AU2831801A - Alkynylsubstituted propionic acid derivatives and their use against diabetes and obesity - Google Patents

Alkynylsubstituted propionic acid derivatives and their use against diabetes and obesity Download PDF

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Publication number
AU2831801A
AU2831801A AU28318/01A AU2831801A AU2831801A AU 2831801 A AU2831801 A AU 2831801A AU 28318/01 A AU28318/01 A AU 28318/01A AU 2831801 A AU2831801 A AU 2831801A AU 2831801 A AU2831801 A AU 2831801A
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Australia
Prior art keywords
phenyl
ethoxy
pent
propionic acid
ynyloxy
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AU28318/01A
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Paul Stanley Bury
Lone Jeppesen
John Patrick Mogensen
Ingrid Pettersson
Per Sauerberg
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Novo Nordisk AS
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Novo Nordisk AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers

Description

WO 01/55086 PCT/DKO1/00057 1 NEW COMPOUNDS, THEIR PREPARATION AND USE 5 FIELD OF INVENTION The present invention relates to novel compounds, pharmaceutical compositions containing them, methods for preparing the compounds and their use as medicaments. More specifi cally, compounds of the invention can be utilised in the treatment and/or prevention of condi 10 tions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Re ceptors (PPAR). BACKGROUND OF THE INVENTION 15 Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the 'deadly quartet' category of impaired glu cose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity). The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately 20 effective triglyceride-lowering activities although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 dia betic or metabolic syndrome patients. The thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans. However, the fibrate class of compounds are without beneficial effects on glycaemia. Studies on the molecular actions of 25 these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key-players in regulation of plasma triglyceride content. Fibrates, on the one hand, are PPARx activators, acting primarily in the liver. Thiazolidinediones, on the other 30 hand, are high affinity ligands for PPARy acting primarily on adipose tissue. Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates. Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional WO 01/55086 PCT/DKO1/00057 2 deprivation. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Much evidence points to the central role of PPARy activation in initiating and regulating this cell differentiation. Several highly specialised proteins are induced during adipocyte differentiation, most of them being involved in lipid 5 storage and metabolism. The exact link from activation of PPARy to changes -in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified. A possible link is via free fatty acids such that activation of PPARy induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue. This, in turn, reduces the concentration of 10 free fatty acids in plasma dramatically, and due to substrate competition at the cellular level, skeletal muscle and other tissues with high metabolic rates eventually switch from fatty acid oxidation to glucose oxidation with decreased insulin resistance as a consequence. PPARcc is involved in stimulating p-oxidation of fatty acids. In rodents, a PPARa-mediated 15 change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents. The phenomenon of peroxisome proliferation is not seen in man. In addition to its role in peroxisome proliferation in rodents, PPARa is also involved in the control of HDL cholesterol levels in 20 rodents and humans. This effect is, at least partially, based on a PPARa-mediated transcrip tional regulation of the major HDL apolipoproteins, apo A-- and apo A-l. The hypotriglyceridemic action of fibrates and fatty acids also involves PPARa and can be summarised as follows: (1) an increased lipolysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-111 levels, (11) a stimulation of cellular fatty acid 25 uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (lli) an induction of fatty acid 8-oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic 30 effect of fibrates. A number of compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. 5,306,726, PCT Publications nos.
WO 01/55086 PCT/DKO1/00057 3 W091/19702, WO 95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO 97/36579, WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313 and WO 99/16758). SUMMARY OF THE INVENTION 5 Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome. Novel treatments of Type 2 dia betes and metabolic syndrome must therefore aim at lowering both the overt hypertriglyceri daemia associated with these syndromes as well as alleviation of hyperglycaemia. 10 The clinical activity of fibrates and thiazolidinediones indicates that research for compounds displaying combined PPARa and PPARy activation should lead to the discovery of effica cious glucose and triglyceride lowering drugs that have great potential in the treatment of Type 2 diabetes and the metabolic syndrome (i.e. impaired glucose tolerance, insulin resis 15 tance, hypertriglyceridaemia and/or obesity). DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to compounds of the general formula (1): 20 X Y (I) R (Q)m Ar OR 4
OR
3 WO 01/55086 PCT/DKO1/00057 4 wherein X is hydrogen or X is C 1
.
1 2 -alkyl, C 212 -alkenyl, C 21 2 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocy clyl each of which is optionally substituted with one or more substituents selected from halo 5 gen, perhalomethyl, hydroxy, C 1 .-- alkyl, C 2 -6-alkenyl, C 2 -e-alkynyl, hydroxy, C-alkoxy, C1 alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroary loxy, heteroaralkoxy, C-alkylthio, cyano, amino, C-alkylamino, C-dialkylamino, carboxy or C-alkylester; and 10 Y is hydrogen or Y is C- 1 2 -alkyl, C 2
.
1 2 -alkenyl, C 2
-
1 2 -alkynyl, C4 1 2 -alkenynyl, aryl, heteroaryl, aralkyl or het eroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C alkylester; and 15 Z is hydrogen, halogen, hydroxy or Z is C 1 w-alkyl or C-alkoxy each of which is optionally substituted with one or more substitu ents selected from C-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and 20 Q is 0, S or NR 5 , wherein R 5 is hydrogen, C-alkyl, C 2 -6-alkenyl, C 2 -alkynyl, Cw-alkenynyl, aralkyl or heteroaralkyl and wherein R 5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C-alkoxy, amino or carboxy; and Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally 25 substituted with one or more substituents selected from C 1 -alkyl, aryl or C 1 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C 1 w-alkylester; and
R
1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and
R
2 is hydrogen or Cw,6-alkyl; or R 2 forms a bond together with R 1 ; and 30
R
3 is hydrogen, C-alkyl, C 2 -alkenyl, C 2 -e-alkynyl, Cw-alkenynyl, aryl, aralkyl, C 1 alkoxyC-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted WO 01/55086 PCT/DKO1/00057 5 with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, car boxy or C 1 .salkylester; and
R
4 is hydrogen, C-alkyl, C 2 -e-alkenyl, C 2 -6-alkynyl, C-alkenynyl or aryl; 5 n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 1; 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a race mic mixture, or polymorphs. In a preferred embodiment, the present invention is concerned with compounds of formula (I) 15 X Y (I) R z CH2) 1i O (Q)m Ar
OR
4
OR
3 20 wherein X is hydrogen or X is C 1
-
1 2 -alkyl, C 2
-
1 2 -alkenyl, C 2
-
1 2 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocy clyl each of which is optionally substituted with one or more substituents selected from halo- WO 01/55086 PCT/DKO1/00057 6 gen, perhalomethyl, hydroxy, C 1 --alkyl, C 2 -e-alkenyl, C 2 -6-alkynyl, hydroxy, C1.e-alkoxy, C alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroary loxy, heteroaralkoxy, C-alkylthio, cyano, amino, C-alkylamino, C-dialkylamino, carboxy or C-alkylester; and 5 Y is hydrogen or Y is C 1 r 1 2 -alkyl, C 2 -1 2 -alkenyl, C 2 -1 2 -alkynyl, C 4
-
1 2 -alkenynyl, aryl, heteroaryl, aralkyl or het eroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C 1 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C 6 10 alkylester; and Z is hydrogen, halogen, hydroxy or Z is C-alkyl or Cw 4 -alkoxy each of which is optionally substituted with one or more substitu ents selected from C-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and 15 Q is 0, S or NR 5 , wherein R 5 is hydrogen, C-alkyl, C 2 -6-alkenyl, C 2 -alkynyl, Cw-alkenynyl, aralkyl or heteroaralkyl and wherein Rs is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1
.
6 -alkoxy, amino or carboxy; and 20 Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C-alkyl, aryl or C 1 -alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C-alkylester; and
R
1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and 25 R 2 is hydrogen or C 1 -alkyl; or R 2 forms a bond together with R 1 ; and
R
3 is hydrogen, C 1 -alkyl, C 2 e-alkenyl, C 2 -alkynyl, C"-alkenynyl, aryl, aralkyl, C 1 w alkoxyC-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, car 30 boxy or C 1 -ealkylester; and
R
4 is hydrogen, C 1 -alkyl, C 2 -alkenyl, C 2 -alkynyl, Cw-alkenynyl or aryl; WO 01/55086 PCT/DKO1/00057 7 n is an integer ranging from 1 to 3; and m is 1; 5 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 is concerned with compounds of 10 formula I X Y (I) R z CH2) 1i O (Q)m Ar OR 4
OR
3 15 wherein X is hydrogen, Cr 1 2 -alkyl, C 2 1 2 -alkenyl, C 2 -1 2 -alkynyl, aryl, heteroaryl, aralkyl, het eroaralkyl or heterocyclyl optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C-alkyl, C 2 -alkenyl, C 2 -alkynyl, hydroxy, C-alkoxy, C-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, 20 heteroaryloxy, heteroaralkoxy, C-alkylthio, cyano, amino, C-alkylamino, C dialkylamino, carboxy or C-alkylester; and WO 01/55086 PCT/DKO1/00057 8 Y is hydrogen, C 1
-
1 2 -alkyl, C 2
-
1 2 -alkenyl, C 2
-
1 2 -alkynyl, C4- 1 2 -alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C-alkylester; and 5 Z is hydrogen, halogen, hydroxy, C-alkyl or C 1 .-- alkoxy optionally substituted with one or more substituents selected from C-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and Q is 0, S or NR 5 , wherein Rs is hydrogen, C-alkyl, C 2 -e-alkenyl, C 2 -6-alkynyl, C4-alkenynyl, aralkyl or heteroaralkyl and wherein R 5 is optionally substituted with one or more substituents 10 selected from halogen, hydroxy, C 1 -alkoxy, amino or carboxy; and Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C 1 -alkyl, aryl or C-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C-alkylester; and 15 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 .-- alkyl; or R 2 forms a bond together with R 1 ; and
R
3 is hydrogen, C 1 -- alkyl, C 2 -6-alkenyl, C 2 -e-alkynyl, C4-akenynyl, aryl, aralkyl, Cw 20 alkoxyC-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, car boxy or C-alkylester; and R4 is hydrogen, C-alkyl, C 2 -e-alkenyl, C 2 -6-alkynyl, Cw-alkenynyl or aryl; 25 n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 1; 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a race mic mixture, or polymorphs.
WO 01/55086 PCT/DKO1/00057 9 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein X is aryl, heteroaryl or heterocyclyl optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1 -alkoxy, C 14 -alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroarakyl, heteroaryloxy or heteroaralkoxy. 5 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein X is aryl, heteroaryl or heterocyclyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1 -alkoxy, C 1 -alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or 10 heteroaralkoxy. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein X is aryl optionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1 -alkoxy, C 1 -alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy. 15 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein X is phenyl or naphthyl each of which is optionally substituted with one or more substituents selected from halogen or perhalomethyl. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein X is phenyl optionally substituted with one or more substituents selected 20 from halogen. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein X is phenyl. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein X is heteroaryl optionally substituted with one or more substituents se 25 lected from halogen, perhalomethyl, C 1 -alkoxy, C 1
.
6 -alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein X is heterocyclyl optionally substituted with one or more substituents se- WO 01/55086 PCT/DKO1/00057 10 lected from halogen, perhalomethyl, C-alkoxy, C 1 .-- alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein Y is hydrogen, C 1
..
1 2 -alkyl or aryl. 5 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein Y is hydrogen or methyl. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein Y is hydrogen. 10 In another preferred embodiment, the-present invention is concerned with compounds of for mula I wherein Z is hydrogen or C 1 .-- alkoxy. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein Z is hydrogen. 15 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein Q is 0. In another preferred embodiment, the present invention is concerned with compounds of for 20 mula I wherein Ar is arylene optionally substituted with one or more substituents selected from C 1 .e-alkyl or C 1 w-alkoxy each of which can be optionally substituted with carboxy. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein Ar is phenylene. 25 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein R 1 is hydrogen or R 1 forms a bond together with R 2 . In another preferred embodiment, the present invention is concerned with compounds of for 30 mula I wherein R 1 is hydrogen.
WO 01/55086 PCT/DKO1/00057 11 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein R 2 is hydrogen or R 2 forms a bond together with R 1 . In another preferred embodiment, the present invention is concerned with compounds of for 5 mula I wherein R 2 is hydrogen. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein R 3 is C-alkyl. 10 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein R 3 is C 1
-
2 -alkyl. In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein R 4 is hydrogen. 15 In another preferred embodiment, the present invention is concerned with compounds of for mula I wherein n is 1. In another preferred embodiment, the present invention is concerned with compounds of for 20 mula I wherein m is 1. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein alkyl is methyl or ethyl. 25 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein alkenyl is vinyl or 1-propenyl. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein alkynyl is 1-propynyl. 30 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein alkenynyl is 1 -pentene-4-yne.
WO 01/55086 PCT/DKO1/00057 12 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein alkoxy is methoxy, ethoxy, isopropoxy or cyclopropoxy. In another preferred embodiment, the present invention is concerned with compounds of 5 formula I wherein aryl is phenyl or naphthyl optionally substituted with halogen. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein arylene is phenylene. 10 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein halogen is chlorine. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein perhalomethyl is trifluoromethyl. 15 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein heteroaryl is furan, pyrrole, pyridine, indole or benzofuran. In another preferred embodiment, the present invention is concerned with compounds of 20 formula I wherein heteroarylene is furan, pyrrole, pyridine, indole or benzofuran. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein aralkyl is benzyl. 25 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein aryloxy is phenoxy. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein aralkoxy is benzyloxy. 30 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein n is an integer ranging from 1 to 3 and m is 1.
WO 01/55086 PCT/DKO1/00057 13 In another preferred embodiment, the present invention is concerned with compounds of formula I wherein the substituents Z and Y are arranged in a trans-configuration. In another preferred embodiment, the present invention is concerned with compounds of formula I wherein the substituents Z and Y are arranged in a cis-configuration. 5 Preferred compounds of the invention are: (E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, (E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, 10 (Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, (Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, (E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyoxy)-phenyl]-propionic acid ethyl ester, 15 (E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. 20 Also preferred compounds of the invention are: Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] 25 propionic acid, Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid, 30 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyl]-propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid, WO 01/55086 PCT/DKO1/00057 14 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyi-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyl]-propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid; 5 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. Also preferred compounds of the invention are: 10 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-niaphthyl)-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-(I-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, 15 Ethyl (E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate, (E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyoxy)-phenyl]-propionic acid, Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] 20 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. 25 Also preferred compounds of the invention are: (Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, (Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, (E)-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester; 30 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. Also preferred compounds of the invention are: WO 01/55086 PCT/DKO1/00057 15 (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy-phenyl}-2-ethoxy 5 propionic acid, (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2 ethoxy-propionic acid, 10 (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-pheny}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2 20 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, 25 (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyoxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2 30 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 16 (E)-(S)-3-{4-15-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyI pent-2-en-4-ynyoxy] phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-( 1,3-Bis-(2,2,2-trifluoroethoxy)-phelyl)-3-methy-pelt-2-el-4-yyloxy-pheny} 2-ethoxy-propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pelt-2-en-4-ynyoxy-phel-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Dibromo-pheny)-3-methy-pet-2-e-4-yyioxy-pheyl}-2-ethoxy propionic acid, (E-(S)-3-{4-[5-(3,5-Diiodo-phel)-3-methyl-pet-2-e-4-yloxy]-phelyi}-2ethoxy-propiolic 10 acid, (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phelyl)-3-methyl-pet-2-e-4-yyloxyI-phel-2 ethoxy-propionic acid, (E-S--4[-35Dmtoypey)3mthlpn--n4yyoy-hni--toy propionic acid, 15 (E)-(S)-3-{4-[5-(3,5-Diethoxy-pheny)-3-methy-pet-2-e-4-yyloxy-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phel)-3-methyl-pelt-2-el4-yflYoxy] phenyl}-2-ethoxy-propionic acid, '(E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pet-2-e-4-yloxy-pheny} 20 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy-3-choro-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-( 1,3-Dibromo-pheny)-pent-2-en-4-ynyoxy]-3-choro-phelyl-2-ethoxy propionic acid, 25 (E)-(S)-3-{4-[5-(1 ,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propiolic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyoxy-3-choro-phel}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dimethoxy-phenyl)-pent-2-en-4-ynyoxy]-3-choro-phel}-2-ethoxy 30 propionic acid, (E)-(S)-3-(4-[5-(1 , 3Diethoxy-pheny)-pent-2-en-4-ynyoXyI-3-choro-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-pheny)-pent-2-en-4-yloxyI-3-chloro phenyi}-2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 17 (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 10 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, 15 (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 20 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, 25 (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 30 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en- 4 -ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 18 (E-S--4[-35Dfur-hnl--ehlpn--n4yyoy--hoopey}2 ethoxy-prop ionic acid, (E-S--4[-35Dboopey)3mtylpn--n4yyoy--hoopeyl2 ethoxy-propionic acid, 5 (E-S--4[-35Did-hnl--ehipet2e--nlx]3clr-hnl--toy propionic acid, (E-S--4[-35Bstilooehlpenl--ehlpn--n4yyoy--hoo phenyl)-2-ethoxy-propioflic acid, (E)-(S)-3-{4-[5-(3, 5-Dimethoxy-phel)-3-methyI-pelt-2-el-4-yloxyl-3-chloro-phel 2 10 ethoxy-propionic acid, (E-S--4[-35Dehx-hnl--ehlpn--n4yyoy--hoopey)2 ethoxy-propionic acid, (E-S--4[-35Bs(,,-rfurmtox)pey)3mty-et2e--nlx]3 chloro-phenyl-2-ethoxy-propioflic acid, 15 (E-S--4[-35Bs(,,-rfurehx)pey)3mty-et2e--nlx]3 chloro-phenyl}-2-ethoxy-propioflic acid, (E)-(S)-3-{4-[5-(1 ,3-Difluoro-pheny)-pent-2-el-4-yfloxy]-3-bromo-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dibromo-pheny)-pent-2-e-4-yfloxy]-3-bromo-phefl}-2ethoxy 20 propionic acid, (E)-(S)-3-{4-[5-( 1, 3-Diiodo-pheny)-pent-2-en-4-yfloxy]-3-bromlo-phel}-2-ethoxy-propiofic acid, (E)-(S)-3-{4-[5-(1 , 3Bis-trifluoromethy-phel)-pelt-2-el-4-yfloxy]-3-bromo-phel}- 2 ethoxy-prop ionic acid, 25 (E)-(S)-3-{4-[5-(1 ,3-Dimethoxy-pheny)-pent-2-e-4-yfloxy]-3-bromo-phelI-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 , 3Diethoxy-pheny)-pelt-2-e-4-yfloxy]-3-bromo-phel}-2ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phel)-pet-2-e-4-yfloxy]-3-bromo 30 phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-(4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phel)-pelt-2-el-4-yflyioxy]3bromo-phel} 2-ethoxy-propionic acid, (E-S--4[-35Dfur-hnl-et--n4yyoy--rm-hnl--toy propionic acid, WO 01/55086 PCT/DKO1/00057 19 (E)-(S)-3-{4-(5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-{5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionic acid, 5 (E)-(S)-3-{4-(5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyt)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyi}-2-ethoxy 10 propionic acid, (E)-(S)-3-{4-{5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy)-3-bromo phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl} 2-ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-(5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy 20 propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-methyl-2 ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en- 4 -ynyloxy]-3 30 bromo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-(5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-{5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 20 (E)-(S)-3-{4-I5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-bromo-phenyl1-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)73-methyl-pent-2-en.-4-ynyloxy-3-bromophenyll2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3 ,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-pheny)-3-methy-pent-2-en-4-ynyoxy]-3 10 bromo-pheny}-2-ethoxy-propionic acid, (E)-(S)-3-{4-E5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl)-2-ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-( 1,3-Dibromo-phenyl)-pent-2-en-4-ynyoxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-r5-( 1, 3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyll-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-trifluoromethyI-phenyl)-pent-2-en-4-ynyloxy-3-iodo-pheny}-2-ethoxy 20 propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-pheny}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Diethoxy-phenyi)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3, 5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyll-2-ethoxy-propionic 30 acid, (E)-(S)-3-{4-(5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxyl-3-iodo-phenyll-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxyl-3-iodo-phenyl-2-ethoxy-proponic acid, WO 01/55086 PCT/DKO1/00057 21 (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxyl-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-pheny}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 10 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, 15 (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-methyl-2 20 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 iodo-phenyl}-2-ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy 30 propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-iodo-phenyl} 2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 22 (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3 iodo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo phenyl}-2-ethoxy-propionic acid; 10 or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms. Also preferred compounds of the invention are: 15 (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyi}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy 20 propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy-phenyl}-2 ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-pheny}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, 30 (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2 35 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 23 (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyoxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-(5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy-phenyl}-2-ethoxy propionic acid, 5 (Z)-(S)-3-{4-{5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-pheny}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2 10 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-3-methyl-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy-phenyl}-2-ethoxy propionic acid, 15 (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methy pent-2-en-4-ynyloxy] phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy 20 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-pheny}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyll-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy 30 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy] phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl} 2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 24 (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, 5 (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyIoxy]-3-chloro-phenyl}-2-ethoxy 10 propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyioxy]-3-chloro phenyl}-2-ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyi} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy 20 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyioxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chioro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro 30 phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 25 (Z)-(S)-3-{4-[5-(1,3-Dibromo-pheny)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, 5 (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-pheny)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyI}-2 10 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3 chloro-pheny}-2-ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Difiuoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy 20 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyi)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyi-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-.pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 30 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-(5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 26 (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, 5 (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo 10 phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyoxy]-3-bromo-phenyl}-2-ethoxy propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 20 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyoxy]-3-bromo-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 30 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 27 (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyll-3-methyl-2 ethoxy-propionic acid, 5 (Z)-(S)-3-{4-(5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 10 bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 20 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic 30 acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 28 (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, 5 (Z)-(S)-3-{4-(5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-pheny} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-{5-(1,3-Bis-(2,2,2-trifluoroethoxy)-pheny)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic 10 acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl)-2-ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic 20 acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy 30 propionic acid, (Z)-(S)-3-{4-(5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy-3-iodo-phenyl}-3-methyl-2 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 29 (Z)-(S)-3-{4-(5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 iodo-phenyl)-2-ethoxy-propionic acid, 5 (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy 10 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-iodo-pheny} 2-ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 20 iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo phenyl}-2-ethoxy-propionic acid; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or 25 mixture of optical isomers, including a racemic mixture, or any tautomeric forms. In the above structural formulas and throughout the present specification, the following terms have the indicated meaning: 30 The term "C..
12 -alkyl" as used herein, alone or in combination is intended to include those alkyl groups of the designated length in either a linear or branched or cyclic configuration represents e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like. Typical C 1
-
12 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, 35 butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, cyclopropyl, cyclob- WO 01/55086 PCT/DKO1/00057 30 utyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl and the like, especially preferred is methyl and ethyl. The term "C 2 2 -alkenyl" as used herein, represents an olefinically unsaturated branched or 5 straight group having from 2 to the specified number of carbon atoms and at least one dou ble bond. Examples of such groups include, but are not limited to, vinyl, 1-propenyl, 2 propenyl, allyl, iso-proppenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like, espe cially preferred is vinyl and 1-propenyl 10 The term "C 2 1 2 -alkynyl" as used herein, represent an unsaturated branched or straight group having from 2 to the specified number of carbon atoms and at least one triple bond. Exam ples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2 butynyl, 1-pentynyl, 2-pentynyl and the like especially preferred is 1-propynyl. 15 The term "C 41 2 -alkenynyl" as used herein, represent an unsaturated branched or straight hy drocarbon group having from 4 to the specified number of carbon atoms and both at least one double bond and at least one triple bond. Examples of such groups include, but are not limited to, 1-penten-4-yne, 3-penten-1-yne, 1,3-hexadiene-5-yne and the like, especially pre ferred is 1-pentene-4-yne. 20 The term "C-alkoxy" as used herein, alone or in combination is intended to include those C alkyl groups of the designated length in either a linear or branched or cyclic configuration linked thorugh an ether oxygen having its free valence bond from the ether oxygen. Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like especially 25 preferred is methoxy and ethoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy and the like especially preferred is isopropoxy. Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like, especially preferred is cyclopropoxy. 30 The term "C-alkylthio" as used herein, alone or in combination, refers to a straight or branched or cyclic monovalent substituent comprising a C-alkyl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom and having I to 6 carbon atoms e.g. methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.
WO 01/55086 PCT/DKO1/00057 31 Examples of cyclic alkylthio are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like. The term "C-alkylamino" as used herein, alone or in combination, refers to a straight or 5 branched or cyclic monovalent substituent comprising a C-alkyl group linked through amino having a free valence bond from the nitrogen atom e.g. methylamino, ethylamino, propylamino, butylamino, pentylamino and the like. Examples of cyclic alkylamino are cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and the like. 10 The term "C-alkoxyC-alkyl" as used herein, alone or in combination, refers to a C-aikyl as defined herein whereto is attached a C-alkoxy as defined herein, e.g. methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like. The term "aryl" is intended to include aromatic rings, such as carbocyclic aromatic rings 15 selected from the group consisting of phenyl, naphthyl, (1 -naphthyl or 2-naphthyl) and the like optionally substituted with halogen, amino, hydroxy, C-alkyl, C 1 -alkoxy, C 1 -alkylester or carboxy and the like, especially preferred is phenyl and naphtyl optionally substituted with halogen. 20 The term "arylene" is intended to include divalent aromatic rings, suhch as carbocyclic aromatic rings selected from the group consisting of phenylene, naphthylene and the like optionally substituted with halogen, amino, hydroxy, C 1 -alkyl, C 1 -alkoxy, C-alkylester or carboxy and the like, especially preferred is phenylene. 25 The term "halogen" means fluorine, chlorine, bromine or iodine especially preferred is chlorine The term "perhalomethyl" means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl, especially preferred is trifluoromethyl. 30 The term "C-dialkylamino" as used herein refers to an amino group wherein the two hydrogen atoms independently are substituted with a straight or branched, saturated hydrocarbon chain having the indicated number of carbon atoms; such as dimethylamino, N- WO 01/55086 PCT/DKO1/00057 32 ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n pentyl)amino and the like. The term "acyl" as used herein refers to a monovalent substituent comprising a C 6 -alkyl 5 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 10 bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine and the like especially preferred is furan, pyrrole, pyridine, indole and benzofuran. 15 The term "heteroarylene" as used herein, alone or in combination, refers to a divalent group comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, e.g. furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, 20 pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine and the like, especially preferred is furan, pyrrole, pyridine, indole and benzofuran. The term "heteroaryloxy" as used herein, alone or in combination, refers to a heteroaryl as 25 defined herein linked to an oxygen atom having its free valence bond from the oxygen atom e.g. pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothi azole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine and purine linked to oxygen, and the like. 30 The term "aralkyl" as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride; such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like, especially preferred is benzyl.
WO 01/55086 PCT/DKO1/00057 33 The term "aryloxy" as used herein refers to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like especially preferred is phenoxy. The term "aralkoxy" as used herein refers to a C alkoxy group substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 3 5 phenylpropoxy, 1 -naphthylmethoxy, 2-(1 -naphtyl)ethoxy and the like, especially preferred is benzyloxy. The term "heteroaralkyl" as used herein refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl group; such as (2 10 furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl 1-(2-pyrimidyl)ethyl and the like. The term "heteroaralkoxy" as used herein refers to a heteroarylalkyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, e.g. (2-furyl)methyl, 15 (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2 pyrimidyl)ethyl linked to oxygen, and the like. The term "arylthio" as used herein, alone or in combination, refers to an aryl group linked through a divalent sulfur atom having its free valence bond from the sulfur atom, the aryl group 20 optionally being mono- or polysubstituted- with C 1 --alkyl, halogen, hydroxy or C-alkoxy; e.g. phenylthio, (4-methylphenyl)- thio, (2-chlorophenyl)thio and the like. As used herein, the phrase "heterocyclyl" means a monovalent saturated or unsaturated non aromatic group being monocyclic and containing one or more, such as from one to four car 25 bon atom(s), and from one to four N, 0 or S atom(s) or a combination thereof. The phrase "heterocyclyl" includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and the like); 5-membered heterocycles having two heteroa toms in 1,2 or 1,3 positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine, imi dazoline, 4-oxazolone and the like); 5-membered heterocycles having three heteroatoms 30 (e.g. tetrahydrofurazan and the like); 5-membered'heterocycles having four heteroatoms; 6 membered heterocycles with one heteroatom (e.g. piperidine and the like); 6-membered het erocycles with two heteroatoms (e.g. piperazine, morpholine and the like); 6-membered het erocycles with three heteroatoms; and 6-membered heterocycles with four heteroatoms, and the like.
WO 01/55086 PCT/DKO1/00057 34 As used herein, the phrase "a divalent heterocyclic group" means a divalent saturated or un saturated system being monocyclic and containing one or more, such as from one to four carbon atom(s), and one to four N, 0 or S atom(s) or a combination thereof. The phrase a 5 divalent heterocyclic group includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. pyrrolidine, pyrroline and the like); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. pyrazoline, pyrazolidine, 1,2-oxathiolane, imida zolidine, imidazoline, 4-oxazolone and the like); 5-membered heterocycles having three het eroatoms (e.g. tetrahydrofurazan and the like); 5-membered heterocycles having four het 10 eroatoms; 6-membered heterocycles with one heteroatom (e.g. piperidine and the like); 6 membered heterocycles with two heteroatoms (e.g. piperazine, morpholine and the like); 6 membered heterocycles with three heteroatoms; and 6-membered heterocycles with four heteroatoms, and the like. 15 As used herein the term "treatment" includes treatment, prevention and management of such condition. Certain of the above defined terms may occur more than once in the above formula (1), and upon such occurrence each term shall be defined independently of the other. 20 The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceu tically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as 25 organic acids. Representative examples of suitable inorganic acids include hydrochloric, hy drobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative exam ples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, 30 bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sul phates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphtho ates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable WO 01/55086 PCT/DKO1/00057 35 salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Exam ples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Exam ples of ammonium and alkylated ammonium salts include ammonium, methylammonium, di methylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethyl 5 ammonium, 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 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hy 10 dride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like, in sol vents like ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of sol-. vents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever appli cable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, ni 15 tric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used. 20 The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by re solving the mixture of stereoisomers by conventional methods. Some of the preferred meth 25 ods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lac tic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S) phenylethylamine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley 30 Interscience, 1981). More specifically the compound of formula I may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the dia-stereomers may be separated either by fractional crystallization or WO 01/55086 PCT/DKO1/00057 36 chromatography and the stereoisomers of compound of formula I may be prepared by hydro lysing the pure diastereomeric amide. Various polymorphs of compound of general formula I forming part of this invention may be 5 prepared by crystallization of compound of formula I under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cool ing during crystallizations. Polymorphs may also be obtained by heating or melting the com pound followed by gradual or fast cooling. The presence of polymorphs may be determined 10 by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques. The invention also encompasses prodrugs of the present compounds, which on administra tion undergo chemical conversion by metabolic processes before becoming active pharma 15 cological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. 20 The invention also encompasses active metabolites of the present compounds. Furthermore, the present compounds of formula I can be utilised in the treatment and/or pre vention of conditions mediated by nuclear receptors, in particular the Peroxisome Prolifera tor-Activated Receptors (PPAR). 25 In a further aspect, the present invention relates to a method of treating and/or preventing Type I or Type II diabetes. In a still further aspect, the present invention relates to the use of one or more compounds of the 30 general formula I or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment and/or prevention of Type I or Type I diabetes. In a still further aspect, the present compounds are useful for the treatment and/or prevention of IGT.
WO 01/55086 PCT/DKO1/00057 37 In a still further aspect, the present compounds are useful for the treatment and/or prevention of Type 2 diabetes. 5 In a still further aspect, the present compounds are useful for the delaying or prevention of the progression from IGT to Type 2 diabetes. In a still further aspect, the present compounds are useful for the delaying or prevention of the progression from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabe 10 tes. In another aspect, the present compounds reduce blood glucose and triglyceride levels and are accordingly useful for the treatment and/or prevention of ailments and disorders such as diabetes and/or obesity. 15 In still another aspect, the present compounds are useful for the treatment and/or prophylaxis of insulin resistance (Type 2 diabetes), impaired glucose tolerance, dyslipidemia, disorders related to Syndrome X such as hypertension, obesity, insulin resistance, hyperglycaemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial ischemia and other car 20 diovascular disorders. In still another aspect, the present compounds are effective in decreasing apoptosis in mam malian cells such as beta cells of Islets of Langerhans. 25 In still another aspect, the present compounds are useful for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis. In still another aspect, the present compounds may also be useful for improving cognitive 30 functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) and prevention and treatment of bone loss, e.g. osteoporosis. The invention also relates to pharmaceutical compositions comprising, as an active ingredi ent, at least one compound of the formula I or any optical or geometric isomer or tautomeric WO 01/55086 PCT/DKO1/00057 38 form thereof including mixtures of these or a pharmaceutically acceptable salt thereof to gether with one or more pharmaceutically acceptable carriers or diluents. Furthermore, the invention relates to the use of compounds of the general formula I or their 5 tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR) such as the conditions mentioned above. 10 The present invention also relates to a process for the preparation of the above said novel compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates. 15 The method comprises: a) Reacting a compound of formula 11 (prepared for example according to methods described in: Chem. Commun., 718-719, 1967; Org. Syntheses, Coll. Vol 3, 731-733, 1955; Org. Synthe ses, Coll. Vol IV, 801-803, 1963. 20 x ' Y 0 25 wherein X and Y are defined as above, through a Wittig-like process with for example (EtO) 2
PO(CHZ)(CH
2 )tCOOR6 (wherein R 6 is an alkyl group), in the presence of a base such as sodium hydride, EtONa and the like to give a compound of formula IlIl 30 WO 01/55086 PCT/DKO1/00057 39 Xy Y o O 5 (II) wherein X, Y, Z and R 6 are defined as above, and wherein t is 0-2, and b) 10 reducing a compound of formula 1ll, wherein X, Y, Z, R6 and t are defined as above with a suitable reagent such as diisobutylaluminium hydride, to give a compound of formula IV Xy x " z H2 OH 15 (IV) wherein X, Y, Z and t are defined as above, and 20 c) WO 01/55086 PCT/DKO1/00057 40 reacting a compound of formula IV, wherein X, Y, Z and t are defined as above, with a com pound of formula V 5
R
1 o H-(Q)-Ar OR 4
OR
3 (V) 10 wherein Q, Ar, R 1 , R 2 , R 3 , R4 and m are defined as above, except that m is not 0, under Mit sunobu conditions, using a reagent such as triphenylphosphine/diethylazodicarboxylate and the like to obtain a compound of formula 1, wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R 4 , n and m are defined as above, except that R4 is not H,1 n and m are not 0, or 15 d) by converting the -OH functionality in a compound of formula IV, wherein X, Y, Z and t are defined as above, to an appropriate leaving group (L) such as p-toluenesulfonate, methane sulfonate, halogen (for example by methods according to: Houben-Weyl, Methoden der or ganischen Chemie, Alkohole l1l, 6/1b, Thieme-Verlag 1984, 4th Ed., pp. 927-939; Compre 20 hensive Organic Transformations. A guide to functional group preparations, VCH Publishers 1989, 1 st Ed., pp. 353-363 and J. Org. Chem. ,Vol. 36 (20), 3044-3045, 1971), triflate and the like, to give a compound of formula VI X Y z H2)t
L
WO 01/55086 PCT/DKO1/00057 41 (VI) wherein L, X, Y, Z and t are defined as above, or e) reacting a compound of formula VI 5 wherein L is a leaving group such as p-tolkenesulfonate, methanesulfonate, halogen, triflate and the like and wherein X, Y, Z and t are defined as above with a compound of formula V 10
R
1 r H-(Q)-Ar
OR
4
OR
3 (V) 15 wherein Q, Ar, R 1 , R 2 , R 3 , R 4 and m are defined as above except that m is not 0, to give a compound of formula I wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R 4 , n and m are defined as above except that R 4 is not H, n and m are not 0, or f) 20 by chemical or enzymatic saponification of a compound of formula I WO 01/55086 PCT/DKO1/00057 42 X Y RO z CH 2 )n R 2 (Q)Ar
OR
4
OR
3 (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 not H, to obtain a compound of formula I, wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R4, n and m are de 5 fined as above except that R4 is H. Alternative methods for the synthesis of a compound of formula 1, a compound of formula 111, a compound of formula IV and a compound of formula VI are: g) reacting a compound -of formula Vil 10 X (Vil) wherein X is defined as above with a compound of formula Vill Y O 0
R
6 15 (Vill) WO 01/55086 PCT/DKO1/00057 43 under Pd catalysed cross-coupling conditions (for example as described in: Tetrahedron Lett, 39 (36), 6445-6448,1998), to give a compound of formula III wherein X, Y and R 6 are defined as above, and wherein t is 0, and Z is hydrogen. h) 5 reacting a compound of formula VII with a compound of formula IX Y o o (IX) according to a method analogous to that described in Tetrahedron Lett, 39 (37), 6719-6720, 1998, to give a compound of formula IlIl wherein X, Y, Z and R 6 are defined as above, and 10 wherein t is 0. i) Trans-cis or cis-trans isomerization of compounds 1, 111, IV, and Vi (Arai et al., Chem. Rev., 15 93, pp 23-39, 1993; J. March, Advanced Organic Chemistry, 4"' Ed., J. Wiley & Sons, New York 1992, pp. 218, 245, 745). 20 PHARMACOLOGICAL METHODS 25 In vitro PPAR alpha and PPAR gamma activation activity.
WO 01/55086 PCT/DKO1/00057 44 Principle The PPAR gene transcription activation assays were based on transient transfection into human HEK293 cells of two plasmids encoding a chimeric test protein and a reporter protein 5 respectively. The chimeric test protein was a fusion of the DNA binding domain (DBD) from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR proteins. The PPAR LBD harbored in addition to the ligand binding pocket also the native activation domain (activating function 2 = AF2) allowing the fusion protein to function as a PPAR ligand dependent transcription factor. The GAL4 DBD will force the fusion protein to 10 bind only to Gal4 enhancers (of which none existed in HEK293 cells). The reporter plasmid contained a Gal4 enhancer driving the expression of the firefly luciferase protein. After trans fection, HEK293 cells expressed the 6AL4-DBD-PPAR-LBD fusion protein. The fusion pro tein will in turn bind to the Gal4 enhancer controlling the luciferase expression, and do noth ing in the absence of ligand. Upon addition to the cells of a PPAR ligand, luciferase protein 15 will be produced in amounts corresponding to the activation of the PPAR protein. The amount of luciferase protein is measured by light emission after addition of the appropriate substrate. Methods 20 In vitro transactivation assays. Cell culture and transfection: HEK293 cells were grown in DMEM + 10% FCS. Cells 25 were seeded in 96-well plates the day before transfection to give a confluency of 50-80 % at transfection. A total of 0,8 pg DNA containing 0,64 p.g pMIa/yLBD, 0,1 pjg pCMVPGal, 0,08 ig pGL2Gal4DBD and 0,02 ptg pADVANTAGE was transfected per well using FuGene trans fection reagent according to the manufacturers instructions (Roche). Cells were allowed to express protein for 48 h followed by addition of compound. 30 Plasmids: Human PPAR a and y was obtained by PCR amplification using cDNA synthesized by reverse transcription of mRNA from liver and adipose tissue respectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. The ligand binding domain (LBD) of each PPAR isoform was generated by PCR (PPARa: aa 167 - C-terminus; PPARy: aa 165 - C- WO 01/55086 PCT/DKO1/00057 45 terminus) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by subcloning fragments in frame into the vector pM1 generating the plasmids pM1aLBD and pMlyLBD. Ensuing fusions were verified by sequencing. The reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x 5 CGGAGTACTGTCCTCCG(AG)) into the vector pGL2 promotor (Promega) generating the plasmid pGL2(GAL4) 5 . pCMVPGal was purchased from Clontech and pADVANTAGE was purchased from Promega. Luciferase assay: Medium including test compound was aspirated and 100 pl PBS incl. 1mM 10 Mg++ and Ca++ was added to each well. The luciferase assay was performed using the Lu cLite kit according to the manufacturers instructions (Packard Instruments). Light emission was quantified by counting SPC mode on -a Packard Instruments top-counter. To measure p galactosidase activity 25 pl supernatant from each transfection lysate was transferred to a new microplate. P-galactosidase assays were performed in the microwell plates using a kit 15 from Promega and read in a microplate reader. The P-galactosidase data were used to nor malize (transfection efficiency, cell growth etc.) the luciferase data. Compounds: All compounds were dissolved in DMSO and diluted 1:1000 upon addition to the cells. Compounds were tested in quadruple in five concentrations ranging form 0.01 to 30 20 pM. Cells were treated with compound for 24 h followed by luciferase assay. Each compound was tested in three separate experiments. EC5o values were calculated via non-linear regres sion using GraphPad PRISM 3.02 (GraphPad Software, San Diego, CA).The results were expressed as means. 25 WO 01/55086 PCT/DKO1/00057 46 Table 1. In vitro PPAR alpha and PPAR gamma activation of examples according to the present in vention. 5 In vitro activation PPARcc PPARy Example no EC 50 , ptM % max' EC 50 , pM % maxb 6 0.20 217 0.7 108 8 0.06 139 0.31 126 12 0.05 195 0.34 105 18 0.16 181 2.67 91 20 0.04 154 1.42 112 Compounds were tested in at least three separate experiments in five concentrations ranging from 0.01 to 30 ptM. EC 50 's were not calculated for compounds producing transactivation lo 10 wer than 25% at 30 p.M. aFold activation relative to maximum activation obtained with Wyl 4643 (approx. 20 fold corresponded to 100%) and with brosiglitazone (approx. 120 fold corresponded to 100%). 15 PHARMACEUTICAL COMPOSITIONS In another aspect, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or 20 diluent.
WO 01/55086 PCT/DKO1/00057 47 The present compounds may also be administered in combination with one or more further pharmacologically active substances eg., selected from antiobesity agents, antidiabetics, an tihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complica 5 tions and disorders resulting from or associated with obesity. Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents. 10 Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tunfior necrosis factor) agonists, CRF (corticotropin releas ing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, uro cortin agonists, p3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH 15 (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antago nists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA 20 agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor) modulators or TR P agonists. In one embodiment of the invention the antiobesity agent is leptin. 25 In another embodiment the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine. In still another embodiment the antiobesity agent is sibutramine. 30 In a further embodiment the antiobesity agent is orlistat. In another embodiment the antiobesity agent is mazindol or phentermine.
WO 01/55086 PCT/DKO1/00057 48 Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1) derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by refer ence as well as orally active hypoglycaemic agents. 5 The orally active hypoglycaemic agents preferably comprise sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potas sium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase-IV) 10 inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), com pounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potas sium channel of the p-cells. 15 In one embodiment of the invention the present compounds are administered in combination with insulin. In a further embodiment the present compounds are administered in combination with a sul 20 phonylurea eg. tolbutamide, glibenclamide, glipizide or glicazide. In another embodiment the present compounds are administered in combination with a bi guanide eg. metformin. 25 In yet another embodiment the present compounds are administered in combination with a meglitinide eg. repaglinide or senaglinide. In a further embodiment the present compounds are administered in combination with an ox-glucosidase inhibitor eg. miglitol or acarbose. 30 In another embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the p-cells eg. tolbutamide, gliben clamide, glipizide, glicazide or repaglinide.
WO 01/55086 PCT/DKO1/00057 49 Furthermore, the present compounds may be administered in combination with nateglinide. In still another embodiment the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent eg. cholestyramine, colestipol, clofibrate, 5 gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine. In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a 10 sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc. Furthermore, the present compounds-nay be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are p-blockers such as alpre nolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting en 15 zyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, ni modipine, diltiazem and verapamil, and ca-blockers such as doxazosin, urapidil, prazosin and terazosin. Further reference can be made to Remington: The Science and Practice of Phar macy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. 20 It should be understood that any suitable combination of the compounds according to the in vention with one or more of the above-mentioned compounds and optionally one or more fur ther pharmacologically active substances are considered to be within the scope of the pre sent invention. 25 Pharmaceutical compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19* Ed., 1995. The compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications. 30 Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. In making the compositions, WO 01/55086 PCT/DKO1/00057 50 conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid 5 material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or 10 lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, 15 emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. 20 The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring sub stances and the like, which do not deleteriously react with the active compounds. The route of administration may be any route, which effectively transports the active com 25 pound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, in tranasal, ophthalmic solution or an ointment, the oral route being preferred. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a 30 hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
WO 01/55086 PCT/DKO1/00057 51 For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as 5 parabenes. For parenteral application, particularly suitable are injectable solutions or suspensions, pref erably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. 10 Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or cap sules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. 15 A typical tablet which may be prepared by conventional tabletting techniques may contain: Core: Active compound (as free compound or salt thereof) 5 mg Colloidal silicon dioxide (Aerosil) 1.5 mg 20 Cellulose, microcryst. (Avicel) 70 mg Modified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Ad. Coating: 25 HPMC approx. 9mg *Mywacet 9-40 T approx. 0.9 mg *Acylated monoglyceride used as plasticizer for film coating. 30 The compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar. Such mammals include also animals, both domestic animals, e.g. household pets, and non domestic animals such as wildlife.
WO 01/55086 PCT/DKO1/00057 52 The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used. A most preferable dosage is about 0.1 mg to 5 about 70 mg per day. In choosing a regimen for patients it may frequently be necessary to begin with a dosage of from about 2 to about 70 mg per day and when the condition is under control to reduce the dosage as low as from about 0.1 to about 10 mg per day. The exact dosage will depend upon the mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and 10 the preference and experience of the physician or veterinarian in charge. * Generally, the compounds of the present invention are dispensed in unit dosage form comprising from about 0.1 to about 100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage. 15 Usually, dosage forms suitable for oral, nasal, pulmonary or transdermal administration comprise from about 0.001 mg to about 100 mg, preferably from about 0.01 mg to about 50 mg of the compounds of formula I admixed with-a pharmaceutically acceptable carrier or diluent. 20 Any novel feature or combination of features described herein is considered essential to this invention. EXAMPLES 25 The process for preparing compounds of formula I, and preparations containing them, is further illustrated in the following examples, which however, are not to be construed as limiting. The structures of the compounds are confirmed by either elemental analysis (MA) nuclear 30 magnetic resonance (NMR), mass spectrometry (MS) or optical rotation. NMR shifts (3) are given in parts per million (ppm) and only selected peaks are given. mp is melting point and is given in 0 C. Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art 9385). The optical rotation was measured on a Advanced Laser Polarimeter.
WO 01/55086 PCT/DKO1/00057 53 Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se. Abbrevations: 5 THF: tetrahydrofuran DMSO: dimethylsulfoxide MTBE: tertbutylmethylether CDC1 3 : deutorated chloroform DMF: N,N-dimethylformamide 10 min: minutes h: hours EXAMPLE 1 15 H H (E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyll-propionic acid ethyl ester 20 Method 1 a) A solution of triethyl phosphonoacetate (25.8 g, 115 mmol) in toluene (100 mL) was added at 00C to a stirred suspension of sodium hydride (60% in oil, 3.12 g, 130 mmol) in toluene (300 25 mL) and the mixture stirred at 0*C for 30 min. A solution of 3-phenylpropargyl aldehyde (Org. Syntheses, Coll. Vol 3, 731-733, 1955) (10.0 g, 77 mmol) in dry THF (15 mL) was added, the mixture slowly warmed to room temperature, and stirring continued for 16 h. The reaction mixture was quenched with ethanol (25 mL) and water (300 mL), the organic phase sepa- WO 01/55086 PCT/DKO1/00057 54 rated, and the aqueous phase extracted with dichloromethane (300 mL). The combined or ganic phases were concentrated in vacuo, and submitted to flash column chromatography, petroleum ether/toluene (1:1) graduated to petroleum ether/toluene (1:9) as eluent, to give (1.21 g, 8%) of (E)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester. 5 'H NMR (CDCl 3 , 300 MHz) 5: 1.30 (t, 3H), 4.25 (q, 2H), 6.30 (d, IH, Jtn, = 15 Hz), 6.98 (d, 1H, Jtns = 15 Hz), 7.30-7.40 (m, 3H), 7.45-7.50 (m, 2H). b) Diisobutylaluminium hydride (1.0 M solution in toluene, 42 mL, 42 mmol) was added, under a 10 nitrogen atmosphere at -70*C, to a stirred solution of (E)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester (1.2 g, 5.99 mmol) in dry THF (105 mL). After stirring for 1.5 h, the reaction mix ture was quenched with methanol (5 mL) followed by saturated aqueous Rochelle's salt (90 mL) and 1 N sodium hydroxide (40 mL). The organic phase was separated, and the aqueous phase extracted with ethyl acetate (250 mL, 2x). The combined organic phases were dried 15 (MgSO 4 ), filtered and concentrated in vacuo to give 948 mg (100%) of (E)-5-phenyl-pent-2 en-4-yn-1 -ol. 'H NMR (CDCl 3 , 300 MHz) 5: 2.20 (bs, 1H), 4.25 (d, 2H), 5.95 (dt, 1H, Jtns = 15 Hz), 6.35 (dt, 1 H, Jbn, = 15 Hz), 7.23-7.35 (m, 3H), 7.35-7.48 (m, 2H). 20 c) (E)-5-Phenyl-pent-2-en-4-yn-1-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) were successively dissolved in dry ben zene (30 mL) under a nitrogen atmosphere and the solution cooled to 0*C. Solid 1,1' 25 (azodicarbonyl) dipiperidine (756 mg, 3.0 mmol) was added, the mixture stirred for 10 min., then warmed to room temperature and stirred for 16 h. The reaction mixture was filtered and the filtrate concentrated in vacuo. The product was purified by flash column chromatography eluting with toluene graduated to toluene/ethyl acetate (19:1) to give 450 mg (57%) of the title compound. 30 'H NMR (CDC 3 , 300 MHz) 5: 1.18 (t, 3H), 1.25 (t, 3H), 2.95 (d, 2H), 3.30-3.42 (m, 1H), 3.55 3.67 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.60 (d, 2H), 6.15 (dt, 1H, Jen, = 15 Hz), 6.48 (dt, 1H, J~ns = 15 Hz), 6.85 (d, 2H), 7.15 (d, 2H), 7.28-7.35 (m, 3H), 7.40-7.46 (m, 2H). = 30 ± 40 WO 01/55086 PCT/DKO1/00057 55 Method 2 a) 5 To a mixture of (E)-5-phenyl-pent-2-en-4-yn-1 -ol (Method 1b) (4.9 g, 31.0 mmol) and triethyl amine (3.8 g, 38.0 mmol) in dry dichloromethane (200 mL) was added methanesulfonyl chlo ride (3.8 g, 33 mmol) dropwise. Stirring, was continued at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue washed with hep tane/dichloromethane (x2) to give 4.5 g (82 %) crude (E)-(5-chloro-pent-3-en-1-ynyl) 0 benzene. 'H NMR (CDCl 3 , 300 MHz) 5: 4.13 (d, 2H)), 6.0 (d, 1H, Jtn, = 15 Hz), 6.29 (dt, 1H, Jn, = 15 Hz), 7.28-7.35 (m, 3H), 7.40-7.48 (m,~2H). b) 15 To a solution of (E)-(5-chloro-pent-3-en-1-ynyl)-benzene (177 mg, 1.0 mmol) and (S)-2 ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (238 mg, 1.0 mmol) in acetone (15 mL) was added potassium carbonate (700 mg, 5.0 mmol) and potassium iodide (17 mg, 0.1 mmol). The mixture was heated to reflux over night with stirring. Water was added and the product extracted with tert-butyl-methyl ether (x3) The combined organic phases were dried 20 (MgSO 4 ), filtered and concentrated in vacuo, to give the title compound as a crude product. Method 3 a) 25 A solution of (E)-5-phenyl-pent-2-en-4-yn-1 -ol (Method 1b) (980 mg, 6.2 mmol) in dry toluene (20 mL) was cooled on ice and phosphorus tribromide (0.59 mL, 6.2 mmol) added slowly. After 16 h at 5oC the mixture was diluted with ethyl acetate and washed with water (x3). The organic phase was concentrated in vacuo and the residue extracted with heptane (x3). The combined heptane phases were concentrated in vacuo to give 900 mg of crude (E)-(5 30 bromo-pent-3-en-1-ynyl)-benzene. (According to NMR the product contained -5 % of the (Z) isomer). 1 H NMR (CDCl 3 , 300 MHz) 5: 4.02 (d, IH), 4.25 (d, 0.05 H), 5.82 (d, 0.05 H, Jets = 8 Hz), 5.95 (d, 1H, Jun, = 16 Hz), 6.18 (dt, 0.05 H, Jej, = 8 Hz), 6.35 (dt, IH, Jn, = 16 Hz), 7.26-7.35 (m, 3H), 7.35-7.48 (m, 2H).
WO 01/55086 PCT/DKO1/00057 56 EXAMPLE 2 H H 0 0 OH 5 (E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid 10 Aqueous sodium hydroxide (IN, 5 mL, 5.0 mmol) was added to a stirred solution of (E)-(S)-2 ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester (example 1) (450 mg, 1.18 mmol) in ethanol (5 mL) and the resulting mixture stirred at room temperature for 16 h. The ethanol was evaporated in vacuo and the mixture acidified to pH 1 with 1 N hy drochloric acid. The product was extracted into ethyl acetate (30 mL x 2), and the combined 15 organic phases dried (MgSO4), filtered and evaporated to give 225 mg (54%) of the title com pound as white crystals. 'H NMR (CDCl 3 , 300 MHz) S: 1.20 (t, 3H), 2.97 (dd,1H), 3.10 (dd, IH), 3.42-3.65 (m, 2H), 4.05 (dd, 1H), 4.63 (dd, 2H), 6.08 (dt, 1H, Jtn, = 15 Hz), 6.39 (dt, 1H, Jlm, = 15 Hz), 6.85 (d, 2H), 7.15 (d, 2H), 7.30-7.35 (m, 3H), 7.40-7.48 (m, 2H). 20 [ar = 230 30 WO 01/55086 PCT/DKO1/00057 57 EXAMPLE 3 0 0 0 y _ 0 5 (Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester 1,1'-(azodicarbonyl) dipiperidine (0.504 g, 2.0 mmol) was added at 0*C to a stirred solution of tributylphosphine (0.493 mL, 2.0 mmol), (Z)-3-methyl-5-phenyl-pent-2-en-4-yn-1-o (0.172 g, 10 1.0 mmol) (J. Org. Chem. 1999, 64 (21), 7687-7692), and (S)-ethyl 2-ethoxy-3-(4-hydroxy phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL), the mixture allowed to warm to room temperature, and stirring continued for 24 h. The resulting mixture was evaporated in vacuo, and the residue purified by flash column chromatography on silica gel (20% ethyl ace tate in n-heptane eluent) to give (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4 15 ynyloxy)-phenyl]-propionic acid ethyl ester as an oil; 0.267 g (68%). 'H NMR (300 MHz, CDCI 3 ) 5: 1.1-1.25 (6H, m), 2.0 (3H, d), 2.93 (2H, d), 3.25-3.38 (1H, m), 3.51-3.62 (1H, m), 3.97 (1H, 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). 20 WO 01/55086 PCT/DKO1/00057 58 EXAMPLE 4 HO 0 5 (Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid Sodium hydroxide (1 N, 1.25 mL, 1.25 mmol) was added to a solution of (Z)-(S)-2-ethoxy-3 [4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester (example 3) (0.246 g, 0.627 mmol) in ethanol (20 mL) and the mixture stirred at 70*C for 2.5 h. After cool 10 ing to room temperature the resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was collected, acidified with 1 N hydrochloric acid (5 mL) and extracted into ethyl acetate (100 mL). The organic phase was washed with brine, dried (Na 2
SO
4 ) and evaporated to give (E)-(S)-3-[ 4-( 3-biphenyl-4-yl-but-2-enyoxy)-phenyl ] 2-ethoxy-propionic acid as an oil; 0.150 g (66%). 15 'H NMR (300 MHz, CDCI 3 ) 5:1.05 (3H, t), 1.92 (3H, d), 2.8 (1H, dd), 2.92 (1H, dd), 3.2-3.3 (IH, m), 3.4-3.5 (1H, m), 3.9 (1H, dd), 4.7 (2H, dd), 5.85 (1H, dt), 6.8 (2H, d), 7.1 (2H, d), 7.2-7.25 (3H, m), 7.3-7.4 (2H, m), 8.9 (1H, br s). 20 WO 01/55086 PCT/DKO1/00057 59 EXAMPLE 5 5 (E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester The title compound was prepared from of (E)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 10 g, 1.0 mmol), (J. Med. Chem. 1998, 41(14), 2524-2536), tributylphosphine (0.370 mL, 1.5 mmol), 1,1'-(azodicarbonyl) dipiperidine (0.378 g, 1.5 mmol) and (S)-ethyl 2-ethoxy-3-(4 hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL) by a procedure analogous to that described in example 3, yielding 0.276 g (68%) of (E)-(S)-2-ethoxy-3-[4-(3 methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester. 15 1 H NMR (300 MHz, CDCI 3 ) 5: 1.1-1.25 (6H, m), 1.98 (3H, d), 2.95 (2H, d), 3.29-3.4 (1H, m), 3.53-3.65 (1H, m), 3.95 (1H, 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). 20 EXAMPLE 6 OH 0 (E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid 25 The title compound was prepared from (E)-(S)-2-ethoxy-3-(4-(3-methyl-5-phenyl-pent-2-en-4 ynyloxy)-phenyl]-propionic acid ethyl ester (example 5) (0.270 g,0.698 mmol ) and sodium WO 01/55086 PCT/DKO1/00057 60 hydroxide (1 N, 1.4 mL, 1.4 mmol) by a procedure analogous to that described in example 4 yielding 0.100 g (39%) of (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy) phenyl]-propionic acid. 'H NMR (300 MHz, CDC13) 8: 1.18 (3H, t), 1.98 (3H, d), 2.9 (1H, dd), 2.05 (1H, dd), 3.4-3.5 5 (1H, m), 3.55-3.65 (1H, m), 4.05 (1H, dd), 4.62 (2H, dd), 6.15 (1H, m), 6.8 (2H, d), 7.15 (2H, d), 7.3 ( 3H, m), 7.43 (2H, m). EXAMPLE 7 10 N.N ci Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate 15 Method 1 a) To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220 mL) was 20 added PdCl 2 (PPh 3
)
2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), cop per(l)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4 (3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield. 25 'H NMR (300 MHz, CDC13) 8: 2.46 (s, 3H), 7.45 (s, 3H). b) To a solution of sodium (163 mg, 6.8 mmol) in ethanol (6 mL) at -10 0C was added triethyl phosphonoacetate (1.37 mL, 6.8 mmol) and the reaction mixture was stirred for 5 minutes. A 30 solution of 4-(3,5-dichloro-phenyl)-3-butyn-2-one (214 mg, 5.7 mmol) in ethanol (4 mL) was WO 01/55086 PCT/DKO1/00057 61 added and the reaction mixture stirred overnight at room temperature and evaporated. The residue was treated with water (10 mL) and extracted with 3x30 mL ethyl acetate. The dried organic phases were evaporated to give a mixture of (E)- and (Z)-3-methyl-5-(3,5-dichloro phenyl)-pent-2-en-4-ynoic acid ethyl esters. The mixture was separated by column chroma 5 tography using hexanes:methylene chloride (10:1) as eluent, giving pure (E) in 130 mg, and pure (Z) in 160 mg yields. (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester: 'H NMR (300 MHz,
CDCI
3 ) : 1.29 (t, 3H), 2.36 (s, 3H), 4.20 (q, 2H), 6.16 (m, IH), 7.34 (s, 3H). (Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester: 'H NMR (300 MHz, 10 CDC1 3 ) S: 1.29 (t, 3H), 2.12 (s, 3H), 2.25 (q, 2H), 6.09 (m, 1H), 7.34 (m, 1H), 7.40 (m, 2H). c) To a solution of (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (130 mg, 0.46 mmol) in THF (0.5 mL) was added dropwise diisobutylaluminium hydride (1.0 M so 15 lution in toluene, 2.1 mL, 2.1 mmol) at -20 0C. The reaction mixture was stirred for 2 hours at -20 *C, whereafter saturated ammonium chloride was added. The mixture was treated with ethyl acetate and decalite and filtered. The filtrate was evaporated to give crude (E)-3 methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol in 113 mg yield. 'H NMR (300 MHz, CDC1 3 ) 8: 1.85 (s, 3H), 2.00 (br.s, 1H), 4.20 (d, 2H), 6.04 (m, 1H), 7.20 (s, 20 3H). d) To a solution of (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol (113 mg, 0.46 mmol) in THF (10 mL) was added triphenylphosphine (218 mg, 0.71 mmol) at 0 0 C. To the 25 mixture was added diethyl azodicarboxylate (0.109 mL, 0.71 mmol) and (S)-2-ethoxy-3-(4 hydroxy-phenyl)-propionic acid ethyl ester (169 mg, 0.71 mmol) and the reaction mixture was stirred at 0 'C for 2 h and then at room temperature overnight. Water (15 mL) was added and the mixture was extracted with methylene chloride (3x30 mL). The combined and dried or ganic phases were evaporated and the residue purified by column chromatography using 30 methylene chloride as eluent to give the title compound in 35 mg yield. 'H NMR (300 MHz, CDC1) :1.16 (t, 3H), 1.23 (t, 3H), 1.98 (s, 3H), 2.97 (d, 2H), 3.42-3.30 (m, 1H), 3.65-3.55 (m, IH), 3.97 (t, IH), 4.16 (q, 2H), 4.62 (d, 2H), 6.20 (m, 1H), 8.83 (d, 2H), 7.16 (d, 2H), 7.37 (m, 3H).
WO 01/55086 PCT/DKO1/00057 62 Method 2 a) A solution of 1-bromo-3,5-dichloro-benzene (904 mg, 4.0 mmol), PdCl 2 (PPh 3
)
2 (96 mg, 0.08 5 mmol), 2-methyl-3-butyn-2-ol (672 mg, 8.0 mmol) and Cul (4 mg, 0.02 mmol) in diethylamine (16 mL) was stirred at room temperature for 50 h. The reaction mixture was evaporated and the residue purified by column chromatography using methylene chloride as eluent. The de sired product 3-(2,5-dichlorophenyl)-2-methyl-3-butyn-2-ol was isolated in 910 mg (99%) yield. 10 -H NMR (300 MHz, CDC1 3 ) 8:1.62 (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 sodium hydroxide pellets (45 mg) at room temperature. The re 15 action mixture was heated and a mixture of toluene and formed acetone was distilled of. The reaction mixture was washed with aqueous potassium carbonate (1 M, 2.5 mL), water (2.5 mL) and brine (2.5 mL). The organic phase was dried and evaporated to give the desired product 1,3-dichloro-phenyl acetylene in 537 mg (91%) yield. 'H NMR (300 MHz, CDCl 3 ) 5: 3.15 (1H, s), 7.37 (3H, s). 20 c) To a solution of 1,3-dichloro-phenyl acetylene (6.07 g, 35.5 mmol) in dry THF (60 mL) was added palladium acetate (186 mg, 0.68 mmol), ethyl 2-butynoate (5.97 g, 53.2 mmol) and tris (2,6-dimethoxyphenyl)phosphine (316 mg, 0.68 mmol) at room temperature. The reaction 25 mixture was stirred for 18 h and filtered. The filtrate was washed with water (10 mL), and the water phase was extracted with ether (10 mL). The combined organic phases were dried and evaporated. The residue was purified by column chromatography using heptane:THF (20:1) as eluent. (E)-3-Methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester was iso lated in 4.65 g (46%) yield. 30 d) The title compound was prepared from (E)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4 ynoic acid ethyl ester according to the procedure described in method 1,c-d.
WO 01/55086 PCT/DKO1/00057 63 EXAMPLE 8 00 5 ci (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid 10 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate was hydrolysed as described in Example 2 to give the title compound. 'H NMR (300 MHz, CDCl 3 ) 8:1.12 (t, 3H), 1.95 (s, 3H), 3.12-2.85 (m, 2 H), 3.48-3.32 (m, 1H), 3.65- 3.53 (m, 1H), 4.03 (m, 1H), 4.59 (d, 2H), 6.17 (t, IH), 6.80 (d, 2H), 7.15 (d, 2H), 7.30 (s, 3H). 15 EXAMPLE 9 0 0 0 ci 20 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate 25 WO 01/55086 PCT/DKO1/00057 64 a) (Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-ol was made from (Z)-3-methyl-5-(3,5 dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (160 mg) (example 7b) using the condi tions described in example 7c. Yield 140 mg. 5 'H NMR (300 MHz, CDCl 3 ) 5: 1.88 (s, 3H), 1.92 ( br. s, 1 H), 4.33 (d, 2H), 5.90 (t, 1 H), 7.21 (s, 3H). b) The title compound was prepared from (Z)-3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn 10 1-ol (140 mg) using the conditions described in example 7d. Yield 172 mg. 'H NMR (300 MHz, CDCl 3 ) : 1.17 (t, 3H), 1.25 (t, 3H), 2.00 (s, 3H), 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, 2H), 6.02 (t, 1H), 6.86 (d, 2H), 7.28 (d, 2H), 7.32 (s, 3H). 15 EXAMPLE 10 0 OH ci/0 ci 20 (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate was hydrolysed as described in Example 2 to give the title compound. Yield 164 25 mg. 1 H NMR (300 MHz, CDCl 3 ) 8: 1.18 (t, 3H), 2.01 (s, 3H), 3.10-2.90 (m, 2H), 3.46-3.33 (m, 1H), 3.67-3.55 (m, 1H), 4.04 (m, 1H), 4.75 (d, 2H), 6.02 (t, 1H), 6.87 (d, 2H), 7.18 (d, 2H), 7.33 (s, 3H). 30 WO 01/55086 PCT/DKO1/00057 65 EXAMPLE 11 F 0 o O..~ F F O 5 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyll-propionate The title compound was made as described in example 7a-d using 3-trifluoromethyl-1-iodo benzene instead of 1,3-dichloro-5-iod-benzene in example 7a. 10 1 H NMR (300 MHz, CDCl 3 ) 5:1.18 (t, 3H), 1.24 (t, 3H), 2.00 (s, 3H), 2.96 (d, 2H), 3.42-3.31 (m, 1H), 3.66-3.55 (m, 1H), 3.98 (t, IH), 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). 15 EXAMPLE 12 F O OOH F (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl] 20 propionic acid Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyl]-propionate was hydrolysed as described in Example 2 to give the title compound. 'H NMR (300 MHz, CDCI 3 ) 5: 1.19 (t, 3H), 1.98 (s, 3H), 3.12-2.90 (m, 2H), 3.48-3.36 (m, IH), 25 3.69-3.56 (m, 1H), 4.50 (m, IH), 4.64 (d, 2H), 6.21 (t, 1H), 6.85 (d, 2H), 7.18 (d, 2H), 7.70 7.49 (m, 5H).
WO 01/55086 PCT/DKO1/00057 66 EXAMPLE 13 o_/ F F / - 0 FFO F 5 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyl]-propionate The title compound was synthesised from (Z)-3-methyl-5-(3-trifluromethyl-phenyl)-pent-2-en 10 4-yn-1-ol which was derived from the reaction sequence described in example 11 using the conditions described in example 7c-d. 'H NMR (300 MHz, CDCI 3 ) 8: 1.18 (t, 3H), 2.23 (t, 3H), 2.03 (s, 3H), 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). 15 EXAMPLE 14 OH F O 20 (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid 25 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methy-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyl]-propionate was hydrolysed as described in Example 2 to give the title compound.
WO 01/55086 PCT/DKO1/00057 67 1 H NMR (300 MHz, CDC1 3 ) 6: 1.16 (t, 3H), 2.02 (s, 3H), 3.10-2.92 (m, 2H), 3.47-3.36 (m, 1H), 3.68-3.57 (m, IH), 4.03 (m, 1H), 4.80 (d, 2H), 6.02 (t, 1H), 6.89 (d, 2H), 7.18 (d, 2H), 7.72 7.42 (m, 5H). 5 EXAMPLE 15 \ 0 Z~ / 0 10 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate The title compound was made as described in example 7a-d using 1-iodonaphthalene in stead of 1,3-dichloro-5-iodo-benzene in example 7a. 1 H NMR (300 MHz, CDC1 3 ) 5:1.18 (t, 3H), 1.24 (t, 3H), 2.08 (s, 3H), 2.96 (d, 2H), 3.42-3.30 15 (m, 1H), 3.66-3.53 (m, 1H), 3.98 (t, 1H), 4.15 (q, 2H), 4.65 (d, 2H), 6.30 (m, 1H), 6.86 (d, 2H), 7.18 (d, 2H), 7.86-7.38 (m, 6H), 8.33 (d, 1H). EXAMPLE 16 20 OH 0 - 0 (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid 25 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate was hydrolysed as described in Example 2 to give the title compound.
WO 01/55086 PCT/DKO1/00057 68 1 H NMR (300 MHz, CDC13) 5: 1.19 (t, 3H), 1.98 (s, 3H), 3.12-2.90 (m, 2H), 3.48-3.36 (m, 1H), 3.69-3.56 (m, 1H), 4.05 (m, 1H), 4.66 (d, 2H), 6.30 (t, IH), 6.85 (d, 2H), 7.18 (d, 2H), 7.90 7.45 (m, 6H), 8.44 (d, IH). 5 EXAMPLE 17 o-/ 0 10 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate The title compound was synthesised from (Z)-3-methyl-5-(1-naphthyl)-pent-2-en-4-yn-1-o isolated in example 15 using the conditions described in example 7c-d. 1 H NMR (300 MHz, CDC13) 8: 1.18 (t, 3H), 1.23 (t, 3H), 2.14 (s, 3H), 2.97 (d, 2H), 3.42-3.30 15 (m, 1H), 3.66-3.53 (m, 1H), 3.98 (t, IH), 4.15 (q, 2H), 4.95 (d, 2H), 6.06 (m, IH), 6.94 (d, 2H), 7.18 (d, 2H), 7.86-7.40 (m, 6H), 8.30 (m, 1H). EXAMPLE 18 20 OH 0 (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(1 -naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid 25 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methy-5-(1-naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate was hydrolysed as described in Example 2 to give the title compound.
WO 01/55086 PCT/DKO1/00057 69 'H NMR (300 MHz, CDCI 3 ) 5: 1.04 (t, 3H), 2.02 (s, 3H), 3.00-2.80 (m, 2H), 3.34-3.22 (m, 1H), 3.57-3.46 (m, 1H), 3.94 (m, 1H), 4.83 (d, 2H), 5.94 (t, 1H), 6.84 (d, 2H), 7.08 (d, 2H), 7.75 7.26 (m, 6H), 8.20 (m, 1H), 9.2 (br.s, 1H). 5 EXAMPLE 19 1 Eh 0 1 0 Ethyl (E)-(S)-2-ethoxy-3-{4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate a) To a solution of 1,3-dichloro-5-iodo-benzene (5.44 g, 20 mmol) in diethylamine (75 mL) was added PdC 2 (PPh 3
)
2 (280 mg, 0.4 mmol), trimethylsilylacetylene (2.36 g, 24.0 mmol) and 15 copper(I)iodide (20 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 24 h, filtered and evaporated. The residue was purified by column chromatography using heptane:ethyl acetate (8:2) as eluent. The desired (3,5-dichloro-phenylethynyl)-trimethyl silane product was isolated in 4.85 g yield. 1 H NMR (300 MHz, CDCI 3 ) 8: 0.09 (s, 9H), 7.15 (m, 3H). 20 b) To a solution of (3,5-dichloro-phenylethynyl)-trimethylsilane (4.85 g, 19.9 mmol) in methanol (50 mL) was added 1 M potassium hydroxide (30 mL). The reaction mixture was stirred 1 h at room temperature and evaporated. The residue was treated with water (10 mL) and ex 25 tracted with 3x40 mL diethyl ether. The tried organic phases were evaporated to give the de sired 1,3-dichloro-5-ethynyl-benzene product in 2.3 g yield. 'H NMR (300 MHz, CDCl 3 ) 8: 2.13 (s, 1H), 7.38 (s, 3H). c) 30 To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdCl 2 (PPh 3
)
2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester WO 01/55086 PCT/DKO1/00057 70 (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 500C, whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3x20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic 5 acid ethyl ester in 1.1 g yield. 'H NMR (300 MHz, CDC 3 ) 8:1.32 (t, 3H), 4.22 (q, 2H), 6.32 (d, 1H, J= 16 Hz), 6.92 (d, 1H, J = 16 Hz), 7.37 (s, 3H). d) 10 To a solution of diisobutylaluminium hydride (1.0 M solution in toluene, 20 mL, 20 mmol) at 78 *C was slowly added (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester (1.1 g, 4.08 mmol). The reaction mixture was stirred for 2 h at -78 0C, where after the reaction mix ture was poured into hydrocloride acid (6N, 50mL ) and extracted with diethyl ether (3X40 mL) The combined and dried organic phases were evaporated to give crude (E)-5-(3,5 15 dichloro-phenyl)-pent-2-en-4-yn-1-o in 750 mg yield. 1 H NMR (300 MHz, CDCl 3 ) 5: 4.3 (dd, 2H), 5.95 (dt, 1H,J= 5 and 16 Hz), 6.4 (dt, IH, J =5and16 Hz), 7.30 (s, 3H). e) 20 The title compound was prepared from (E)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-o (454 mg, 2 mmol) using the conditions described in example 7d. Yield 125 mg yield. 1 H NMR (300 MHz, CDC1 3 ) 5: 1.14 (t, 3H), 1.22 (t, 3H), 2.95 (d, 2H), 3.30-3.42 (m, IH), 3.55 3.67 (m, 1H), 3.95 (t, 1H), 4.16 (q, 2H), 4.6 (dd, 2H, J = 1.5 and5 Hz), 6.05 (dt, IH, J = 1.5and 16 Hz), 6.35 (dt, IH, J= Sand 16 Hz), 6.83 (d, 2H), 7.15 (d, 2H), 7.36 (m, 3H). 25 EXAMPLE 20 ci o 0oOH 0 ci 30 (E)-(S)-2-Ethoxy-3-{4-(5-(3,5-dichloro-pheny)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid WO 01/55086 PCT/DKO1/00057 71 Ethyl (E)-(S)-2-ethoxy-3-(4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate was hydrolysed as described in Example 2 to give the title compound. 'H NMR (300 MHz, CDCl 3 ) 5: 1.19 (t, 3H), 2.88-3.12 (m, 2 H), 3.37-3.50 (m, 1H), 3.65- 3.70 5 (m, 1 H), 4.05 (m, 1 H), 4.70 (dd, 2H, J = 1.5 and 5 Hz), 6.1 (dt, 1 H, J = 1.5 and 16 Hz), 6.45 (dt, 1H, J = 5 and 16 Hz), 6.85 (d, 2H), 7.18 (d, 2H), 7.30 (s, 3H). EXAMPLE 21 10 ci ci Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate 15 a) (Z)-5-(3,5-Dichloro-phenyl)-pent-2-en-4-ynoic acid ethyl ester was made from cis-3-iodo acrylic acid ethyl ester (Can J Chem, 72 (8), 1816-1819, 1994). (4 g) using the conditions described in example 19 c. Yield 4.62 g. 20 'H NMR (300 MHz, CDCI 3 ) S: 1.4 (t, 3H), 4.3 (q, 2H), 6.2 (d, 1H, J= 11 Hz), 6.34 (d, 1H, J= 11 Hz), 7.32 (s, 1 H) 7.4 (s, 2H). b) (Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-o was made from (Z)-5-(3,5-dichloro-phenyl) 25 pent-2-en-4-ynoic acid ethyl ester (4.6 g) using the conditions described in example 19 d. Yield 3.63 g. 'H NMR (300 MHz, CDCl 3 ) 5: 4.4 (dd, 2H, J = 1.5 and 6.5 Hz), 5.75 (dt, 1 H, J =1.5 and 11 Hz), 6.21 (dt, 1H, J= 6.5 and 11 Hz), 7.3 (s, 3H). 30 c) WO 01/55086 PCT/DKO1/00057 72 The title compound was from (Z)-5-(3,5-dichloro-phenyl)-pent-2-en-4-yn-1-o (300 mg, 1.32 mmol) using the conditions described in example 19 e. Yield 180 mg yield. 'H NMR (300 MHz, CDC1 3 ) 5: 1.12 (t, 3H), 1.2 (t, 3H), 2.9 (d, 2H), 3.26-3.44 (m, 1H), 3.51 3.69 (m, 1 H), 3.94 (t, I H), 4.14 (q, 2H), 4.85 (dd, 2H, J = 1.8 and 6.3 Hz), 5.87 (dt, 1 H, J = 5 1.8 and 11 Hz), 6.25 (dt, IH, J= 6.3 and 11 Hz), 6.82 (d, 2H), 7.15 (d, 2H), 7.33 (m, 3H). EXAMPLE 22 ci 0 OH 10 ci (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid 15 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate was hydrolysed as described in Example 2 to give the title compound. Yield 100 Mg. 1H NMR (300 MHz, DMSO-D 6 ) 5: 1.16 (t, 3H), 2.85-3.05 (m, 2H), 3.3-3.45 (m, 1H), 3.6-3.7 (m, 1H), 4.06 (m, 1H), 4.9 (dd, 2H, J = 1.8 and 6.2 Hz), 6.1 (dt, 1H, J = 1.8 and 11 Hz), 6.45 20 (dt, 1H, J = 6.2 and 11 Hz), 6.93 (d, 2H), 7.20 (d, 2H), 7.65 (d, 2H), 7.71 (d,1H).
WO 01/55086 PCT/DKO1/00057 73 EXAMPLE 23 0 0 5 (Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester a) (Z)-5-phenyl-pent-2-en-4-ynoic acid ethyl ester was made from cis-3-iodo acrylic acid ethyl ester (2 g) and phenylacetylene using the conditions described in example 19 c. Yield 1.24 g. 10 1 H NMR (300 MHz, CDC1 3 ) 6: 1.3 (t, 3H), 4.25 (q, 2H), 6.12 (d, 1H, Jr, = 11.3 Hz), 6.35 (d, I H, Je;2 = 11.3 Hz), 7.36 (m, 3H) 7.53 (m, 2H). b) (Z)-5-phenyl-pent-2-en-4-yn-1 -ol was made from (Z)-5-phenyl-pent-2-en-4-ynoic acid ethyl 15 ester (1.0 g) using the conditions described in example 19 d. Yield 0.7 g. 'H NMR (300 MHz, CDCl 3 ) 8: 4.5 (dd, 2H, J = 1.5 and 6.5 Hz), 5.80 (dt, IH, J=1.5 and 10.5 Hz), 6.14 (dt, 1H, J = 6.4 and 10.5 Hz), 7.31 (m, 3H), 7.43 (m, 2H). c) 20 The title compound was prepared from (Z)-5-phenyl-pent-2-en-4-yn-1-ol (200 mg, 1.3 mmol) using the conditions described in example 19 e. Yield 380 mg. 'H NMR (300 MHz, CDC1 3 ) 8: 1.2 (dt, 6H), 2.98 (d, 2H), 3.3-3.41 (m, 1H), 3.53-3.68 (m, 1H), 3.95 (t, 1H), 4.18 (q, 2H), 4.9 (dd, 2H, J = 1.6 and 6.4 Hz), 5.95 (dt, IH, J= 1.6 and 11 Hz), 6.2 (dt, 1H, J= 6.4 and 11 Hz), 6.89 (d, 2H), 7.17 (d, 2H), 7.35 (m, 3H) ), 7.47 (m, 2H). 25 WO 01/55086 PCT/DKO1/00057 74 EXAMPLE 24 0OH 0 5 (Z)-(S)-2-Ethoxy-3-[4-(5-pheny-pent-2-en-4-ynyloxy)-phenyl]-propionic acid Ethyl (Z)-(S)-2-ethoxy-3-[4-(phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionate was hydrolysed as described in Example 2 to give the title compound. Yield 264 mg. 1 H NMR (300 MHz,
DMSO-D
6 ) 5: 1.15 (t, 3H), 2.8-3.0 (m, 2H), 3.3-3.4 (m, 1H), 3.5-3.65 (m, 1H), 3.96 (m, 1H), 10 4.89 (dd, 2H, J = 1.6 and 6.3 Hz), 6.08 (dt, 1H, J = 1.6 and 11 Hz), 6.3 (dt, 1H, J =6.3 and 11 Hz), 6.9 (d, 2H), 7.20 (d, 2H), 7.4 (m, 3H), 7.5 (m, 2H). EXAMPLE 25 15 H H 0 0 0 (E)-(RS)-2-Ethoxy-3-[3-(5-pheny-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester 20 a) NaH 60% in paraffin oil (1.1 8g, 29.5 mmol) was added to a solution of diethoxy-phosphoryl ethoxy-ethylacetate (7.46g, 27.8mmol)) in dry THF (40 mL) at 0 *C. 3 Benzyloxybenzaldehyde (ALDRICH) (5,0 g, 23.6 mmol) dissolved in dry THF (20 mL) was added dropwise keeping the temperature below 10 *C. The reaction mixture was allowed to 25 reach room temperature followed by the addition of water. The product was extracted into WO 01/55086 PCT/DKO1/00057 75 MTBE, and the combined organic phases dried (Na 2 SO4), filtered and evaporated to give 7.6 g (99%) of (EZ)-3-(3-benzyoxyphenyl)-2-ethoxyacrylic acid ethyl ester as a yellow oil. 'H NMR (CDC 3 , 400 MHz) 8: 1.09 (t), 1.34 (t), 1.37 (t), 3.92 (q), 3.98 (q), 4.12 (q), 4.30 (q), 5.04 (s), 5.09 (s), 6.95 (s), 7.26 (s), 7.2-7.5 (m). 5 b) (E,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 10 to be completed by HPLC. The reaction mixture was filtered through a pad of celite and the solvent evaporated. The product was purified by column chromatography eluting with ethyl acetate/heptane 1:2 to give 3.1 g (62%) of (RS)-2-ethoxy-3-hydroxyphenyl)propanoic acid ethyl ester. 1 H NMR (CDC1 3 , 400 MHz) 5: 1.16 (t, 3H), 1.23 (t, 3H), 2.97-2.95 (m, 2H), 3.41- 3.33 (dq, 15 1H), 3.65-3.57 (dq, 1H), 4.02(t, IH), 4.17 (q, 2H), 5.33 (s, 1H), 6.81- 6.70 (m, 3H), 7.15 (t, IH). ' 3 C-NMR (75 MHz, CDC1 3 ) S 14.51, 15.36, 39,58, 61,48, 66,74, 80.52, 114.15, 116.87, 121.79, 129.81, 139.07, 156.20, 173.27. MS m/z (MH*) 239.2. Elemental analysis: Anal. Calcd. for C 13
H
18 0 4 : C, 65.53; H, 7.61 %. Found: C, 65.98; H, 7.96. 20 c) The title compound (120 mg, 63%) was prepared from (R,S)-2-ethoxy-3-(3 hydroxypheny)propanoic acid ethyl ester (120 mg, 0.5 mmol) and (E)-5-phenyl-pent-2-en-4 yn-1-ol (example 1, method 1b)(79 mg, 0.5 mmol), by a procedure analogous to that de scribed in example 1 (method Ic). 25

Claims (80)

1. A compound of formula (1) 5 X Y R z CH2) 1 O R2 (Q)m Ar OR 4 OR 3 10 wherein X is hydrogen or X is C 1 2 -alkyl, C2 1 2 -alkenyl, C 2 . 1 2 -alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocy clyl each of which is optionally substituted with one or more substituents selected from halo gen, perhalomethyl, hydroxy, C-alkyl, C 2 -alkenyl, C 2 -alkynyl, hydroxy, C-alkoxy, C 1 alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroary 15 loxy, heteroaralkoxy, C-alkylthio, cyano, amino, C-alkylamino, C-dialkylamino, carboxy or C-alkylester; and Y is hydrogen or Y is CI- 1 2 -alkyl, C 2 - 1 2 -alkenyl, C 2 - 1 2 -alkynyl, C4 1 2 -alkenynyl, aryl, heteroaryl, aralkyl or het 20 eroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C 1 w alkylester; and WO 01/55086 PCT/DKO1/00057 77 Z is hydrogen, halogen, hydroxy or Z is C 1 -- alkyl or C-alkoxy each of which is optionally substituted with one or more substitu ents selected from C-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and 5 Q is 0, S or NR 5 , wherein R 5 is hydrogen, C-alkyl, C 2 -6-alkenyl, C 2 -alkynyl, C4-alkenynyl, aralkyl or heteroaralkyl and wherein R 5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1 .-- alkoxy, amino or carboxy; and Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally 10 substituted with one or more substituents selected from C-alkyl, aryl or C-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C 1 .-- alkylester; and R 1 is hydrogen, hydroxy or halogen; or R, forms a bond together with R 2 ; and R 2 is hydrogen or C 1 -alkyl; or R 2 forms a bond together with R 1 ; and 15 R 3 is hydrogen, C-alkyl, C 2 -e-alkenyl, C 2 - 4 -alkynyl, C4-alkenynyl, aryl, aralkyl, C alkoxyC 1 .e-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, car boxy or C 1 .-alkylester; and, 20 R4 is hydrogen, C 1 .e-alkyl, C 2 -e-alkenyl, C 2 -e-alkynyl, C4-alkenynyl or aryl; n is an integer ranging from 0 to 3; and 25 m is an integer ranging from 0 to 1; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a race mic mixture, or polymorphs. 30
2. A compound according to claim 1 of formula (1) WO 01/55086 PCT/DKO1/00057 78 X Y R RR (Q)m -Ar OR4 OR 3 5 wherein X is hydrogen or X is C 1 12 -alkyl, C 2 - 12 -alkenyl, C 2 - 12 -alkynyl, aryl, heteroaryl, aralky, heteroaralkyl or heterocy clyl each of which is optionally substituted with one or more substituents selected from halo gen, perhalomethyl, hydroxy, C 1 -alkyl, C 2 e-alkenyl, C 2 e-alkynyl, hydroxy, C 1 -alkoxy, C 1 alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroary 10 loxy, heteroaralkoxy, C 1 -alkylthio, cyano, amino, C 1 -alkylamino, C 1 -dialkylamino, carboxy or C 1 -alkylester; and Y is hydrogen or Y is C 112 -alkyl, C 2 - 12 -alkenyl, C 2 . 12 -alkynyl, C4 12 -alkenynyl, aryl, heteroaryl, aralkyl or het 15 eroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C 1 -alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C 1 , alkylester; and Z is hydrogen, halogen, hydroxy or 20 Z is C 1 -alkyl or C 1 -alkoxy each of which is optionally substituted with one or more substitu ents selected from C 1 -alkoxy, halogen, hydroxy, carboxy, amino or cyano; and WO 01/55086 PCT/DKO1/00057 79 Q is 0, S or NR 5 , wherein R 5 is hydrogen, C 1 . 6 -alkyl, C 2 -6-alkenyl, C 2 -6-alkynyl, C4.e-alkenynyl, aralkyl or heteroaralkyl and wherein Rq is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1 .e-alkoxy, amino or carboxy; and 5 Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C 1 .-- alkyl, aryl or C 1 .e-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C-alkylester; and R 1 is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and 10 R 2 is hydrogen or C 1 .e-alkyl; or R 2 forms a bond together with R 1 ; and R 3 is hydrogen, C 1 .e-alkyl, C 2 -6-alkenyl, C 2 -6-alkynyl, C4-alkenynyl, aryl, aralkyl, C 1 . alkoxyC 1 .e-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, car 15 boxy or C 1 .ealkylester; and R 4 is hydrogen, C 1 .e-alkyl, C 2 -6-alkenyl, C 2 -e-alkynyl, C4-alkenynyl or aryl; n is an integer ranging from I to 3; and 20 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 25 racemic mixture, or polymorphs.
3. A compound according to any one of the preceding claims of formula (1) WO 01/55086 PCT/DKO1/00057 80 X Y R (Q)m-Ar OR 4 OR 3 5 wherein X is hydrogen, C 1 . 12 -alkyl, C 2 -1 2 alkenyl, C 2 -1 2 -alkynyl, aryl, heteroaryl, aralkyl, het eroaralkyl or heterocyclyl optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C 1 .e-alkyl, C 2 -6-alkenyl, C 2 a6-alkynyl, hydroxy, C 1 .e-alkoxy, C 1 .--alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, het eroaryloxy, heteroaralkoxy, C 1 .e-alkylthio, cyano, amino, C 1 .e-alkylamino, C 1 .-- dialkylamino, 10 carboxy or C 1 .- alkylester; and Y is hydrogen, C 1 . 12 -alkyl, C 212 -alkenyl, C 2 -1 2 -alkynyl, C4-1 2 -alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted with one or more substituents selected from halogen, C 1 .e-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C 1 .6-alkylester; and 15 Z is hydrogen, halogen, hydroxy, C 1 .- alkyl or C 1 .6-alkoxy optionally substituted with one or more substituents selected from C 1 .e-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and Q is 0, S or NR 5 , wherein Rs is hydrogen, C 1 .6-alkyl, C 2 -6-alkenyl, C 2 -6-alkynyl, C4-alkenynyl, 20 aralkyl or heteroaralkyl and wherein R 5 is optionally substituted with one or more substituents selected from halogen, hydroxy, C 1 .6-alkoxy, amino or carboxy; and WO 01/55086 PCT/DKO1/00057 81 Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C 1 -alkyl, aryl or C-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C-alkylester; and R, is hydrogen, hydroxy or halogen; or R 1 forms a bond together with R 2 ; and 5 R 2 is hydrogen or C 1 -alkyl; or R 2 forms a bond together with R 1 ; and R 3 is hydrogen, C 1 -alkyl, C 2 -alkenyl, C 2 -alkynyl, Cw-alkenynyl, aryl, aralkyl, Cw alkoxyC-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted 10 with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, car boxy or C-alkylester; and R 4 is hydrogen, C 1 -alkyl, C 2 -alkenyl, C 2 -alkynyl, C"-alkenynyl or aryl; 15 n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 1; or a pharmaceutically acceptable salt.thereof, or a pharmaceutically acceptable solvate 20 thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a race mic mixture, or polymorphs.
4. A compound according to any one of the preceding claims wherein X is aryl, heteroaryl or heterocyclyl optionally substituted with one or more substituents selected from halogen, per 25 halomethyl, C 1 -alkoxy, C-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy.
5. A compound according to any one of the preceding claims wherein X is aryl, heteroaryl or heterocyclyl each of which is optionally substituted with one or more substituents selected 30 from halogen, perhalomethyl, C-alkoxy, C-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy. WO 01/55086 PCT/DKO1/00057 82
6. A compound according to any one of the preceding claims wherein X is aryl optionally substituted with one or more substituents selected from halogen, perhalomethyl, C-alkoxy, C-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy or heteroaralkoxy. 5
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 or perhalomethyl.
8. A compound according to any one of the preceding claims wherein X is phenyl optionally substituted with one or more substituents selected from halogen. 10
9. A compound according to any one bf the preceding claims wherein X is phenyl.
10. A compound according to any one of the preceding claims wherein X is heteroaryl op tionally substituted with one or more substituents selected from halogen, perhalomethyl, C alkoxy, C-alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, het eroaryloxy or heteroaralkoxy. 15
11. A compound according to any one of the preceding claims wherein X is heterocyclyl op tionally substituted with one or more substituents selected from halogen, perhalomethyl, C 1 w alkoxy, C 6 -alkylthio, aryl, aryloxy, arylthio, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, het eroaryloxy or heteroaralkoxy.
12. A compound according to any one of the preceding claims wherein Y is hydrogen, C 1 12 20 alkyl or aryl.
13. A compound according to any one of the preceding claims wherein Y is hydrogen or methyl.
14. A compound according to any one of the preceding claims wherein Y is hydrogen. 25
15. A compound according to any one of the preceding claims wherein Z is hydrogen or C alkoxy.
16. A compound according to any one of the preceding claims wherein Z is hydrogen. WO 01/55086 PCT/DKO1/00057 83
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 wherein Ar is arylene option ally substituted with one or more substituents selected from C-alkyl or C 1 .-- alkoxy each of 5 which can be optionally substituted with carboxy.
19. 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 wherein R 1 is hydrogen or R 1 10 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 15 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-alkyl. 20
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. 25
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 30 ethyl.
30. A compound according to any one of the preceding claims wherein alkenyl is vinyl or 1 propenyl. WO 01/55086 PCT/DKO1/00057 84
31. 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 pentene-4-yne. 5
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 10 naphthyl optionally substituted with halogen.
35. A compound according to any one of the preceding claims wherein arylene is phenylene.
36. A compound according to any one of the preceding claims wherein halogen is chlorine. 15
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, 20 pyrrole, pyridine, indole or benzofuran.
39. A compound according to any one of the preceding claims wherein heteroarylene is furan, pyrrole, pyridine, indole or benzofuran. 25
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 aralkoxy is benzyloxy. 30
43. A compound according to any one of the preceding claims wherein n is an integer ranging from 1 to 3 and m is 1. WO 01/55086 PCT/DKO1/00057 85
44. A compound according to any of the preceding claims wherein the substituents Z and Y are arranged in a trans-configuration.
45. A compound according to any of the preceding claims wherein the substituents Z and Y are arranged in a cis-configuration. 5
46. The compound according to claim 1, 2 or 3 which is (E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, (E)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, 10 (Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, (Z)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, (E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, 15 (E)-(S)-2-Ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-pheny]-propionic acid; or a pharmaceutically acceptable salt thereof.
47. The compound according to claim 1, 2 or 3 which is 20 Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid, 25 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid, Ethyl (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) 30 phenyl]-propionate, (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid, WO 01/55086 PCT/DKO1/00057 86 Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy) phenyl]-propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid; 5 or a pharmaceutically acceptable salt thereof.
48. The compound according to claim 1, 2 or 3 which is 10 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-methy-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-methy-5-(1 -naphthyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, Ethyl (E)-(S)-2-ethoxy-3-[4-(-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionate, 15 (E)-(S)-2-ethoxy-3-[4-(5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, Ethyl (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionate, (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-(3,5-dichloro-phenyl)-pent-2-en-4-ynyloxy)-phenyl] propionic acid; 20 or a pharmaceutically acceptable salt thereof.
49. The compound according to claim 1, 2 or 3 which is 25 (Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester, (Z)-(S)-2-Ethoxy-3-[4-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid, (E)-(RS)-2-Ethoxy-3-[3-(5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester; or a pharmaceutically acceptable salt thereof. 30
50. The compound according to claim 1, 2 or 3 which is (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, WO 01/55086 PCT/DKOI/00057 87 (E)-(S)-3-{4-[5-(1 , 3Diiodo-phenyl)-pent-2-en-4-yloxy-phel-2-ethoxy-propioflic acid, (E)-(S)-3-(4-[5-(1 ,3-Bis-trifluoromethy-phel)-pet-2-e-4-yloxyiJ-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-D imethoxy-pheny)-pent-2-e-4-yloxy-phel-2-ethoxy-prop ioic acid, 5 (E)-(S)-3-{4-[5-(1 ,3-Diethoxy-pheny)-pent-2-en-4-yyloxyI-phel-2-ethoxy-propoflic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-pheyi)-pet-2-e-4-yloxy1-phel-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phel)-pet-2-e-4-Ylyioxy]-phel-2-ethoxy prop ionic acid, 10 (E-S--4[-35Dfur-hnl-et2e--nlx]pey}2ehx-rpoi acid, (E-S--4[-35Dboopey)pn-2e--nlx]pey}2ehx-rpoi acid, (E-S--4[-35Did-hnl-eh-2e--nlx]peyl2ehx-rpoi acid, (E-S--4[-35Bstilooehlpey)pn--n4yyoy-hnl--toy propionic acid, 15 (E)-(S)-3-{4-[5-(3, 5-Dimethoxy-pheny)-pent-2-e-4-yflyloxy-phel}-2-ethoxy-propioflic adid, (E-S--4(-35,itoypey)pn-2e--nlx]pey)2ehx-rpoi acid, (E-S--4[-35Bs(,,-rfurmtoy-hnl-et2e--nlx]pey}2 ethoxy-propionic acid, (E-S--4[-35Bs(,,-rfurehx)pey)pn--n4yyoy-hnl--toy 20 propionic acid, (E)-(S)-3-{4-[5-(1I,3-Difluoro-pheny)-3-methy-pent-2-en-4-yloxy]-phel-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1I,3-Dibromo-pheny)-3-methy-pent-2-e-4-ylyioxyI-phel-2-ethoxy propionic acid, 25 (E)-(S)-3-{4-[5-(1I,3-Diiodo-pheny)-3-methy-pet-2-en-4-yloxy-phel}-2-ethoxy-propioflic acid, (E)-(S)-3-{4-[5-(I ,3-Bis-trifluoromethyl-phenyl)-3-lethyl-pet-2-e-4-yloxy]-phel-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-( 1,3-Dimethoxy-pheny)-pent-2-e-4-yyixy-phel-3-methyI-2-ethoxy 30 propionic acid, (E)-(S)-3-{4-(5-(1 ,3-Diethoxy-phenyl)-3-methy-pet-2-e-4-yloxy]-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-nlethyI pent-2-en-4-ynyloxyl phenyl}-2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 88 (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-(5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, 5 (E)-(S)-3-{4-{5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-{5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2 10 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, 15 (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-pheny1)-3-methyl-pent-2-en-4-ynyloxy] phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-(5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-{5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy 20 propionic acid, (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyIoxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-pheny)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyoxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-(5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy 30 propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-(5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl} 2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 89 (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy 10 propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 20 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-3-methyl-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-chloro-phenyl}- 2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyioxy]-3 30 chloro-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 90 (E)-(S)-3-{4-[5-(3 ,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxyl-3-chloro-phel}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-pheny)-3-methy-pent-2-e-4-yyloxy]-3-chloro-phenl}-2-ethoxy propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phelyl)-3-methy-pet-2-e-4-yyIOXy]-3-choro phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-yloxyl-3-chloro-phel-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-el-4-ynyoxy-3-choro-phenyl-2 10 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,-trifluoromlethoxy)-phel)-3-ethyl-pet-2-e-4-yfloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3, 5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-yloxy-3 chloro-phenyl}-2-ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phel}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1I,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]J-3-bromo-pheny}-2-ethoxy-propionic 20 acid, (E)-(S)-3-{4-[5-(I ,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phelyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dimethoxy-phenyl)-pent-2-en-4-ynyioxy]-3-bromo-phenyl}-2-ethoxy propionic acid, 25 (E)-(S)-3-{4-[5-( 1, 3-Diethoxy-phenyl)-pent-2-en-4-ynyloxyl-3-bromo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-pheny-pelt-2-en-4-yloxy]-3-bromlo phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-(5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pet-2-e-4-yloxy-3-bromo-phel} 30 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3 ,5-Difluoro-phenyf)-pent-2-en-4-ynyloxy]-3-bromo-phelyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Dibromo-pheny)-pent-2-en-4-yyoxy]-3-brom-phel}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 91 (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionic acid, (E)-(.S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-. ethoxy-propionic acid, 5 (E)-(S)-3-{4-(5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-(5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-(5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo 10 phenyll-2-ethoxy-propionic acid, (E)-(S)-3-{4-E5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyoxy]-3-bromo-phenyl.. 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy)-3-bromo-pheny}-2 ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-(1 ,3-Dibromo-phenyl)-3-methyi-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-E5-(1I,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl)-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo 20 phenyl)-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl)-3-methyl-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-pheny)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyf}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 30 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3, 5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 92 (E)-(S)-3-{4-(5-(3,5-Bis-trifluoromethyl-pheny)-3-methyl-pent-2-en-4-ynyloxyj-3-bromo phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-pheny}-2 ethoxy-propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Diethoxy-phenyI)-3-methyI-pent-2-en-4-ynyloxy]-3-bromo-phenyI}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyi)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 10 bromo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyl)-pe nt-2-en-4-ynyloxyl-3-iodo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-pheny}-2-ethoxy-propionic acid, 15 (E)-(S)-3-{4-[5-(1 ,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1I,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-( 1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy 20 propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyoxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Difluoro-pheny9)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (E)-(S)-3-(4-(5-(3,5-Dibromo-pheny)-pent-2-en-4-ynyloxy1-3-iodo-phenyl1-2-ethoxy-proponic 30 acid, (E)-(S)..3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyI}-2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyI-pheny1)-pent-2-en-4-gny~oxy-3-iodo-phenyi}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 93 (E-S--4(-35Dmtoypey)pnt2e--nlx]3id-hnl--toy propionic acid, (E)-(S)-3-{4-[5-(3,5-Diethoxy-phel)-pet-2-e-4-yylYoxyI-3-iodo-phel-2-ethoxy-propioflic acid, 5 (E-S--4[-35Bs(,,-rfurmtoy)pey)pn--n4yyoy--oopey} 2-ethoxy-propionic acid, (E-S--4[-35Bs(,,-rfurehx)pey)pn--n4yyoy--oopey}2 ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Difluoro-pheny)-3-methy-pet-2-e-4-yyoxy]-3-iodo-phelyi}-2-ethoxy 10 propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dibromo-pheny)-3-methy-pent-2-e-4-yloxy]-3-iodo-phel-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Diiodo-pheny)-3-methy-pent-2-e-4-ynyoxyI-3-iodo-phel}-2-ethoxy propionic acid, 15 (E)-(S)-3-{4-15-(1 ,3-Bis-trifluoromethy-phenyl-3-methy-pet-2-e-4-yloxyI-3-iodo-phel} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(1 ,3-Dimethoxy-pheny)-pent-2-e-4-yloxy]-3-iodo-phel-3-mlethyI-2 ethoxy-propionic acid,, (E)-(S)-3-{4-[5-(1 ,3-Diethoxy-pheny)-3-methy-pet-2-e-4-yloxy]-3-iodo-phel-2-ethoxy 20 propionic acid, (E)-(S)-3-{4-[5-(1I,3-Bis-(2,2,2-trifluoromethoxy)-phel)-3-ethy-pet-2-e-4-yfloxy]-3 iodo-phenyl)-2-ethoxy-propioflic acid, (E)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-pheny)-3-nethy-pet-2-e-4-yloxy]-3-iodo phenyl}-2-ethoxy-propionic acid, 25 (E)-(S)-3-{4-[5-(3 ,5-Difluoro-phel)-3-methy-pelt-2-e-4-yloxyI-3-iodo-phel}-2-ethoxy propionic acid, (E-S--4[-35Dboopey)3mty-et2e--nlx]3id-hnl--toy propionic acid, (E-S--4[-35Did-hnl--ehlpet2e--nlx]3id-hnl--toy 30 propionic acid, (E-S--4(-35Bstilooehlpey)--ehlpn--n4yyoy--oopey} 2-ethoxy-propionic acid, (E)-(S)-3-{4-[5-(3 ,5-Dimethoxy-pheny)-3-methy-pet-2-e-4-yloxy1-3-iodo-pheli}-2 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 94 (E)-(S)-3-{4-[5-(3,5-Diethoxy-pheny)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 iodo-phenyl}-2-ethoxy-propionic acid, 5 (E)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo phenyl}-2-ethoxy-propionic acid; or a pharmaceutically acceptable salt thereof. 10
51. The compound according to claim 1, 2 or 3 which is (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-p-ent-2-en-4-ynyloxy]-pheny}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2 20 ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy-propionic acid, 30 (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-phenyl}-2-ethoxy propionic acid, WO 01/55086 PCT/DKO1/00057 95 (Z)-(S)-3-{4-15-(1 ,3-Difluoro-phenyl)-3-methy-pet-2-e-4-yloxy]-phel}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Dibromo-pheny)-3-methyl-pet-2-e-4-yflyioxyI-phel-2-ethoxy propionic. acid, 5 (Z)-(S)-3-{4-15-(1 ,3-Diiodo-pheny)-3-methy-pet-2-e-4-yloxyII-phel-2-ethoxy-propioflic acid,. (Z)-(S)-3-{4-[5-(1 ,3-Bis-trifluoromethy-pheny-3-methyI-pet-2-e-4-yloxy]-phel}- 2 ethoxy-propionic acid, (Z)-(S)-3-{4-E5-(1,3Dmtoypey)pn--n4ynlx]pey}3mty--toy 10 propionic acid, (Z)-(S)-3-{4-E5-( 1,3-Diethoxy-phel)-3-methy-pelt-2-e-4-yfyioxy1-phenl}-2ethoxy propionic acid, (Z)-(S)-3-{4-[5-( 1,3-Bis-(2,2,2-trifluoromethoxy)-phel)-3-mlethyI pent-2-en-4-ynyloxyl phenyi}-2-ethoxy-propioflic acid, 15 (Z)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phel)-3-methyk-pet-2-el4-yflYoxy1-phel} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3, 5-Difluoro-phenyl)-3-methy-pet-2-e-4-yfloxy]-phel2-ethoxy propionic acid,, (Z-S--4[-35Dboopey)3mthlpn--n4yyoy-hnl--toy 20 propionic acid, (Z-S--4[-35Did-hnl--ehlpet2e--nlxlpey}2ehx-rpoi acid, (Z-S--4[-35Bstilooehlpey)3mty-et2e--nlxlpey}2 ethoxy-propionic acid, 25 (Z-S--4(-35Dmtoypey)3mthlpn--n4yyoy-hnl--toy propionic acid, (Z-S--4[-35Dehx-hnl--ehlpn--n4yyoy-hnl--toy propionic acid, (Z-S--4[-35Bs(,,-rfurmthx)pey)3mty-et2e--nlx] 30 phenyl}-2-ethoxy-propionic acid, (Z-S--4[-35Bs(,,-rfurehx)pey)3mty-et2e--nlx]pey} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1,3Dfur-hnl en--n4yyoy--hlr-hnl--toy propionic, acid, WO 01/55086 PCT/DKO1/00057 96 (Z)-(S)-3-{4-[5-(1 ,3-Dibromo-phenyl)-pent-2-en-4-ynyloxyl-3-ch Ioro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phelyl}-2-ethoxy-propionic acid, 5 (Z)-(S)-3-{4-[5-(1 ,3-Bis-trifluoromethyl-pheny)-pent-2-en-4-ynyoxy]-3-chloro-phenyi}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-E5-(1 ,3-Dimethoxy-phenyl)-pent-2-en-4-yyloxyl-3-chloro-phelyl-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Diethoxy-phenyl)-pent-2-en-4-ynyoxyl-3-chloro-phelyl-2-ethoxy 10 propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy-3-chloro phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phenyD)-pent-2-en-4-yloxy]-3-chloro-phenyl} 2-ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Difluoro-pheny)-pent-2-en-4-ynyoxy]-3-choro-phel}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-pheny)-pent-2-en-4-ynyloxy]-3-choro-pheny}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diodo-phenyl)-pet-2-en-4-ynyloxy]-3-choro-phelyl-2-ethoxy-propioflic 20 acid, (Z-S--4[-35Bstilooehlpey)pn--n4yyoy--hoopey}2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyoxy]-3-choro-phel-2-ethoxy propionic acid, 25 (Z)-(S)-3-{4-(5-(3,5-Diethoxy-pheny)-pent-2-en-4-ynyoxy]-3-chloro-phel}-2-ethoxy propionic acid, (Z)-(S)-3-{4-(5-(3,5-Bis-(2,2,2-trifluoromethoxy)-pheny)-pent-2-en-4-yyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-(4-(5-(3,5-Bis-(2,2,2-trifluoroethoxy)-pheny)-pent-2-e-4-yloxy-3-chloro-pheyl} 30 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-chloro-phelyl-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyoxyl-3-choro-phely(}-2 ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 97 (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro phenyl}-2-ethoxy-propionic acid, 5 (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-chloro-phenyi}-3-methyl-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]- 3 10 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro 20 phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-chloro-phenyl}-2 ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 chloro-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy 30 propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 98 (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, 5 (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-pent-2-en-4-ynyIoxy]-3-bromo-phenyI}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyioxy]-3-bromo phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-peq-2-en-4-ynyloxy]-3-bromo-phenyi} 10 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy)-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy 20 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}- 2 30 ethoxy-propionic acid, (Z)-(S)-3-{4-5-(1,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, WO 01/55086 PCT/DKO1/00057 99 (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-3-methyl-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, 5 (Z)-(S)-3-{4-(5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyoxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methy-pent-2-en-4-ynyoxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 10 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2-ethoxy propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-pheny}-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-bromo-phenyl}-2 20 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3 bromo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifiuoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 bromo-phenyl}-2-ethoxy-propionic acid, 25 (Z)-(S)-3-{4-[5-(1,3-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dibromo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1,3-Diiodo-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic 30 acid, (Z)-(S)-3-{4-[5-(1,3-Bis-trifluoromethyl-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, I WO 01/55086 PCT/DKO1/00057 100 (Z)-(S)-3-{4-[5-(1 ,3-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1 ,3-Bis-(2,2,2-trifluoromethoxy)-phenyi)-pent-2-en-4-ynyloxy-3-iodo-pheny} 2-ethoxy-propionic acid, 5 (Z)-(S)-3-{4-[5-(1 ,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyoxy-3-iodo-phenyl-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Difluoro-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-pheny}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyI)-pent-2-en-4-ynytoxy]-3-iodo-pheny}-2-ethoxy-propionic 10 acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyI)-pent-2-en-4-ynyloxy]-3-iodo-pheny1}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyD)-pent-2-en-4-ynyloxy]-3-iodo-pheny}-2-ethoxy propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-pheny}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-pheny)-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 20 2-ethoxy-propionic acid,, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl-2 ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Difluoro-phenyf)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, 25 (Z)-(S)-3-{4-[5-( 1,3-Dibromo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl)-2-ethoxy propionic acid, (Z)-(S)-3-{4-(5-(1 ,3-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxyj-3-iodo-phenyl} 30 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(1 ,3-Dimethoxy-phenyl)-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-3-methyl-2 ethoxy-propionic acid,, (Z)-(S)-3-{4-[5-(1 ,3-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-iodo-phenyl}-2-ethoxy propionic acid,I WO 01/55086 PCT/DKO1/00057 101 (Z)-(S)-3-{4-[5-(1,3-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-(5-(1,3-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy-3-iodo phenyl}-2-ethoxy-propionic acid, 5 (Z)-(S)-3-{4-(5-(3,5-Difluoro-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dibromo-phenyl)-3-methyi-pent-2-en-4-ynyioxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Diiodo-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy 10 propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl} 2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Dimethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2 ethoxy-propionic acid, 15 (Z)-(S)-3-{4-[5-(3,5-Diethoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo-phenyl}-2-ethoxy propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoromethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3 iodo-phenyl}-2-ethoxy-propionic acid, (Z)-(S)-3-{4-[5-(3,5-Bis-(2,2,2-trifluoroethoxy)-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-3-iodo 20 phenyl}-2-ethoxy-propionic acid; or a pharmaceutically acceptable salt thereof.
52. A pharmaceutical composition comprising, as an active ingredient, a compound 25 according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
53. A composition according to claim 52 in unit dosage form, comprising from about 0.05 to about 100 mg, preferably from about 0.1 to about 50 mg of the compound according to any 30 one of the preceding compound claims or a pharmaceutically acceptable salt thereof.
54. A pharmaceutical composition useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR), the composition comprising, as an active ingredient, a compound according to any WO 01/55086 PCT/DKO1/00057 102 one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
55. A pharmaceutical composition useful in the treatment and/or prevention of diabetes 5 and/or obesity, the composition comprising, as an active ingredient, a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
56. A pharmaceutical composition according to any one of the claims 52-55 for oral, nasal, 10 transdermal, pulmonal, or parenteral administration.
57. A method for the treatment of ailnients, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a composition according 15 to any one of the preceding claims 52-56.
58. A method for the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR), the method comprising administering to a subject in need thereof an effective amount of a compound 20 according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a composition according to any one of the preceding claims 52-56.
59. A method for the treatment and/or prevention of diabetes and/or obesity, the method comprising administering to a subject in need thereof an effective amount of a compound 25 according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof, or of a composition according to any one of the preceding claims 52-56.
60. The method according to claims 57, 58 or 59 wherein the effective amount of the compound according to any one of the preceding compound claims or a pharmaceutically 30 acceptable salt or ester thereof is in the range of from about 0.05 to about 100 mg per day, preferably from about 0.1 to about 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 preparation of a medicament. WO 01/55086 PCT/DKO1/00057 103
62. Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament useful in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the 5 Peroxisome Proliferator-Activated Receptors (PPAR).
63. Use of a compound according to any one of the preceding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment and/or prevention of diabetes and/or obesity. 10
64. A process for the preparation of a compound of formula (I) which comprises reacting a compound of formula IV x Y z H2 OH 15 (IV) wherein X, Y, Z are as defined in claim 1 and t is 0-2 with a compound of formula V 20 R 1 O Ri H-(Q)m-Ar OR 4 OR 3 25 WO 01/55086 PCT/DKO1/00057 104 (V) wherein Q, Ar, R 1 , R 2 , R 3 , R 4 and m are as defined in claim 1, except that m is not 0, under 5 Mitsunobu conditions, using a reagent such as triphenylphosphine/diethylazodicarboxylate and the like to obtain a compound of formula I, wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R 4 , n and m are as defined in claim 1, except that R 4 is not H and n and m are not 0.
65. The process according to claim 64 wherein tributylphosphine and 1,1'-(azodicarbonyl) dipiperidine are used as coupling reagent and wherein either dry benzene or dry THF are 10 used as solvent.
66. A process for the preparation of a compound of formula (I) which comprises: a) converting the -OH functionality in a compound of formula IV X Y z H2 15 OH (IV) wherein X, Y, Z and t are as defined in claim 64 to an appropriate leaving group (L) such as 20 p-toluenesulfonate, methanesulfonate, halogen, triflate and the like, to give a compound of formula VI WO 01/55086 PCT/DKO1/00057 105 x z H2 L (VI) wherein 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 b) reacting a compound of formula VI x z H 2 )t L 10 (VI) wherein X, Y, Z and t are as defined in claim 64 and wherein L is a leaving group such as p toluenesulfonate, methanesulfonate, halogen, triflate and the like with a compound of formula V 15 WO 01/55086 PCT/DKO1/00057 106 R 1 o H-(Q);Ar OR 4 OR 3 (V) 5 wherein Q, Ar, R 1 , R 2 , R 3 , R 4 and m are as defined in claim 1, except that m is not 0, to give a compound of formula I wherein X, Y, Z, Q, Ar, R 1 , R 2 , R 3 , R4, n and m are as defined in claim 1 except that R4 is not H and n and m-are not 0.
67. The process as in claim 66 wherein L is chlorine and wherein the reagent used in step a) 10 are triethyl amine, dry dichloromethane and methanesulfonylchloride.
68. The process as in claim 66 wherein L is chlorine and wherein the reagent used in step b) is potassium carbonate, and sodium- or potassium iodide and wherein the solvent is acetone and wherein the reaction temperature is reflux. 15
69. A pharmaceutical composition suitable for treating type I diabetes, type I diabetes, im paired glucose tolerance, insulin resistance or obesity comprising a compound according to any of the claims 1 to 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 ac 20 ceptable carriers or diluents and an ACE (angiotensin converting enzyme) inhibitor.
70. The use of a compound according to any one of the claims I to 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 25 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 Il diabetes, impaired glucose tolerance, insulin resistance or obesity. WO 01/55086 PCT/DKO1/00057 107
71. A method of treating type I diabetes, type 11 diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 51 or a pharmaceutically 5 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 to said subject. 10
72. A pharmaceutical composition suitable for treating type I diabetes, type I diabetes, im paired glucose tolerance, insulin resistance or obesity comprising a compound according to any of the claims I to 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 ac 15 ceptable carriers or diluents and an agent stimulating insulin release from P cells such as a meglitinide, like repaglinide or senaglinide.
73. The use of a compound according to any one of the claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric 20 forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs together with one or more pharmaceutically acceptable carriers or diluents and an agent stimulating insulin release from p cells such as a meglitinide, like repaglinide or senaglinide, for the preparation of a medicament suitable for the treatment of type I diabetes, type Il diabetes, impaired glucose tolerance, insulin resistance or obesity. 25
74. A method of treating type I diabetes, type Il diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 51 and an agent stimulating insulin release from P cells such as a meglitinide, like repaglinide or senaglinide, to said 30 subject.
75. A pharmaceutical composition suitable for treating type I diabetes, type II diabetes, im paired glucose tolerance, insulin resistance or obesity comprising a compound according to any of the claims I to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutically WO 01/55086 PCT/DKO1/00057 108 acceptable solvate thereof, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs together with one or more pharmaceutically ac ceptable carriers or diluents and a biguanide like metformin. 5
76. The use of a compound according to any one of the claims 1 to 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, like metformin, for the preparation of a medicament suitable for the treatment of type I 10 diabetes, type 11 diabetes, impaired glucose tolerance, insulin resistance or obesity.
77. A method of treating type I diabetes, type I diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 51 or a pharmaceutically 15 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, like metformin, to: said subject. 20
78. A pharmaceutical composition suitable for treating type I diabetes, type II diabetes, im paired glucose tolerance, insulin resistance or obesity comprising a compound according to any of the claims 1 to 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 ac 25 ceptable carriers or diluents and a HMG CoA inhibitor.
79. The use of a compound according to any one of the claims 1 to 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 30 together with one or more pharmaceutically acceptable carriers or diluents and a HMG CoA inhibitor for the preparation of a medicament suitable for the treatment of type I diabetes, type I diabetes, impaired glucose tolerance, insulin resistance or obesity. WO 01/55086 PCT/DKO1/00057 109
80. A method of treating type I diabetes, type I diabetes, impaired glucose tolerance, insulin resistance or obesity comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or any tautomeric 5 forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs together with one or more pharmaceutically acceptable carriers or diluents and a HMG CoA inhibitor to said subject. 10
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