2 H, m) , 8.9 (1 H, br s) .

Example 5

( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5- phenylpent- 2- en- 4- ynyloxy)-phenyl] propionic acid ethyl ester

The title compound was prepared from (E)-3-methyl-5-phenylpent-2-en-4-yn-l-ol (0.172 g, 1.0 mmol) (J. Med. Chem., 1998, 42(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-Hydroxyphenyl)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%) (E) -(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid ethyl ester.

<1>H-NMR (300 MHz, CDCl 3 ) δ : 1.1-1.25 (6 H, m), 1.98 (3 H,

d) , 2.95 (2 H, 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 (1H, dt) , 6.8

(2H, d), 7.15 (2H, d), 7.20-7.3 (3H, m), 7.35-7.45 (2H, m).

Example 6

( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5- phenylpent- 2- en- 4- ynyloxy)-phenyl] propionic acid

The title compound was prepared from (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid ethyl ester (Example 5) (0.270 g ,0.698 mmol) and sodium hydroxide (IN, 1.4 ml, 1.4 mmol) using a procedure analogous to that described in Example 4, whereby 0.100 g (39%) of (E)-( S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.18 (3 H, t) , 1.98 (3 H, d) , 2.9 (1 H, dd), 2.05 (1 H , dd), 3.4-3.5 (1 H, m) , 3.55-3.65 (1 H, m), 4.05 (1 H, dd), 4.62 (2 H, dd ), 6.15 (1 H, m) , 6.8 (2 H, d) , 7.15 (2 H, d) , 7.3 (3 H, m) , 7.43 (2 H, m ).

Example 7

Ethyl-( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3, 5- dichlorophenyl) pent- 2-en- 4- ynyloxy) phenyl] propionate

Procedure 1

a) To a solution of 1,3-dichloro-5-iodobenzene (3.44 g, 12.6 mmol) in THF (220 ml) was added PdCl2(PPh3)2 (904 mg,

1.29 mmol), 3-butyn-2-one (1.18 g, 31.0 mmol), copper (I) iodide

(380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 h, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4-(3,5-dichlorophenyl)-3-butyn-2-one product was isolated in 977 mg yield.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 2.46 (s, 3 H), 7.45 (s, 3 H).

b) To a solution of sodium (163 mg, 6.8 mmol) in ethanol (6 ml) at -10 °C was added triethylphosphonoacetate

(1.37 mL, 6.8 mmol), and the reaction mixture was stirred for 5 min. A solution of 4-(3,5-dichlorophenyl)-3-butyn-2-one (214 mg,

5.7 mmol) in ethanol (4 mL) was added and the reaction mixture was stirred overnight at room temperature and evaporated. The residue was treated with water (10 mL) and extracted with 3 x 30 mL ethyl acetate. The dried organic phases were evaporated, whereby a mixture of (E)- and (Z)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynoic acid ethyl esters was obtained. The mixture was separated by column chromatography using hexane/methylene chloride (10:1) as eluent to give pure (E) and pure (Z)

in yields of 130 and 160 mg, respectively. (E)-3-Methyl-5-(3,5-dichlorophenyl)pent-2-en-4-acetic acid ethyl ester:<1>H-NMR (300 MHz, CDCl 3 ) δ : 1.29 (t, 3 H) , 2.36 (s, 3 H) ,

4.20 (q, 2H), 6.16 (m, 1H), 7.34 (s, 3H).

(Z)-3-Methyl-5-(3,5-dichlorophenyl)pent-2-en-4-acetic acid ethyl ester:<1>H-NMR (300 MHz, CDCl 3 ) δ : 1.29 (t, 3 H) , 2.12 (s, 3 H) , 2.25 (q, 2 H) , 6.09 (m, 1 H), 7.34 (m, 1 H), 7.40 (m, 2 H).

c) To a solution of (E)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-acetic acid ethyl ester (130 mg, 0.46 mmol) in THF

(0.5 ml) was added dropwise diisobutylaluminum hydride (1.0 M solution in toluene, 2.1 ml, 2.1 mmol) at -20 °C. The reaction mixture was stirred for 2 h at -20 °C, after which saturated ammonium chloride was added. The mixture was treated with ethyl acetate and decalite and filtered. The filtrate was evaporated, whereby impure (E)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-yn-l-ol was obtained in 113 mg yield.

<X>H-NMR (300 MHz, CDCl3) δ: 1.85 (s, 3 H), 2.00 (br.s, 1 H), 4.20 (d, 2 H), 6.04 ( m, 1H), 7.20 (s, 3H).

d) To a solution of (E)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-yn-l-ol (113 mg, 0.46 mmol) in THF (10 mL ) became

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-hydroxyphenyl)propionic acid ethyl ester (169 mg, 0.71 mmol), and the reaction mixture was stirred at 0 °C in 2 h and then at room temperature overnight. Water (15 mL) was added and the mixture was extracted with methylene chloride (3 x

30 ml). The combined and dried organic phases were evaporated and the residue was purified by column chromatography using methylene chloride as eluent to give the title compound in 35 mg yield. 1 H-NMR (300 MHz, CDCl 3 ) δ: 1.16 (t, 3 H), 1.23 (t, 3 H), 1.98 (s, 3 H), 2.97 (d, 2 H) , 3.42-3.30 (m, 1 H) , 3.65-3.55 (m, 1 H), 3.97 (t, 1 H), 4.16 (q, 2 H) , 4 .62 (d, 2H), 6.20 (m, 1H), 8.83 (d, 2H), 7.16 (d, 2H), 7.37 (m, 3H).

Procedure 2

a) A solution of l-bromo-3,5-dichlorobenzene (904 mg, 4.0 mmol), PdCl2(PPh3)2(96 mg, 0.08 mmol), 2-methyl-3-butyn-2-ol

(672 mg, 8.0 mmol) and Cul (4 mg, 0.02 mmol) in diethylamine (16 mL) were 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 desired product, 3-(2,5-dichlorophenyl)-2-methyl-3-butyn-2-ol, was isolated in a yield of 910 mg (99%).

δ-NMR (300 MHz, CDCl 3 ) δ: 1.62 (6H, s), 7.30 (3H, s). b) To a solution of 3-(2,5-dichlorophenyl)-2-methyl-3-butyn-2-ol (840 mg, 3.46 mmol) in dry toluene (15 ml) was added

added sodium hydroxide pellets (45 mg) at room temperature. The reaction mixture was heated and a mixture of toluene and acetone formed was distilled off. The reaction mixture was washed with aqueous potassium carbonate (1M, 2.5 mL), water (2.5 mL) and brine (2.5 mL). The organic phase was dried and evaporated, whereby the desired product 1,3-dichloro-phenylacetylene was obtained in 537 mg (91%) yield.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 3.15 (1 H, s) , 7.37 (3 H, s) .

c) To a solution of 1,3-dichlorophenylacetylene

(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 aqueous 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. (E)-3-Methyl-5-(3,5-dichlorophenyl)pent-2-en-4-yne acid ethyl ester was isolated in a yield of 4.65 g (46%).

d) The title compound was prepared from (E)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynoic acid ethyl ester according to the method described in method 1,c-d. Example 8

( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3, 5- dichlorophenyl) pent- 2- en- 4-ynyloxy) phenyl] propionic acid

Ethyl-(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate was hydrolyzed as described in Example 2, giving the title compound.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.12 (t, 3 H), 1.95 (s, 3 H), 3.12-1.85 (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, 2 H) , 6.17 ( t, 1H) , 6.80 (d, 2H) , 7.15 (d,

2 H) , 7.30 (s, 3 H) . Example 9 Ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)-pent-2-en-4-ynyloxy)phenyl]propionate a ) (Z)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-yn-l-ol was prepared from (Z)-3-methyl-5-(3,5-dichlorophenyl )pent-2-en-4-ynoic acid ethyl ester (160 mg) (Example 7b) using the conditions described in Example 7c. Yield: 140 mg. <1>H-NMR (300 MHz, CDCl 3 ) δ: 1.88 (s, 3 H), 1.92 ( br. s, 1 H), 4.33 (d, 2 H), 5.90 ( t, 1H), 7.21 (s, 3H). b) The title compound was prepared from (Z)-3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-yn-1-ol (140 mg) using the conditions described in Example 7d. Yield: 172 mg. <1>H-NMR (300 MHz, CDCl 3 ) δ : 1.17 (t, 3 H) , 1.25 (t, 3 H) , 2.00 (s, 3 H) , 2.95 (d, 2H) , 3.42-3.28 (m, 1H) , 3.67-3.55 (m, 1H) , 3.98 (t, 1H), 4.16 (q, 2H ) , 4.77 (d, 2 H) , 6.02 (t, 1 H) , 6.86 (d, 2 H) , 7.28 (d,. 2 H) , 7.32 (s, 3 H). Example 10

( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3, 5- dichlorophenyl) pent- 2- en- 4-ynyloxy) phenyl] propionic acid

Ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate was hydrolyzed as described in Example 2, giving the title compound. Yield: 164 mg.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.18 (t, 3 H) , 2.01 (s, 3 H) , 3.10-2.90 (m, 2 H) , 3, 46-3.33 (m, 1 H) , 3.67-3.55 (m, 1 H) , 4.04 (m, 1 H) , 4.75 (d, 2 H) , 6.02 ( t, 1H) , 6.87 (d, 2H) , 7.18 (d, 2H) , 7.33 (s, 3H) .

Example 11

Ethyl-( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3- trifluoromethylphenyl)-pent- 2- en- 4- ynyloxy) phenyl] propionate

The title compound was prepared as described in Example 7a-d using 3-trifluoromethyl-1-iodobenzene instead of 1,3-dichloro-5-iodobenzene in Example 7a.

<1>H-NMR (300 MHz, CDCl 3 ) δ : 1.18 (t, 3 H) , 1.24 (t, 3 H) , 2.00 (s, 3 H) , 2.96 (d, 2H) , 3.42-3.31 (m, 1H) , 3.66-3.55 (m, 1H), 3.98 (t, 1H), 4.27 (q, 2H ), 4.65 (d, 2H), 6.23 (1H), . 6.84 (d, 2H), 7.18 (d, 2H), 7.71-7.38 (m, 5H).

Example 12

( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3- trifluoromethylphenyl) pent- 2-en- 4- ynyloxy) phenyl] propionic acid

Ethyl-(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionate was hydrolyzed as described in Example 2, whereby the title compound was obtained.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.19 (t, 3 H) , 1.98 (s, 3 H) , 3.12-2.90 (m, 2 H) , 3, 48-3.36 (m, 1 H) , 3.69-3.56 (m, 1 H) , 4.50 (m, 1 H), 4.64 (d, 2 H) , 6.21 ( t, 1H), 6.85 (d, 2H), 7.18 (d, 2H), 7.70-7.49 (m, 5H).

Example 13

Ethyl-( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3- trifluoromethylphenyl)-pent- 2-en- 4- ynyloxy) phenyl] propionate

The title compound was synthesized from (Z)-3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-yn-l-ol, which was derived from the reaction sequence described in Example 11, using the conditions described in Example 7c-d.

<1>H-NMR (300 MHz, CDCl 3 ) 6 : 1.18 (t, 3 H), 2.23 (t, 3 H), 2.03 (s, 3 H), 2.96 (d, 2H) , 3.42-3.30 (m, 1H) , 3.66-3.55 (m, 1H) , 3.96 (t, 1H) , 4.15 (q, 2H ) , 4.82 (d, 2H) , 6.03 (t, 1H), 6.87 (d, 2H), 7.17 (d, 2H), 7.70-7.43 ( m, 5H).

Example 14

( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3- trifluoromethylphenyl) pent- 2-en- 4- ynyloxy) phenyl] propionic acid

Ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenylDpent 2-en-4-ynyloxy)phenyl]propionate was hydrolyzed as described in Example 2 , whereby the title compound was obtained.

<1>H-NMR (300 MHz, CDCl3) δ: 1.16 (t, 3 H) , 2.02 (s, 3 H) , 3.10-2.92 (m, 2 H) , 3, 47-3.36 (m, 1 H) , 3.68-3.57 (m, 1 H) , 4.03 (m, 1 H), 4.80 (d, 2 H) , 6.02 ( t, 1H), 6.89 (d, 2H), 7.18 (d, 2H), 7.72-7.42 (m, 5H).

Example 15

Ethyl-( E )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 1- naphthyl) pent- 2- en- 4- ynyloxy) phenyl] propionate

The title compound was prepared as described in Example 7a-d by using 1-iodonaphthalene instead of 1,3-dichloro-5-iodobenzene in Example 7a.

<1>H-NMR (300 MHz, CDCl 3 ) δ : 1.18 (t, 3 H) , 1.24 (t, 3 H) , 2.08 (s, 3 H) , 2.96 (d, 2H) , 3.42-3.30 (m, 1H) , 3.66-3.53 (m, 1H) , 3.98 (t, 1H), 4.15 (q, 2H ) , 4.65 (d, 2 H) , 6.30 (m, 1 H) , 6.86 (d, 2 H) , 7.18 (d, 2 H) , 7.86-7.38 ( m, 6 H) , 8.33 (d,

1H).

Example 16

( 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 hydrolyzed as described in Example 2, whereby the title compound was obtained.

<1>H-NMR (300 MHz, CDCl3) δ: 1.19 (t, 3 H) , 1.98 (s, 3 H) , 3.12-2.90 (m, 2 H) , 3, 48-3.36 (m, 1 H) , 3.69-3.56 (m, 1 H) , 4.05 (m, 1 H), 4.66 (d, 2 H) , 6.30 ( t, 1H), 6.85 (d, 2H), 7.18 (d, 2H), 7.90-7.45 (m, 6H), 8.44 (d, 1H).

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 synthesized from (Z)-3-methyl-5-(1-naphthyl)pent-2-en-4-yn-1-ol isolated in Example 15 using the conditions described in Example 7c-d.

<1>H-NMR (300 MHz, CDCl 3 ) δ : 1.18 (t, 3 H), 1.23 (t, 3 H), 2.14 (s, 3 H), 2.97 (d, 2 H), 3.42-3.30 (m, 1 H), 3.66-3.53 (m, 1 H), 3.98 (t, 1 H), 4.15 (q, 2 H ) , 4.95 (d, 2 H) , 6.06 (m, 1 H) , 6.94 (d, 2 H) , 7.18 (d, 2 H) , 7.86-7.40 ( m, 6 H) , 8.30 (m,

1H).

Example 18

( 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 hydrolyzed as described in Example 2, thereby obtaining the title compound.

1 H-NMR (300 MHz, CDCl 3 ) δ: 1.04 (t, 3 H), 2.02 (s, 3 H), 3.00-2, 80 (m, 2 H), 3.34-3 , 22 (m, 1 H) , 3.57-3, 46 (m, 1 H) , 3.94 (m, 1 H), 4.83 (d, 2 H), 5.94 (t, 1 H) , 6.84 (d, 2 H), 7.08 (d, 2 H) , 7.75-7.26 (m, 6 H) , 8.20 (m, 1 H) , 9.2 (br.s, 1 H) .

Example 19

Ethyl-( E )-( S )- 2- ethoxy- 3-[ 4-( 5-( 3, 5- dichlorophenyl) pent- 2- en- 4- ynyloxy) phenyl propionate

a) To a solution of 1,3-dichloro-5-iodobenzene (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-dichlorophenylethynyl)trimethylsilane product was isolated in 4.85 g yield.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 0.09 (s, 9 H), 7.15 (m, 3 H).

b) To a solution of (3,5-dichlorophenylethynyl)trimethylsilane (4.85 g, 19.9 mmol) in methanol (50 ml) was added

1 M potassium hydroxide (30 ml). The reaction mixture was stirred in

1 h at room temperature and evaporated. The residue was treated with water (10 mL) and extracted with 3 x 40 mL of diethyl ether. The dried organic phases were evaporated, whereby the desired 1,3-dichloro-5-ethynylbenzene product was obtained in a yield of 2.3 g.

<X>H-NMR (300 MHz, CDCl 3 ) δ: 2.13 (s, 1 H), 7.38 (s, 3 H). c) To a solution of 1,3-dichloro-5-ethynylbenzene (1.52 g, 8.9 mmol) in triethylamine (32.4 ml) was added PdCl2-(PPh3)2 (57.15 mg, 0 .08 mmol), (E)-3-iodoprop-2-enoic acid ethyl ester (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, after which the reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with diethyl ether (3 x 20 mL). The combined and dried organic phases were evaporated, whereby impure (E)-5-(3,5-dichlorophenyl)pent-2-en-4-yne acid ethyl ester was obtained in a yield of 1.1 g.

<1>H-NMR (300 MHz, CDC13) δ: 1.32 (t, 3 H), 4.22 (q, 2 H), 6.32 (d, 1 H, J =16 Hz), 6 .92 (d, 1 H, J= 16 Hz), 7.37 (s, 3 H) .

d) To a solution of diisobutylaluminum hydride

(1.0 M solution in toluene, 20 mL, 20 mmol) at -78 °C gave

slowly added (E)-5-(3,5-dichlorophenyl)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, after which the reaction mixture was poured into hydrochloric acid

(6 N, 50 mL), and it was extracted with diethyl ether (3 x 40 mL). The combined and dried organic phases were evaporated, whereby

impure (E)-5-(3,5-dichlorophenyl)pent-2-en-4-yn-l-ol was obtained in a yield of 750 mg.

^"H-NMR (300 MHz, CDCl 3 ) δ: 4.3 (dd, 2 H), 5.95 (dt, 1 H, J= 5 and 16 Hz), 6.4 (dt, 1H, J = 5 and 16 Hz), 7.30 (s, 3H).

e) The title compound was prepared from (E)-5-(3,5-dichlorophenyl)pent-2-en-4-yn-1-ol (454 mg, 2 mmol). by applying

the conditions described in example 7d. Yield: 125 mg.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.14 (t, 3 H), 1.22 (t, 3 H), 2.95 (d, 2 H), 3, 30-3, 42 (m, 1 H) , 3, 55-3, 67 (m, 1 H) , 3.95 (t, 1 H), 4.16 (q, 2 H) , 4.6 (dd, 2 H , J = 1.5 and 5 Hz), 6.05 (dt,

1 H, J = 1.5 and 16 Hz), 6.35 (dt, 1 H, J = 5 and 16 Hz), 6.83 (d, 2 H), 7.15 (d, 2 H), 7.36 (m, 3H) . Example 20

( E )-( S )- 2- ethoxy- 3-[ 4-( 5-( 3, 5- dichlorophenyl) pent- 2-en- 4- ynyloxy)-phenyl] propionic acid

Ethyl-(E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate was hydrolyzed as described in Example 2, thereby obtaining the title compound.

<X>H-NMR (300 MHz, CDCl 3 ) δ : 1.19 (t, 3 H) , 2.88-3.12 (m, 2 H) , 3.37-3.50 (m, 1 H ) , 3.65-3.70 (m, 1 H) , 4.05 (m, 1 H) , 4.70 (dd, 2 H, J = 1.5 and 5 Hz), 6.1 (dt , 1 H, J = 1.5 and 16 Hz), 6.45 (dt, 1 H, J = 5 and 16 Hz), 6.85 (d, 2 H), 7.18 (d, 2 H) , 7, 30 (p, 3H) .

Example 21

Ethyl-( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3, 5- dichlorophenyl) pent- 2-en- 4- ynyloxy) phenyl] propionate a) (Z )-5-(3,5-dichlorophenyl)pent-2-en-4-ynoic acid ethyl ester was prepared from cis-3-iodoacrylic acid ethyl ester (Can J Chem, 72(8),

1816-1819,1994) (4 g) by applying the conditions described in example 19c. Yield: 4.62 g.

<1>H-NMR (300 MHz, CDCl3) δ: 1.4 (t, 3 H), 4.3 (q, 2 H), 6.2 (d, 1 H, J = 11 Hz), 6 .34 (d, 1 H, J = 11 Hz), 7.32 (s, 1 H), 7.4 (s, 2 H) .

b) (Z)-5-(3,5-dichlorophenyl)pent-2-en-4-yn-l-ol was prepared from (Z)-5-(3,5-dichlorophenyl)pent-2-en- 4-ynoic acid ethyl ester (4.6 g)

by applying the conditions described in Example 19 d. Yield: 3.63 g.

<1>H-NMR (300 MHz, CDCl3) δ: 4.4 (dd, 2 H, 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, 3 H).

c) The title compound was obtained from (Z)-5-(3,5-di-chlorophenyl)pent-2-en-4-yn-1-ol (300 mg, 1.32 mmol) using

the conditions described in example 19e. Yield: 180 mg.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.12 (t, 3 H), 1.2 (t, 3 H), 2.9 (d, 2 H), 3.26-3, 44 (m, 1 H), 3.51-3.69 (m, 1 H), 3.94 (t, 1 H) , 4.14 (q, 2 H) , 4.85 (dd, 2 H , 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

( Z )-( S )- 2- ethoxy- 3-[ 4-( 3- methyl- 5-( 3, 5- dichlorophenyl) pent- 2- en- 4-ynyloxy) phenyl] propionic acid

Ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate was hydrolyzed as described in Example 2, giving the title compound. Yield: 100 mg.

<1>H-NMR (300 MHz, DMSO-d6) δ: 1.16 (t, 3 H), 2.85-3.05 (m, 2 H), 3.3-3.45 (m, 1 H) , 3.6-3.7 (m, 1 H) , 4.06 (m, 1 H) , 4.9 (dd, 2 H, 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, 2 H) , 7.20 (d, 2H) , 7.65 (d, 2H), 7.71 (d, 1H) .

Example 23

( Z )-( S )- 2- ethoxy- 3-[ 4-( 5- phenylpent- 2- en- 4- ynyloxy) phenyl]- propionic acid ethyl ester

(a) (Z)-5-phenylpent-2-en-4-ynoic acid ethyl ester was prepared

from cis-3-iodoacrylate ethyl ester (2 g) and phenylacetylene using the conditions described in Example 19c. Yield: 1.24 g.

<:>H-NMR (300 MHz, CDCl3) δ: 1.3 (t, 3 H), 4.25 (q, 2 H), 6.12 (d, 1 H, Jcis=11.3 Hz) , 6.35 (d, 1 H, Jcis=11.3 Hz), 7.36

(m, 3H) 7.53 (m, 2H) . b) (Z)-5-phenylpent-2-en-4-yn-l-ol was prepared from (Z)-5-phenylpent-2-en-4-ynoic acid ethyl ester (1.0 g) using the conditions described in example 19d. Yield: 0.7 g.

<1>H-NMR (300 MHz, CDC13) 6: 4.5 (dd, 2 H, 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-phenylpent-2-en-4-yn-l-ol (200 mg, 1.3 mmol) using

the conditions described in example 19e. Yield: 380 mg.

<1>H-NMR (300 MHz, CDCl 3 ) δ: 1.2 (dt, 6 H) , 2.98 (d, 2 H) , 3.3-3.41 (m, 1 H) , 3, 53-3.68 (m, 1 H) , 3.95 (t, 1 H) , 4.18 (q,

2 H) , 4.9 (dd, 2 H, 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, 2 H), 7.17 (d, 2 H), 7.35 (m, 3H), 7.47 (m, 2H).

Example 24

( Z )-( S )- 2- ethoxy- 3-[ 4-( 5- phenylpent- 2- en- 4- ynyloxy) phenyl)- propionic acid

Ethyl-(Z)-(S)-2-ethoxy-3-[4-(phenylpent-2-en-4-ynyloxy)-phenyl]propionate was hydrolyzed as described in Example 2, whereby the title compound was obtained. Yield: 264 mg.

<1>H-NMR (300 MHz, DMSO-D6) δ: 1.15 (t, 3 H) , 2.8-3.0 (m, 2 H) , 3.3-3.4 (m, 1 H) , 3.5-3.65 (m, 1 H) , 3.96 (m, 1 H) , 4.89 (dd, 2 H, 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, 2 H) , 7.20 (d , 2H) , 7.4 (m, 3H) , 7.5 (m, 2H) .

Example 25

( E )-( RS )- 2- ethoxy- 3-[ 3-( 5- phenylpent- 2- en- 4- ynyloxy) phenyl]- propionic acid ethyl ester a) NaH, 60% in paraffin oil (1.18 g, 29, 5 mmol) was added to a solution of diethoxyphosphorylethoxyethyl acetate (7.46 g, 27.8 mmol) in dry THF (40 mL) at 0 °C. 3-Benzyloxy-benzaldehyde (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 now brought to room temperature, followed by the addition of water. The product was extracted into MTBE, and the combined organic phases were dried (Na 2 SO 4 ), filtered and evaporated to give 7.6 g (99%) of (E,Z)-3-(3-benzyloxy-phenyl)-2- ethoxyacrylic acid ethyl ester as a yellow oil. <1>H-NMR (CDC13, 400 MHz) δ: 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 ). b) (E,Z)-3-(3-benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (6.8 g) dissolved in ethyl acetate (40 ml) was hydrogenated at 10 bar using Pd/C (10%) ( 1.08 g) until the reaction was shown to be complete by HPLC. The reaction mixture was filtered through a celite pad and the solvent was evaporated. The product was purified by means of column chromatography eluting with ethyl acetate/heptane in the ratio 1:2, whereby 3.1 g (62%) of (R,S)-2-ethoxy-3-hydroxy-phenyl)propanoic acid ethyl ester was obtained.

<X>H-NMR (CDCl 3 , 400 MHz) δ : 1.16 (t, 3 H) , 1.23 (t, 3 H) , 2.97-2.95 (m, 2 H) , 3, 41-3.33 (dq, 1H) , 3.65-3.57 (dq, 1H) , 4.02 (t, 1H) , 4.17 (q, 2H) , 5.33 ( s, 1H) , 6.81-6.70 (m, 3H) , 7.15 (t, 1H) .

<13>C-NMR (75 MHz, CDCI3) 8: 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. calculated for C13H18O4: C 65.53, H 7.61%. Found: C 65.98, H 7.96. 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-phenylpent-2-en-4-yn-l-ol (Example 1, Method 1b) (79 mg, 0.5 mmol) using a procedure analogous to the one described in example 1 (method 1c).

Claims (80)

Patent claim 1. Compound of formula (I): where X is hydrogen or X is C 1 -12 -alkyl, C 2 -12 -alkenyl, C 2 -12 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C 1 -6 -alkyl, C 2 -6 -alkenyl, C 2 .6 -alkynyl, hydroxy, C 1 _6 -alkyloxy, C 1 -6 -alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, Ci - 6 -alkylthio, cyano, amino, C 1 -6 -alkylamino, C 1 -6 -dialkylamino, carboxy and C 1 -6 -alkyl ester; and Y is hydrogen or Y is C1 -12 -alkyl, C2 -12 -alkenyl, C2 -12 -alkynyl, C4 -12 -alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, Ci -6 - alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy and C 1 -6 alkyl ester; and Z is hydrogen, halogen, hydroxy or Z is C 1 -6 alkyl or C 1 -6 alkoxy each of which is optionally substituted with one or more substituents selected from C 1 -6 alkoxy, halogen, hydroxy, carboxy, amino and cyan; and Q is 0, S or NR 5 , where R 5 is hydrogen, C 1 -6 -alkyl, C 2 -6 -alkenyl, C 2 -6 -alkynyl, C 4 -6 -alkenynyl, aralkyl or heteroaralkyl, and where R 5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1 -6 alkoxy, amino and carboxy; and Ar is arylene, heteroarylene or a divalent heterocyclic group each of which may optionally be substituted with one or more substituents selected from C 1 -6 -alkyl, aryl and C 1 -6 -alkoxy which may each be optionally substituted with halogen, hydroxy, carboxy or Ci -6-alkyl ester; and R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and R 2 is hydrogen or C 1 -6 alkyl; or R 2 forms a bond together with R 1 ; and R 3 is hydrogen, C 1 -6 -alkyl-, C 2 -6 -alkenyl-, C 2 -6~ alkynyl-, C 1 -6 -alkenynyl-, aryl-, aralkyl-, C 1 -6 -alkoxy-C 1 -6 -alkyl-, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups which are optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, carboxy and C 1 -6 alkyl ester; and R 4 is hydrogen, C 1 -6 -alkyl,. C 2 -6 alkenyl, C 2 -6 alkynyl, C 1 -6 alkenynyl or aryl; n is an integer in the range from 0 to 3; and m is an integer in the range 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 racemic mixture, or polymorphs. 2. Compound according to claim 1, with formula (I) where X is hydrogen or X is C 1 -12 -alkyl, C 2 -12 -alkenyl, C 2 -12 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C 1 -6 -alkyl, C2 -6 -alkenyl, C2 -6 -alkynyl, hydroxy, C1 -6 -alkoxy, C1 -6 -alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroarlkoxy, Ci _6 -alkylthio, cyano, amino, C1 -6 -alkylamino, C1 -6 -dialkylamino, carboxy and C1 -6 -alkyl ester; and Y is hydrogen or Y is C1 -12 -alkyl, C2 -12_alkenyl, C2 -12 -alkynyl, C4 -12 -alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more•substituents selected from halogen, C1_6 -alkyl , perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy and C 1 -6 alkyl ester; and Z is hydrogen, halogen, hydroxy or Z is C 1 -6 alkyl or C 1 -6 alkoxy each of which is optionally substituted with one or more substituents selected from C 1 -6 alkoxy, halogen, hydroxy, carboxy, amino and cyan; and Q is 0, S or NR 5 , where R 5 is hydrogen, C 1 -6 -alkyl, C 2 -6 -alkenyl, C 2 -6 -alkynyl, C 4 -6 -alkenynyl, aralkyl or heteroaralkyl, and where R 5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 -alkoxy, amino and carboxy; and Ar is arylene, heteroarylene or a divalent heterocyclic group each of which may optionally be substituted with one or more substituents selected from C 1 -6 -alkyl, aryl and C 1 -6 -alkoxy which may each optionally be substituted with halogen, hydroxy, carboxy or Ci -6-alkyl ester; and R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and R 2 is hydrogen or C 1 -6 alkyl; or R 2 forms a bond together with R 1 ; and R 3 is hydrogen, C 1 -6 -alkyl-, C 2 -6 -alkenyl-, C 2 -6 -alkynyl-, C 4 -6 -alkenynyl-, aryl-, aralkyl-, C 1 -6 -alkoxy-C 1 -6 -alkyl- , acyl, heterocyclyl, heteroaryl or heteroaralkyl groups which are optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyan, carboxy and C 1 -6 alkyl ester; and R4 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkenynyl or aryl; n is an integer in the range from 1 to 3; and m is 1; 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. 3. Connection according to which horse of the preceding claim with formula (I) where X is hydrogen, C1 -i2 -alkyl, C2 -i2 -alkenyl, C2 -i2 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, Ci - 6 -alkyl, C2 -6 _alkenyl, C2 -6 -alkynyl, hydroxy, C1 -6 -alkyloxy, C1 -6 -alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy, heteroarloxy, Ci -6 -alkylthio, cyan, amino, C1 -6 - alkylamino, C1 -6 -dialkylamino, carboxy and C1 -6 -alkyl ester; and Y is hydrogen, C 1 -i 2 -alkyl, C 2 -i 2 -alkenyl, C 2 -i 2 -alkynyl, C 4 -i 2 -alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, Ci - 6 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy and C 1 -6 -alkyl ester; and Z is hydrogen, halogen, hydroxy, C 1 -6 alkyl or C 1 -6 alkoxy which is optionally substituted with one or more substituents selected from C 1 -6 alkoxy, halogen, hydroxy, carboxy, amino and cyan; and Q is 0, S or NR 5 , where R 5 is hydrogen, C 1 -6 -alkyl, C 2 -6 -alkenyl, C 2 -6 -alkynyl, C 4 -6 -alkenynyl, aralkyl or heteroaralkyl, and where R 5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1 -6 alkoxy, amino and carboxy; and Ar is arylene, heteroarylene or a divalent heterocyclic group each of which may optionally be substituted with one or more substituents selected from C 1 -6 -alkyl, aryl and C 1 -6 -alkyl which may each optionally be substituted with halogen, hydroxy, carboxy or C 1 - 6-alkyl ester; and R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and R 2 is hydrogen or C 1 -6 alkyl; or R 2 forms a bond together with R 1 ; and R 3 is hydrogen, C 1 -6 -alkyl-, C 2 -6 -alkenyl-, C 2 -6 -alkynyl-, C 4 -6 -alkenynyl-, aryl-, aralkyl-, C 1-6 -alkoxy-C 1 -6 -alkyl-, acyl -, heterocyclyl, heteroaryl or heteroaralkyl groups which are optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyan, carboxy and C 1 -6 alkyl ester; and R 4 is hydrogen, C 1 -6 -alkyl, C 2 -6 -alkenyl, C 2 -6 -alkynyl, d -6 -alkenynyl or aryl; n is an integer in the range from 0 to 3; and m is an integer in the range 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 racemic mixture, or polymorphs. 4. Compound according to any one of the preceding claims, where X is aryl, heteroaryl or heterocyclyl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1-6 -alkylthio, C 1-6 -alkylthio, aryl, aryloxy , arylthio, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl. 5. A compound according to any one of the preceding claims, where X is aryl, heteroaryl or heterocyclyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1 -6 -alkyl, C 1 -6 -alkylthio, aryl, aryloxy , arylthio, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl. 6. Compound according to any one of the preceding claims, where X is aryl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C1-6~ alkoxy, C1-6 -alkylthio, aryl, aryloxy, arylthio, aralkyl , aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl. 7. A compound according to any one of the preceding claims, wherein X is phenyl or naphthyl each of which is optionally substituted with one or more substituents selected from halogen and perhalomethyl. 8. A compound according to any one of the preceding claims, where X is phenyl which is optionally substituted with one or more substituents selected from halogen. A compound according to any one of the preceding claims, wherein X is phenyl. 10. A compound according to any one of the preceding claims, where X is heteroaryl which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C1-6~ alkoxy, C1-6 -alkylthio, aryl, aryloxy, arylthio, aralkyl , aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl. 11. Compound according to any one of the preceding claims, where X is heterocyclyl which is optionally substituted with one or more substituents - selected from halogen, perhalomethyl, C1-6~ alkoxy, C1-6 -alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkyl, heteroaryl, heteroaralkyl, heteroaryloxy and heteroaralkyl. 12. A compound according to any one of the preceding claims, wherein Y is hydrogen, C 1-12 alkyl or aryl. A compound according to any one of the preceding claims, wherein Y is hydrogen or methyl. A compound according to any one of the preceding claims, wherein Y is hydrogen. 15. A compound according to any one of the preceding claims, wherein Z is hydrogen or C 1-6 alkoxy. A compound according to any one of the preceding claims, wherein Z is hydrogen. 17. A compound according to any one of the preceding claims, wherein Q is 0. 18. A compound according to any one of the preceding claims, where Ar is the aryl which is optionally substituted with one or more substituents selected from C 1 -6 alkyl and C 1 -6 alkoxy, each of which may optionally be substituted with carboxy. A compound according to any one of the preceding claims, wherein Ar is phenylene. 20. A compound according to any one of the preceding claims, where R 1 is hydrogen or R 1 forms a bond together with R 2 - 21. A compound according to any one of the preceding claims, wherein R 1 is hydrogen. 22. A compound according to any one of the preceding claims, wherein R 2 is hydrogen or R 2 forms a bond together with R 1 . 23. A compound according to any one of the preceding claims, wherein R 2 is hydrogen. 24. A compound according to any one of the preceding claims, wherein R 3 is C 1 -6 alkyl. 25. A compound according to any one of the preceding claims, wherein R 3 is C 1 -2 alkyl. 26. A compound according to any one of the preceding claims, wherein R 4 is hydrogen. 27. A compound according to any one of the preceding claims, wherein n is 1. 28. A compound according to any one of the preceding claims, wherein m is 1. 29. A compound according to any one of the preceding claims, wherein alkyl is methyl or ethyl. 30. A compound according to any one of the preceding claims, wherein alkenyl is vinyl or 1-propenyl. A compound according to any one of the preceding claims, wherein alkynyl is 1-propynyl. 32. A compound according to any one of the preceding claims, wherein alkenynyl is 1-penten-4-yne. 33. A compound according to any one of the preceding claims, wherein alkoxy is methoxy, ethoxy, isopropoxy or cyclopropoxy. 34. A compound according to any one of the preceding claims, wherein aryl is phenyl or naphthyl optionally substituted with halogen. 35. A compound according to any one of the preceding claims, wherein the aryl is phenylene. 36. A compound according to any one of the preceding claims, wherein halogen is chlorine. 37. A compound according to any one of the preceding claims, wherein perhalomethyl is trifluoromethyl. 38. A compound according to any one of the preceding claims, wherein heteroaryl is furan, pyrrole, pyridine, indole or benzofuran. 39. A compound according to any one of the preceding claims, wherein the heteroaryl is furan, pyrrole, pyridine, indole or benzofuran. 40. A compound according to any one of the preceding claims, wherein aralkyl is benzyl. 41. A compound according to any one of the preceding claims, wherein aryloxy is phenoxy. 42. A compound according to any one of the preceding claims, wherein aralkyloxy is benzyloxy. 43. A compound according to any one of the preceding claims, wherein n is an integer in the range from 1 to 3, and m is 1. 44. A compound according to any one of the preceding claims, wherein the substituents Z and Y are arranged in a trans configuration. 45. A compound according to any one of the preceding claims, wherein the substituents Z and Y are arranged in a cis configuration. 46. Compound according to claim 1, 2 or 3, which is (E)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid ethyl ester, (E)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid ethyl ester, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid ethyl ester, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenylpent-2-en-4-ynyloxy)phenyl]propionic acid, or a pharmaceutically acceptable derivative thereof. 47. Compound according to claim 1, 2 or 3, which is ethyl-(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, ethyl-(E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethylphenyl)pent-2-en-4-ynyloxy}phenylpropionic acid, or a pharmaceutically acceptable derivative thereof. 48. Compound according to claim 1, 2 or 3, which is 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-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, (Z)-(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-(5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, ethyl-(Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichlorophenyl)pent-2-en-4-ynyloxy)phenyl]propionic acid, or a pharmaceutically acceptable derivative thereof. 49. Compound according to claim 1, 2 or 3, which is (Z)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid ethyl ester, (Z)-(S)-2-ethoxy-3-[4-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid, (E)-(RS)-2-ethoxy-3-[3-(5-phenylpent-2-en-4-ynyloxy)-phenyl]propionic acid ethyl ester, or a pharmaceutically acceptable derivative thereof. 50. Compound according to claim 1, 2 or 3, which is (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-(4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl}-3-methylpent-2-en-4-yn-yloxyphenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-3-methyl-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (E)-(S)-3-(4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy ]phenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2, 2, 2-trifluoromethoxy)phenyl}-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy)-3-chlorophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4- [5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E )-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl}-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-3-methyl-2-ethoxypropionic acid, (E) - (S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3- methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy] -3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl}-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)- (S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-3-methyl-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3- methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl}-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5- (3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5- (1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy] -3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-3-methyl-2-ethoxypropionic acid, (E) - (S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-ene-4-ynyloxy] -3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-{4- [5- (3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid, (E)-(S)-3-(4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, or a pharmaceutically acceptable derivative thereof. 51. Compound according to claim 1, 2 or 3, which is (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-ene- 4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3- {4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl}pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4- [5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]phenyl}-2- ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy)phenyl}- 2-ethoxypropionic acid, (Z)-(S)-3-{4-(5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]phenyl}-3-methyl-2-ethoxypropionic acid, (Z)-(S )-3-{4- [5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]phenyl}- 2-ethoxypropionic acid, (Z)-(S)-3-{4- [5-(1,3-difluorophenylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S) -3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-chlorophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-chlorophenyl}-3-methyl-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-^ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-chlorophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-stoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)pent-2-ene- 4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2, 2, 2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-bromophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-bromophenyl}-3-methyl-2-ethoxypropionic acid, (Z) -(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4- [5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z )-(S )-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)- (S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2, 2, 2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4- [5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-bromophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)pent-2-en-4-ynyloxy] -3- iodophenyl,} - 2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4- [5-(1,3-bis-trifluoromethylphenyl)pent-2-ene- 4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4 - [5-(1,3-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-(4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl)pent-2-en-4-ynyloxy}-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-pent-2-en-4-ynyloxy]-3-iodophenyl} -2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-pent-2-en-4-ynyloxy] -3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-difluorophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diiodophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-dimethoxyphenyl)pent-2-en-4-ynyloxy]-3-iodophenyl}-3-methyl-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-diethoxyphenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2, 2, 2-trifluoromethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(1,3-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-difluorophenyl)-3-methylpent-2-en-4- ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dibromophenyl)-3-methylpent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-diiodophenyl)-3-methylpent-2-en-4- ) ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-bis-trifluoromethylphenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4-[5-(3,5-dimethoxyphenyl)-3-methylpent-2-ene- 4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, i (Z)-(S)-3-{4-[5-(3,5-diethoxyphenyl)-3-methylpent-2-en-4- ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z)-(S)-3-{4- [5-(3,5-bis-(2,2,2-trifluoromethoxy)phenyl)-3-methylpent -2-en-4-ynyloxy]-3-iodophenyl}-2-ethoxypropionic acid, (Z )-(S)-3-{4-[5-(3,5-bis-(2,2,2-trifluoroethoxy)phenyl)-3-methylpent-2-en-4-ynyloxy]-3- iodophenyl}-2-ethoxypropionic acid, or a pharmaceutically acceptable salt thereof. 52. Pharmaceutical preparation comprising as an active ingredient a compound according to any of the preceding compound claims or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 53. Preparation according to claim 52 in unit dosage form, comprising from approx. 0.05 to approx. 100 mg, preferably from approx. 0.1 to approx. 50 mg, of the compound of any of the preceding compound claims or a pharmaceutically acceptable salt thereof. 54. Pharmaceutical preparation that can be used in the treatment and/or prophylaxis of conditions mediated by nuclear receptors, in particular the peroxisome proliferator-activated receptors (PPAR), where the preparation comprises as an active ingredient a compound according to any of the preceding compound claims or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 55. Pharmaceutical preparation that can be used in the treatment and/or prophylaxis of diabetes and/or obesity, where the preparation comprises as an active ingredient a compound according to any of the preceding compound requirements or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 56. Pharmaceutical preparation according to any one of claims 52-55 for oral, nasal, transdermal, pulmonary or parenteral administration. 57. Method for treating disorders, wherein the method comprises administering to an individual in need thereof an effective amount of a compound according to any of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a preparation according to any of the prior claims 52-56. 58. Method for the treatment and/or prophylaxis of conditions mediated by nuclear receptors, particularly the peroxisome proliferator-activated receptors (PPARs), wherein the method comprises administering to an individual in need thereof an effective amount of a compound according to any of the preceding compound claim or a pharmaceutically acceptable salt thereof, or of a preparation according to any of the preceding claims 52-56. 59. Method for the treatment and/or prophylaxis of diabetes and/or obesity, wherein the method comprises administering to an individual in need of it an effective amount of a compound according to any of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a preparation according to any of the preceding claims 52-56. 60. A method according to claim 57, 58 or 59, wherein the effective amount of the compound according to any of the preceding compound claims or a pharmaceutically acceptable salt or a pharmaceutically acceptable ester thereof is in the range from approx. 0.05 to approx. 100 mg per day, preferably from approx. 0.1 to approx. 50 mg per day. 61. Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. 62. Use of a compound according to any of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a drug that can be used in the treatment and/or prophylaxis of conditions mediated by nuclear receptors, in particular the peroxisome proliferator-activated receptors (PPAR). 63. Use of a compound according to any of the preceding compound claims or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of diabetes and/or obesity. 64. Process for the preparation of a compound of formula (I), which comprises reacting a compound of formula IV where X, Y, Z are as defined in claim 1, and t is 0-2, with a compound of formula V where Q, Ar, Ri, R2 , R3 , R4 and m are as defined in claim 1, except that m is not 0, under Mitsunobu conditions, using such a reagent as triphenylphosphine/diethyl azodicarboxylate and the like, whereby one obtains a compound of formula I, wherein X, Y, Z, Q, Ar, Ri, R2 , R3 , R4 / n and m are as defined in claim 1, except that R4 is not H, and n and m are not 0 . 65. Method according to claim 64, where tributylphosphine and 1,1'-(azodicarbonyl)dipiperidine are used as coupling reagents, and where either dry benzene or dry THF is used as solvent. 66. Process for the preparation of a compound of formula (I), comprising: a) conversion of the -OH group in a compound with formula IV where X, Y, Z and t are as defined in claim 64, to a suitable leaving group (L), such as p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, whereby a compound of formula VI is obtained where X, Y, Z and t are as defined in claim 64, and L is a leaving group, such as p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, and in b) conversion of a compound of formula VI where X, Y, Z and t are as defined in claim 64, and where L is a leaving group, such as p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, with a compound of formula V where Q, Ar, Ri, R2 , R3/ Ri and m are as defined in claim 1, except that m is not 0, thereby obtaining a compound of formula I, where X, Y, Z, Q, Ar, Ri , R2 , R3 , R4 , n and m are as defined in claim 1, except that R4 is not H, and n and m are not 0. 67. Method according to claim 66, where L is chlorine, and where the reagent used in step a) is triethylamine, tert.-dichloromethane and methanesulfonyl chloride. 68. Method according to claim 66, where L is chlorine, and where the reagent used in step b) is potassium carbonate and sodium or potassium iodide, and where the solvent is acetone, and where the reaction temperature is reflux. 69. Pharmaceutical preparation suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and an ACE (angiotensin converting enzyme) inhibitor. 70. Use of a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents, and an ACE (angiotensin converting enzyme) inhibitor for the preparation of a medicament suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity. 71. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and an inhibitor of ACE (angiotensin converting enzyme), to the individual. 72. Pharmaceutical preparation suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and an agent that stimulates insulin release from P cells, such as a meglitinide, such as repaglinide or senaglinide. 73. Use of a compound according to any one of claims 1-51 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or which preferably tautomeric forms, stereoisomers, mixtures of stereoisomers, including a racemic mixture, or polymorphs, together with one or more pharmaceutically acceptable carriers or diluents, and an agent that stimulates insulin release from (3- cells, such as a meglitinide, such as repaglinide or senaglinide, for the manufacture of a medicament suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity. 74. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1-51 and a agent that stimulates insulin release from P cells, such as a meglitinide, such as repaglinide or senaglinide, to the subject. 75. Pharmaceutical preparation suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and a biguanide, such as metformin. 76. Use of a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and a biguanide, such as metformin, for the preparation of a medicament suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity. 77. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and a biguanide, such as metformin, to the subject. 78. Pharmaceutical preparation suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and an HMG-CoA inhibitor. 79. Use of a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and an HMG-CoA inhibitor for the manufacture of a medicament suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity. 80. A method of treating type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1-51 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, together with one or more pharmaceutically acceptable carriers or diluents and an HMG-CoA inhibitor, to the subject.