JP2002542218A - New compounds, their manufacture and use - Google Patents

Abstract

  (57) [Summary] The present invention relates to compounds of general formula (I). These compounds are useful in treating and / or preventing conditions mediated by nuclear receptors, particularly peroxisome proliferator-activated receptor (PPAR).

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to novel compounds, pharmaceutical compositions containing them, processes for preparing the compounds and their use as medicaments. More specifically, the compounds of the present invention can be used in the treatment and / or prevention of conditions mediated by nuclear receptors, particularly peroxisome proliferator-activated receptors (PPARs). BACKGROUND OF THE INVENTION Coronary artery disease (CAD) is a category of patients with type 2 diabetes and metabolic syndrome (ie, impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity "quartet of death"). Is the major cause in

[0002] Hypolipidemic fibrates and antidiabetic thiazolidinedione separately display moderately effective triglyceride-lowering activity, although they are often observed in patients with type 2 diabetes or metabolic syndrome. It is not sufficiently effective and ineffective to be the single treatment of choice for lipemia. Thiazolidinedione also effectively reduces circulating levels in animal models of type 2 diabetes and humans. However, fibrate class compounds have no beneficial effect on glycemia. In studies of the molecular actions of these compounds, thiazolidinedione and fibrate activate specific transcription factors of the peroxisome proliferator-activated receptor (PPAR) family and specific enzymes that are key players in regulating plasma triglyceride content And by increasing and decreasing the expression of apolipoproteins, respectively, to exert their activity. Fibrite, on the other hand, is a PPARα activator that acts primarily in the liver. Thiazolidinedione, on the other hand, is a PPARγ activator that acts primarily on adipose tissue.

[0003] Adipose tissue plays a major role in vertebrates in maintaining fat homeostasis and energy balance. Fat cells store energy in the form of triglycerides during nutrient influx and release energy in the form of free fatty acids upon nutrient depletion. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Most evidence points to a major role for PPARγ activation in initiating and regulating this cell differentiation. Some highly specialized proteins are induced during adipocyte differentiation, most of which are involved in fat storage and metabolism. The exact linkage from activation of PPARγ to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, remains unclear. A possible chain is through free fatty acids so that activation of PPARγ induces lipoprotein lipase (LPL), fatty acid transport protein (FATP) and acyl-CoA synthetase (ACS) in adipose tissue but not in muscle tissue . This, in turn, dramatically reduced the concentration of free fatty acids in plasma, and due to substrate competition at the cellular level, skeletal muscle and other tissues ultimately switched fatty acid oxidation to glucose oxidation at high metabolic rates,
Eventually, it reduces insulin resistance.

[0004] PPARα is involved in the stimulation of β-oxidation of fatty acids. In rodents, PPARα-mediated alterations in the expression of genes involved in fatty acid metabolism are associated with peroxisome proliferative phenomena,
Based on a pleiotropic cellular response, it is primarily restricted to the liver and kidney and may lead to liver cancer development in rodents. The phenomenon of peroxisome proliferation is not seen in humans. In addition to its role in peroxisomal proliferation in rodents, PP
ARα is also involved in controlling HDL cholesterol levels in rodents and humans. This effect is based, at least in part, on PPARα-mediated transcriptional regulation of the major HDL apolipoproteins, ApoA-I and ApoA-II. The hypotriglyceridemia effects of fibrates and fatty acids also involve PPARα and can be summarized as follows: (I) Lipolysis of remnant particles due to changes in lipoprotein lipase and apoC-III levels And increased clearance, (II) stimulation of cellular fatty acid absorption and subsequent conversion to acyl-CoA derivatives by induction of fatty acid binding proteins and acyl-CoA synthase, (III) induction of fatty acid oxidation pathways, (IV) fatty acid and Reduced triglyceride synthesis, and finally (V) V
Reduced LDL production. Therefore, both enhanced catabolism of triglyceride-rich particles as well as reduced VLDL particle secretion constitute a mechanism that contributes to the hypolipidemic effect of fibrates.

A number of compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (US Pat. No. 5,306,726, PCT Publication No. WO 9).
1/19702, WO 95/03038, WO 96/04260, WO 94/13650, WO 94/01420, WO
97/36579, WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313
And WO 99/16758). SUMMARY OF THE INVENTION Glucose lowering as a single approach does not overcome the macrovascular complications associated with type 2 diabetes and metabolic syndrome. Therefore, new treatments for type 2 diabetes and the metabolic syndrome must be aimed at reducing the apparent hypertriglyceridemia and reducing hyperglycemia associated with these syndromes.

[0006] The study of compounds that exert activation of PPARα and PPARγ in combination has led to the discovery of effective glucose and triglyceride-lowering drugs with great potential in the treatment of type 2 diabetes and metabolic syndrome And the clinical activity of thiazolidinedione (ie impaired glucose tolerance, insulin resistance, hypertriglyceridemia and / or obesity). Detailed Description of the Invention Accordingly, the present invention provides a compound of formula (I) or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or racemic mixture, For a mixture of isomers, or any tautomeric form:

[0007]

Embedded image

(Where A¹And A^TwoIs independently a 5- to 6-membered cyclic ring or a 9- to 10-membered bicyclic ring
And these may be optionally substituted by one or more of the following groups:
I: halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, and
Is C_1-12Alkyl, (C_3-6Cycloalkyl) C_1-6Alkyl, C_4-12Alkenyl,
C_2-12Alkenyl, C_2-12Alkynyl, C_1-12Alkoxy, aryl, arylo
Xy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl
, Heteroarylalkyl, heteroaryloxy, heteroarylalkoxy
Si, acyl, acyloxy, hydroxy C_1-12Alkyl, amino, acylamino
, C_1-12Alkyl-amino, C_1-6Dialkylamino, arylamino, aryl
Alkylamino, amino C_1-12Alkyl, C_1-12Alkoxycarbonyl, alkyl
Aminocarbonyl, aryloxycarbonyl, arylalkoxycarbonyl
, C_1-12Alkoxy C_1-12Alkyl, aryloxy C_1-12Alkyl, aryla
Lucoxy C_1-12Alkyl, arylthio, C_1-12Alkylthio, Thio C_1-12Archi
, C_1-12Alkoxycarbonylamino, aryloxycarbonylamino,
Reel alkoxycarbonylamino, -COR¹, Or -SO_TwoR^Two, Where R¹And R ^Two Are independently selected from the following groups: hydroxy, halogen, perhalo
Methyl, C_1-6Alkoxy or amino; said amino is one or more C_1-6A
Alkyl, perhalomethyl or aryl.
Is one or more halogen, perhalomethyl, hydroxy, nitro or
May be substituted with ano; Z is C, CR^ThreeAnd where R^ThreeIs hydrogen, halogen, perhalomethyl, C_1-12Archi
, C_4-12Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl, C_1-12Alkoxy
, Aryloxy, arylalkoxy, heteroaryloxy, heteroaryl
Alkoxy, acyl, acyloxy, hydroxy C_1-12Alkyl, C_1-12Arco
Kiss C_1-12Alkyl, aryloxy C_1-12Alkyl, arylalkoxy C_1-12
Alkyl, Thio C_1-12Alkyl, -COR^Four, Or -SO_TwoR¹¹And where R^FourAnd
And R¹¹Are independently selected from the following groups: hydroxy, halogen, per
Halomethyl, C_1-6Alkoxy or amino; said amino is one or more C_{1- 6} Alkyl, perhalomethyl or aryl,
Is one or more halogen, perhalomethyl, hydroxy, nitro or
May be substituted with cyano; Q is O, S, NR¹²And where R¹²Is hydrogen, perhalomethyl, C_1-12Alkyl, C _4-12 Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl, aryl, arylua
Alkyl, heterocyclyl, heteroaryl, heteroarylalkyl, acyl,
Hydroxy C_1-12Alkyl, amino C_1-12Alkyl, C_1-12Alkoxycarbonyl
, Aryloxycarbonyl, arylalkoxycarbonyl, C_1-12Alkoki
C_1-12Alkyl, aryloxy C_1-12Alkyl, arylalkoxy C_1-12A
Lucil, Thio C_1-12Alkyl, -COR¹³, Or -SO_TwoR¹⁴And where R¹³And
And R¹⁴Are independently selected from the following groups: hydroxy, perhalomethyl
, C_1-6Alkoxy or amino; said amino is one or more C_1-6Alkyl
, Perhalomethyl or aryl, wherein said aryl is one or more
Or more halogen, perhalomethyl, hydroxy, nitro or cyano
May be substituted;

[0009]

Embedded image

Represents a single bond or a double bond; Ar is an arylene, heteroarylene, or divalent heterocyclic group,
Each is one or more halogen, C_1-6Alkyl, amino, hydroxy, C_{1- 6} Optionally substituted with alkoxy or aryl; R^FiveIs hydrogen, hydroxy, halogen, C_1-12Alkoxy, C_1-12Alkyl, C_4-12
Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl or arylalkyl
Said arylalkyl is one or more of halogen, perhalomethyl,
Optionally substituted with droxy, nitro or cyano, or R^FiveIs R⁶And one
To form a bond; R⁶Is hydrogen, hydroxy, halogen, C_1-12Alkoxy, C_1-12Alkyl, C_4-12
Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl, acyl or arylal
Represents one or more halogen, perhalomethyl, hydroxy,
Optionally substituted with a nitro, cyano or cyano, or R⁶Is R^FiveCombined with
Form; M is OR⁷Where R⁷Is hydrogen, C_1-12Alkyl, C_4-12Alkenyl, C_2-12
Alkenyl, C_2-12Alkynyl, aryl, arylalkyl, C_1-12Alkoxy
C_1-12Alkyl, C_1-12Alkoxycarbonyl, aryloxycarbonyl, C_{1-1 Two} Alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl
Represents a lyi, heteroaryl or heteroarylalkyl group, wherein said group is
Is replaced by a further halogen, perhalomethyl, hydroxy, nitro or cyano.
Or M is COYR⁸Represents R⁸Is hydrogen, C_1-12Alkyl, C_4-12Alkenyl, C_2-12Alkenyl, C_2-12Al
Quinyl, aryl, arylalkyl, heterocyclyl, heteroaryl or
Represents a heteroarylalkyl group, said group comprising one or more halogen, per
Optionally substituted by halomethyl, hydroxy, nitro or cyano; Y is oxygen, sulfur or NR^TenWhere R^TenIs hydrogen, C_1-12Alkyl, Ally
, Hydroxy C_1-12Represents alkyl or arylalkyl, or Y is NR ^Ten , Then R⁸And R^TenCan form a 5- or 6-membered nitrogen-containing ring
Wherein said ring has one or more C_1-6May be substituted with alkyl; k is an integer in the range 1-2, n is an integer in the range 0-3, and m is 0-1
Is an integer in the range.

In a preferred embodiment, the present invention relates to compounds of formula I, wherein each symbol has the following meaning: A ¹ and A ² are independently of each other a 5- to 6-membered cyclic ring or a 9 to 10-membered bicyclic ring Are formula rings, which may be optionally substituted with one or more of the following groups: halogen, perhalomethyl, hydroxy, C _1-6 alkyl, (C _3-6 cycloalkyl) C _{1- 6} alkyl, C _4-6 alkenyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl, heteroaryloxy , Heteroarylalkoxy, acyl, hydroxy C _1-6 alkyl, C _1-6 alkyl-amino, C _1-6 dialkylamino, arylamino, arylalkylamino, amino C _1-6 alkyl, C _1-6 alkoxycarbonyl, alkylaminocarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, C _{1 -6} alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl or arylalkoxy C, _{1- 6} alkyl.

In a preferred embodiment, the present invention relates to compounds of formula I, wherein each symbol has the following meaning: A ¹ and A ² are independently of each other a 5- to 6-membered cyclic ring or a 9- to 10-membered bicyclic ring Are formula rings, which may be optionally substituted with one or more of the following groups: halogen, perhalomethyl, hydroxy, C _1-6 alkyl, (C _3-6 cycloalkyl) C _{1- 6} alkyl, C _4-6 alkenyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl, heteroarylalkyl, heteroaryloxy , Heteroarylalkoxy, acyl, hydroxy C _1-6 alkyl, C _1-6 alkyl-amino, C _1-6 dialkylamino, arylamino, arylalkylamino, amino C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, or arylalkoxy C _1-6 alkyl.

In a preferred embodiment, the present invention relates to compounds of formula I, wherein each symbol has the following meaning: A ¹ and A ² independently of one another, one or more halogen, C _1-6 alkyl, C _{1 A} 5- to 6-membered cyclic ring or a 9- to 10-membered bicyclic ring which may be substituted with _-6 alkoxy or aryl.

In another preferred embodiment, the present invention relates to compounds of formula I, wherein each symbol has the following meaning: A ¹ and A ² independently of one another, one or more halogen, C _1-6
It is a 5- to 6-membered cyclic ring optionally substituted with alkyl, C _1-6 alkoxy or aryl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Z is the terminal carbon atom of the double bond, or Z is CR ³ , in R ³ is hydrogen, halogen, perhalomethyl, C _1-12 alkyl, C _4-12 alkenynyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxy C _1-12 alkyl, C _1-12 alkoxy C _1-12 alkyl, aryloxy C _1-12 alkyl, arylalkoxy C _1-12 alkyl, thio C _{1 -12} alkyl, - COR ⁴ or a -SO ₂ R ^11,, wherein R ⁴ and R ¹¹ are independently selected from the following groups: hydroxy, halogen, perhalomethyl, C _1-6 alkoxy or amino; before Amino one or more C _1-6 alkyl, may be substituted with perhalomethyl or aryl, wherein aryl is 1 or more halogen, perhalomethyl, hydroxy, optionally substituted with nitro or cyano.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Z is the terminal carbon atom of the double bond, or Z is CR ³ , in R ³ is hydrogen, halogen, perhalomethyl, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryloxy, arylalkoxy, heteroaryloxy, Heteroarylalkoxy, acyl,
Acyloxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, arylalkoxy C _1-6 alkyl, thio C _1-6 alkyl,
—COR ⁴ , or —SO ₂ R ¹¹ , wherein R ⁴ and R ¹¹ are independently selected from the following groups: hydroxy, halogen, perhalomethyl, C _1-6 alkoxy or amino; It may be substituted with one or more C _1-6 alkyl, perhalomethyl or aryl, said aryl may be substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Z is the terminal carbon atom of the double bond, or Z is CR ³ , wherein in R ³ is hydrogen, halogen, perhalomethyl, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl or arylalkoxy,
C _1-6 alkyl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein Z is the terminal carbon atom of the double bond, or Z is CR ³ , wherein R ³ is hydrogen.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Q is O, S, or NR ¹² , wherein R ¹² is hydrogen, perhalomethyl, C _{1 -6} alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, acyl, hydroxyalkyl C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, arylalkoxy C _{1 -6} alkyl, thio C _1-6 alkyl , -COR ^13, or a -SO ₂ R ^14, wherein R ¹³ and R ¹⁴ are selected from the following groups independently of each other: hydroxy, perhalomethyl, C _1-6 Arukokishima It is amino; the amino 1 or more C _1-6 alkyl, may be substituted by perhalomethyl or aryl, wherein aryl is 1
Or it may be substituted by more halogen or perhalo.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Q is O, S, or NR ¹² , where R ¹² is hydrogen, perhalomethyl, C _{1 -6alkyl} , aryl, arylalkyl, heteroarylalkyl, or acyl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein Q is O or S.

In another preferred embodiment, the invention relates to compounds of formula I, wherein Q is O.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Ar is an arylene or heteroarylene, or a divalent heterocyclic group, each of which is 1 or more halogen, may be substituted by C _1-6 alkyl or C _1-6 alkoxy.

In another preferred embodiment, the invention relates to compounds of formula I, wherein Ar is arylene or heteroarylene.

In another preferred embodiment, the invention relates to compounds of formula I, wherein Ar is arylene.

In another preferred embodiment, the invention relates to compounds of formula I wherein each symbol has the following meaning: R ⁵ is hydrogen, hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkyl, C _{4 -6} alkenyl, C _2-6 alkenyl, C _2-6 alkynyl or arylalkyl; said group may be substituted by one or more halogen, or perhalomethyl, or R ⁵ together with R ⁶ Form a bond.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: R ⁵ represents hydrogen, halogen, C _1-6 alkoxy, C _1-6 alkyl, or perhalomethyl. carded, or R ⁵ forms a bond together with R ^6.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: R ⁵ represents hydrogen, halogen or R ⁵ forms a bond with R ⁶ .

In another preferred embodiment, the invention relates to compounds of formula I, wherein R ⁵ represents hydrogen.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: R ⁶ is hydrogen, C _1-6 alkoxy, C _1-6 alkyl, C _4-6 alkenyl,
Represents C _2-6 alkenyl, C _2-6 alkynyl, acyl or arylalkyl; said group may be substituted by one or more halogen or perhalomethyl, or R ⁶ forms a bond with R ⁵ Form.

[0031] In another preferred embodiment, the present invention relates to compounds of formula I in which the symbols have the following meanings: R ⁶ is hydrogen, halogen, or represents C _1-6 alkoxy, or R ⁶ and R ⁵ Form a bond together.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: R ⁶ represents hydrogen, C _1-6 alkoxy, or R ⁶ together with R ⁵ Form a bond.

In another preferred embodiment, the invention relates to compounds of formula I, wherein R ⁶ represents hydrogen.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: M represents OR ⁷ , wherein R ⁷ is hydrogen, C _1-6 alkyl, C _{4- 6} alkenyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, arylalkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl, aryloxycarbonyl,
Represents a C _1-6 alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl group, which may be substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano .

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: M represents OR ⁷ , wherein R ⁷ is hydrogen, C _1-6 alkyl, C _{4- 6} alkenyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, arylalkyl, C _1-6 alkoxyC _1-6 alkyl, heterocyclyl, heteroaryl or heteroarylalkyl group, wherein said group is one or more May be substituted with halogen or perhalomethyl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: M represents OR ⁷ , wherein R ⁷ represents C _1-6 alkyl, or M Is C
Represents OYR ⁸ .

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: M represents OR ⁷ , wherein R ⁷ represents ethyl or M represents COYR ⁸ Represent.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: R ⁸ is hydrogen, C _1-6 alkyl, C _4-6 alkenyl, C _2-6 alkenyl,
C _2-6 alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl group, said group one or more halogen, perhalomethyl, hydroxy, optionally substituted with nitro or cyano.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: R ⁸ is hydrogen, C _1-6 alkyl, C _4-6 alkenyl, C _2-6 alkenyl,
C _2-6 alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl group, the group may be substituted with 1 or more halogen or perhalomethyl.

In another preferred embodiment, the present invention provides that R ⁸ represents hydrogen or C _1-6 alkyl,
It relates to compounds of formula I.

In another preferred embodiment, the invention relates to compounds of formula I, wherein R ⁸ represents hydrogen or ethyl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Y represents oxygen, sulfur or NR ¹⁰ , wherein R ¹⁰ is hydrogen, C _1-6 alkyl Represents aryl, hydroxy C _1-6 alkyl or arylalkyl, or when Y is NR ¹⁰ , R ⁸ and R ¹⁰ can form a 5- or 6-membered nitrogen-containing ring; _May be substituted with one or more C _1-6 alkyl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein each symbol has the following meaning: Y represents oxygen or NR ¹⁰ , wherein R ¹⁰ is hydrogen, C _1-6 alkyl, aryl Or when Y is NR ¹⁰ , R ⁸ and R ¹⁰ can form a 5- or 6-membered nitrogen-containing ring, said ring being one or more C _{1 It} may be substituted by _-6 alkyl.

In another preferred embodiment, the invention relates to compounds of formula I, wherein Y represents oxygen.

In another preferred embodiment, the invention relates to compounds of formula I, wherein k is an integer in the range 1-2.

In another preferred embodiment, the invention relates to compounds of formula I, wherein n and m are 1.

Preferred compounds of the present invention are: 2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -allyloxy] -phenyl} -propionic acid ethyl ester, 2 -Ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -allyloxy] -phenyl} -propionic acid, 3- {4- [3- (2-chloro-phenyl) -3-phenyl -Allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3- (2-chloro-phenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid, 3 -{4- [3,3-bis- (4-methoxy-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3,3-bis- (4-methoxy -Phenyl) -allyl Xy] -phenyl} -2-ethoxy-propionic acid, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid, 2-ethoxy-3- {4- [3-phenyl-3- (thiophene- 2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester, 2-ethoxy-3- {4- [3-phenyl-3- (thiophen-2-yl) -allyloxy] -phenyl} -propionic acid, 2 -Ethoxy-3- {4- [3-phenyl-3- (pyridin-2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester, 2-ethoxy-3- {4- [3-phenyl-3- (Pyridine-2-a ) -Allyloxy] -phenyl} -propionic acid, 3- [4- (3,3-diphenyl-propoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, 3- [4- (3,3-diphenyl- Propoxy) -phenyl] -2-ethoxy-propionic acid, 2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -propoxy] -phenyl} -propionic acid ethyl ester, 2-ethoxy -3- {4- [3-phenyl-3- (4-methylphenyl) -propoxy] -phenyl} -propionic acid, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -propoxy ] -Phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid, 2-} 4− [3 , 3-Bis- (4-methoxy-phenyl) -allyloxy] -benzyl} -malonic acid-dimethyl ester, (E)-(2S) -2-ethoxy-3- {4- [3- (4-furan- 2-Ethyl-phenyl) -3-phenyl-allyloxy] -phenyl} -propionic acid ethyl ester, (E)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl) -Phenyl) -3-phenyl-allyloxy] -phenyl} -propionic acid, (E)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2 -Ethoxy-propionic acid ethyl ester, (E)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl Allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2 -Ethoxy-propionic acid, 3- {4- [3,3-bis- (3-methyl-thiophen-2-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3,3-bis- (4-bromo-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3,3-bis- (4-bromo-phenyl)- Allyloxy] -phenyl} -2-ethoxy-propionic acid, 2-ethoxy-3- [4- (3-phenyl-3-pyridin-4-yl-allyloxy) -phenyl] -propionic acid ethyl ester, 2-ethoxy- 3- [4- (3- Eniru -3-pyridin-4-yl - allyloxy) - phenyl] - propionic acid, (E, Z) - (2S) -2- ethoxy-3- {4- [3- (4-methoxyphenyl) -3
-Thiophen-2-yl-allyloxy] -phenyl} -propionic acid ethyl ester, (E, Z)-(2S) -2-ethoxy-3- {4- [3- (4-methoxyphenyl) -3
-Thiophen-2-yl-allyloxy] -phenyl} -propionic acid, (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyloxy) -phenyl]- Ethyl propionate, (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyloxy) -phenyl] -propionic acid, (2S) -3- [4 -(3,3-diphenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, (2S) -3- [4- (3,3-diphenyl-allyloxy) -phenyl] -2-ethoxy-propione Acid, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid, (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester, (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid, (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]
-Phenyl} -2-ethoxy-propionic acid ethyl ester, (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]
-Phenyl} -2-ethoxy-propionic acid, (2S) -3- [4- (3,3-di-p-tolyl-allyloxy) -phenyl] -2-
Ethoxy-propionic acid ethyl ester, (2S) -3- [4- (3,3-di-p-tolyl-allyloxy) -phenyl] -2-
Ethoxy-propionic acid, (Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (Z)-(2S ) -3- {4- [3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, (Z)-(2S) -3- {4- [ 3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid, (2S) -3- {4- [3,3-bis-biphenyl-4-yl-allyloxy) -Phenyl] -2-ethoxy-propionic acid ethyl ester, (2S) -3- {4- [3,3-bis-biphenyl-4-yl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (2S ) -3- ｛4- [3,3-Bis- (4-bromophenyl) -allyl Carboxy] -
Phenyl} -2-ethoxy-propionic acid ethyl ester, (2S) -3- {4- [3,3-bis- (4-bromophenyl) -allyloxy]-
Phenyl} -2-ethoxy-propionic acid, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl) -3-phenyl-allyloxy] -phenyl {-Propionic acid ethyl ester, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl) -3-phenyl-allyloxy] -phenyl} -propion Acid, (E)-(2S) -3- {4- [3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, (E)-(2S ) -3- {4- [3- (4-Bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid, (2S) -3- {4- [3,3-bis- (4-furan-2-yl-phenyl) -allyloxy] -phenyl} -2-ethoxy-propio Acid ethyl ester, (2S) -3- {4- [3,3-bis- (4-furan-2-yl-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid, (E, Z) -(2S) -3- [4- (3-biphenyl-4-yl-3-p-tolyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, (E, Z)-(2S)- 3- [4- (3-biphenyl-4-yl-3-p-tolyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (E, Z)-(2R) -3- [4- (3 -Biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or Mixtures of optical isomers, including racemic mixtures, or any tautomers The body of the form.

In the above structural formulas and throughout this specification, the following terms have the indicated meanings: The term “C _1-n 'alkyl” (where n ′ can be 2 to 12) As used herein, represents a branched or straight or cyclic alkyl group having from 1 to the specified number of carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl and the like. And cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl and the like.

The term “C _2-n ′ alkenyl” (where n ′ can be 3 to 15), as used herein, refers to two to the specified number of carbon atoms and at least one Represents an olefinically unsaturated branched or linear hydrocarbon group having a heavy bond.
Examples of such groups include, but are not limited to: vinyl,
1-propenyl, 2-propenyl, allyl, i-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl and the like.

The term “C _2-n 'alkynyl”, where n' can be 3 to 15, as used herein, refers to two to the specified number of carbon atoms and at least one triple Represents an unsaturated branched or linear hydrocarbon group having a bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, and the like.

The term “C _4-n 'alkenyl”, where n' can be from 5 to 15, as used herein, contains from 4 to the specified number of carbon atoms and at least one dicarbon. Represents an unsaturated branched or linear hydrocarbon group having both a heavy 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-hexadien-5-yne and the like.

The term “C _1-12 alkoxy”, alone or in combination, as used herein, is linked through an ether oxygen having its free valency from an ether oxygen, straight or branched. Has the indicated length in a chain or ring configuration
It is intended to include C _1-12 alkyl. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, s-butoxy, t-butoxy, isopentoxy, isohexoxy and the like. Examples of cyclic alkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

The term “C _1-12 alkylthio”, alone or in combination, as used herein, has its free valency from a sulfur atom and has 1 to 12 carbon atoms. Meaning a linear, branched or cyclic monovalent substituent comprising a C _1-12 alkyl group bonded through a divalent sulfur atom, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio, etc. I do. Examples of cyclic alkylthio include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

The term “C _1-12 alkylamino”, alone or in combination, as used herein, refers to a C _1-12 alkyl group attached through an amino having its free valency from a nitrogen atom. It means a straight-chain, branched-chain or cyclic monovalent substituent comprising, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino and the like. Examples of cyclic alkylamino include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, and the like.

The term “hydroxy C _1-12 alkyl,” alone or in combination, as used herein, is a C _1-12 alkyl, as defined herein, to which a hydroxy group is attached, eg, Hydroxyethyl, 1-hydroxypropyl, 2-
It means hydroxypropyl and the like.

The term “arylamino”, as used herein, alone or in combination, as defined herein, is attached through an amino having its free valency from a nitrogen atom, such as aryl, for example, phenylamino , Naphthylamino and the like.

The term “arylalkylamino”, alone or in combination, as used herein, is linked to an arylalkyl as defined herein, eg, through an amino having its free valency from a nitrogen atom, for example, Benzylamino, phenylethylamino, 3-phenylpropylamino, 1-naphthylmethylamino, 2
(1-Naphthyl) ethylamino and the like.

The term "amino C _1-12 alkyl", alone or in combination, as used herein, amino group is bonded thereto, C _{1-1 2} alkyl as defined herein, e.g. , Aminoethyl, 1-aminopropyl, 2-aminopropyl and the like.

The term “aryloxycarbonyl,” as used herein, alone or in combination, is attached through a carbonyl having a free valence bond from a carbon atom, to an aryloxy as defined herein, eg, Phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like are meant.

The term “arylalkoxycarbonyl,” as used herein, alone or in combination, is attached through an carbonyl having a free valence bond from a carbon atom, to an arylalkoxy as defined herein, eg, It means benzyloxycarbonyl, phenethoxycarbonyl, 3-phenylpropoxycarbonyl, 1-naphthylmethoxycarbonyl, 2- (1-naphthyl) ethoxycarbonyl and the like.

The term “C _1-12 alkoxyC _1-12 alkyl,” alone or in combination, as used herein, has attached thereto a C _1-12 alkoxy, as defined herein. C _1-12 alkyl as defined in e.g. methoxymethyl,
It means ethoxymethyl, methoxyethyl, ethoxyethyl and the like.

The term “ _{aryloxyC 1-12} alkyl”, alone or in combination, as used herein, is a C _1- alkyl, as defined herein, to which is attached an aryloxy, as defined herein. ₁₂ alkyl means, for example, phenoxydodecyl, 1-naphthyloxyethyl, 2-naphthyloxypropyl and the like.

The term “arylalkoxy C _1-12 alkyl”, alone or in combination, as used herein, is a C _1- alkyl as defined herein to which an arylalkoxy as defined herein is attached. ₁₂ alkyl means, for example, benzyloxymethyl, phenethoxydodecyl, 3-phenylpropoxyethyl, 1-naphthylpropoxyethyl, 1-naphthylmethoxypropyl, 2- (1-naphthyl) ethoxymethyl and the like.

The term “thio C _1-12 alkyl,” alone or in combination, as used herein, has the formula —SR ′ ″ where R ′ ″ is hydrogen, C _{1 6-1} alkyl or aryl) attached to a C _1-12 alkyl, as defined herein, eg, thiomethyl, methylthiomethyl, phenylthioethyl, and the like.

The term “C _1-12 alkoxycarbonylamino,” as used herein, alone or in combination, refers to a C _1-12 alkoxycarbonylamino group as defined herein attached through an amino having its free valency from a nitrogen atom. _1-12 alkoxycarbonyl, for example,
It means methoxycarbonylamino, carbethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, n-butoxycarbonylamino, t-butoxycarbonylamino and the like.

The term “aryloxycarbonylamino,” as used herein, alone or in combination, is an aryloxycarbonyl, as defined herein, attached through an amino having its free valency from a nitrogen atom. For example, it means phenoxycarbonylamino, 1-naphthyloxycarbonylamino, 2-naphthyloxycarbonylamino and the like.

The term “arylalkoxycarbonylamino”, alone or in combination,
As used herein, an arylalkoxycarbonyl as defined herein attached through an amino having its free valency from a nitrogen atom, e.g., benzyloxycarbonylamino, phenethoxycarbonylamino, 3-phenylpropoxycarbonylamino, 1-naphthylmethoxycarbonyl, 2- (1
-Naphthyl) ethoxycarbonyl and the like.

[0068] The term "aryl", halogen, amino, hydroxy, optionally substituted by C _1-6 alkyl or C _{1 -6} alkoxy, etc., an aromatic ring, e.g., phenyl, naphthyl, (1-naphthyl or 2-naphthyl) and the like.

The term “arylene” refers to halogen, amino, hydroxy, C _1-6 alkyl or
It is intended to include divalent aromatic rings which may be substituted with C _1-6 alkoxy, such as phenylene, naphthylene and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “perhalomethyl” means trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl.

The term “C _1-6 dialkylamino” as used herein is replaced by a straight or branched chain saturated hydrocarbon having the indicated number of carbon atoms where two hydrogen atoms are substituted. An amino group such as dimethylamino, N-ethyl-N-methylamino,
It means 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 _1-6 alkyl group attached through a carbonyl group, for example, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, Valeryl and the like.

The term “acyloxy” as used herein refers to an acyl as defined herein attached through an oxygen atom having its free valency from an oxygen atom, eg, acetyloxy, propionyloxy, butyryloxy, isobutyloxy, It means butyryloxy, pivaloyloxy, valeryloxy and the like.

The term “C _1-12 alkoxycarbonyl” as used herein refers to a monovalent substituent comprising a C _1-12 alkoxy group attached through a carbonyl group, eg, methoxycarbonyl, carbethoxy , Propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, 3-methylbutoxycarbonyl, n-hexoxycarbonyl and the like.

The term “heteroaryl”, alone or in combination, as used herein, refers to a 5- to 6-membered member containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. 1 comprising a monocyclic aromatic system or a 9-10 membered bicyclic aromatic system
Valent substituents such as furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, It means benzimidazole, benzofuran, pteridine, purine and the like.

The term “heteroarylene,” alone or in combination, as used herein, refers to a 5- to 6-membered 5-membered member containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Divalent substituents comprising a monocyclic aromatic system or a 9-10 membered bicyclic aromatic system, such as furan, thiophene, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, iso It means thiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, indole, benzimidazole, benzofuran, pteridine, purine and the like.

The term “heteroaryloxy,” as used herein, alone or in combination, is attached through an oxygen atom having its free valency from an oxygen atom to a heteroaryl, as defined herein, for example, , Pyrrole, imidazole, pyrazole, triazole, pyridine, pyrazine, pyrimidine, pyridazine, isothiazole, isoxazole, oxazole, oxadiazole, thiadiazole, quinoline, isoquinoline, quinazoline, quinoxaline, bonded to oxygen
It means indole, benzimidazole, benzofuran, pteridine, purine and the like.

The term “arylalkyl,” as used herein, refers to a straight or branched saturated carbon chain containing 1-6 carbon atoms that is substituted with an aromatic carbohydrate, for example, Benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl,
2- (1-naphthyl) ethyl and the like.

The term “aryloxy,” as used herein, refers to phenoxy, 1
-Naphthyloxy, 2-naphthyloxy and the like.

The term “arylalkoxy,” as used herein, refers to a C _1-6 alkoxy group substituted with an aromatic carbohydrate, such as benzyloxy, phenethoxy,
It means 3-phenylpropoxy, 1-naphthylmethoxy, 2- (1-naphthyl) ethoxy and the like.

The term “heteroarylalkyl,” as used herein, refers to a straight or branched saturated carbon chain containing 1-6 carbon atoms, which is substituted with a heteroaryl group, for example, , (2-furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (2-pyridyl) methyl, 1-methyl-1-
(2-pyrimidyl) ethyl and the like.

The term “heteroarylalkoxy,” as used herein, is attached to a heteroarylalkyl, eg, oxygen, as defined herein attached through an oxygen atom that has its free valency from an oxygen atom ( (2-furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (2
-Pyridyl) methyl, 1-methyl-1- (2-pyrimidyl) ethyl and the like.

The term “acylamino,” as used herein, refers to an amino group in which one of the hydrogen atoms has been replaced with an acyl group, for example, acetamido, propionamido, isopropylcarbonylamino, and the like.

The term “(C _3-6 cycloalkyl) C _1-6 alkyl”, alone or in combination,
As used herein, monosubstituted at 1-6 and C _3-6 cycloalkyl group having a carbon atom, a cycloalkyl group C _1-6 alkyl, halogen, hydroxy or C _1-6 alkoxy A linear or branched saturated hydrocarbon chain which may be mono- or polysubstituted, for example, cyclopropylmethyl, (1-methylcyclopropyl) methyl, 1- (cyclopropyl) ethyl, cyclopentyl Means methyl, cyclohexylmethyl and the like.

The term “arylthio”, alone or in combination, as used herein, is attached through a divalent sulfur atom having its free valency from a sulfur atom, and the aryl group is C _1-6 1 with alkyl, halogen, hydroxy or C _1-6 alkoxy
An optionally substituted or polysubstituted aryl group such as phenylthio, (4
-Methylphenyl) -thio, (2-chlorophenyl) thio and the like.

The term “C _1-6 alkylaminocarbonyl” as used herein,
Monovalent substituents comprising a C _1-6 monoalkylamino group attached through a carbonyl group, for example, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, s-butylaminocarbonyl, isobutylaminocarbonyl, t-butylaminocarbonyl, n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl, 3-methylbutylaminocarbonyl, n-hexylaminocarbonyl, 4
-Methylpentylaminocarbonyl, neopentylaminocarbonyl, n-hexylaminocarbonyl, 2,2-dimethylpropylaminocarbonyl and the like.

As used herein, the phrase “heterocyclyl” is a unary and
One or more, e.g., 1-4 carbon atoms, and 1-4 N, O or S
A monovalent, saturated or unsaturated, non-aromatic group containing atoms or combinations thereof is meant. The phrase “heterocyclyl” includes, but is not limited to: 5-membered heterocycles having one heteroatom atom (eg, pyrrolidine, pyrroline, etc.)
5-membered heterocycles having two hetero atoms at the 1,2 or 1,3 positions (eg pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidin, imidazoline, 4-
A 5-membered heterocycle having three heteroatoms (eg, tetrahydrofurazan); a 5-membered heterocycle having four heteroatoms; a six-membered heterocycle having one heteroatom ( A 6-membered heterocyclic ring having two hetero atoms (piperazine,
Morpholine, etc.); 6-membered heterocycles having 3 heteroatoms and 6-membered heterocycles having 4 heteroatoms.

As used herein, the phrase “divalent heterocyclic group” is monolithic and includes one or more, for example, 1 to 4 carbon atoms, and 1 to 4 carbon atoms. Means a divalent, saturated or unsaturated, non-aromatic group containing N, O or S atoms or combinations thereof. The phrase “divalent heterocyclic group” includes, but is not limited to: a 5-membered heterocycle having one heteroatom atom (eg, pyrrolidine, pyrroline, etc.); 5-membered heterocyclic ring having two hetero atoms at the 1,3 positions (for example, pyrazoline, pyrazolidine, 1,2-oxathiolane, imidazolidine, imidazoline,
5-membered heterocyclic ring having 3 hetero atoms (eg, tetrahydrofurazan); 5-membered hetero ring having 4 hetero atoms; 6-membered hetero ring having 1 hetero atom Ring (eg, piperidine, etc.); 6-membered heterocycle having 2 hetero atoms (piperazine, morpholine, etc.); 6-membered hetero ring having 3 hetero atoms and 6-member having 4 hetero atoms Heterocycles and the like.

As used herein, the phrase “5- to 6-membered cyclic ring” refers to one or more carbon atoms and optionally 1-4 N, O or S atoms or a group thereof. A saturated or unsaturated or aromatic system containing a combination is meant. The phrase "5- to 6-membered cyclic ring" includes, but is not limited to, for example, cyclopentyl, cyclohexyl, phenyl, cyclohexenyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, pyrrolyl , 2H-pyrrolyl, imidazolyl, pyrazolyl, triazolyl,
5-membered heterocycles having one heteroatom such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiomorpholinyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, 1,3-dioxolanyl, 1,4-dioxolanyl and the like (for example, Thiophene, pyrrole, furan, etc.);
5-membered heterocycle having two hetero atoms at the 1- or 1,3-positions (eg, oxazole, pyrazole, imidazole, thiazole, purine, etc.); 5-membered heterocycle having 3 hetero atoms (eg, triazole , Thiadiazole, etc.); 5 having 4 hetero atoms
6-membered heterocycle having one heteroatom (for example, pyridine, quinoline, isoquinoline, phenanthridine, cyclohepta [b] pyridine, etc.); 6-membered heterocycle having two heteroatoms ( Pyridazine, cinnoline, phthalazine, pyrazine, pyrimidine, quinazoline, morpholine, and the like); a 6-membered heterocycle having three hetero atoms and
6-membered heterocyclic ring having 4 hetero atoms, etc.

As used herein, the phrase “9- to 10-membered bicyclic ring” refers to one or more carbon atoms and optionally 1-4 N, O or S atoms or A saturated or unsaturated or aromatic system containing a combination thereof is meant. The phrase `` 9-10
"Membered bicyclic rings" include, but are not limited to: naphthalene, quinoline, isoquinoline, indole, benzothiophene, benzofuran and the like.

Certain of the terms defined above may occur more than once in formula (I) above, and when so present, each term should be defined independently of one another is there.

The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts.
Acid addition salts include inorganic as well as organic acid salts. Representative examples of suitable inorganic acids are
Hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like are included. Representative examples of suitable organic acids include: formic acid, acetic acid, trichloroic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, Malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, Citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate , Hydroxynaphthoate, glycero Sufeto, keto Kultur rate, and the like. Pharmaceutically acceptable addition salts of inorganic or organic acids are described in J. Pharm. Sci. 1977,66,2, which are incorporated herein by reference. And the above acceptable salts. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium salts and alkylated alkylated salts include ammonium salts, methyl ammonium salts, dimethyl ammonium salts, trimethyl ammonium salts, ethyl ammonium salts, hydroxyethyl ammonium salts, diethyl ammonium salts, butyl ammonium salts, tetramethyl ammonium salts and the like. Include. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.

Pharmaceutically acceptable salts include compounds of formula I in a solvent such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol and the like.
It is prepared by reacting with 44 equivalents of a base, for example, sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesium hydroxide and the like. Mixtures of solvents can be used.
Organic bases such as lysine, arginine, guanidine, diethanolamine, choline, guanidine and derivatives thereof, and the like can also be used. Alternatively, the acid addition salt, if applicable, may be an acid such as hydrochloric acid, hydrobromic acid, in a solvent such as ethyl acetate, ether, alcohol, acetone, THF, dioxane and the like.
With nitric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, etc. Manufactured by processing. Also, mixtures of solvents can be used.

The stereoisomers of the compounds forming part of the present invention may be prepared by using the reactants in the form of single enantiomers in the process, or by using single enantiomers in the presence of reagents or catalysts. It can be prepared by carrying out the reaction in the form of isomers or by resolving a mixture of stereoisomers by conventional methods. Some of the preferred methods use microbial resolution, where applicable, chiral acids such as
Resolving diastereomeric salts formed with mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc., or diastereomeric salts formed with chiral bases such as brucine, quince alkaloids and their derivatives, etc. . Commonly used methods are compiled in the following literature: Jaques et al., "Enantiomers, Racemates and Resolution" (Wiley Inte
rscince, 1981). More particularly, the compounds of formula I include chiral amines, amino acids,
By treatment with amino alcohols derived from amino acids, they can be converted to a 1: 1 mixture of diastereomeric amides; they can be converted to amides using conventional reaction conditions; It can be separated by fractional crystallization or chromatography, and stereoisomers of the compounds of formula I can be prepared by hydrolyzing the pure diastereomeric amide.

By crystallizing the compound of formula I under different conditions, various polymorphs of the compound forming part of the present invention can be prepared. For example, using different solvents or mixtures thereof commonly used for: recrystallization; crystallization at different temperatures; various cooling modes; very rapid to very slow cooling ranges during crystallization. . Also, polymorphs can be obtained by heating or melting the compound followed by gradual or rapid cooling. Presence of polymorph is nmr solid probe
It can be determined by spectroscopy, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other such techniques.

The present invention also encompasses prodrugs of the compounds of the present invention that, upon administration, undergo chemical transformations by metabolic processes before becoming active pharmacological agents. In general, such prodrugs will be functional derivatives of the compounds of the present invention, and are readily convertible in vivo into the required compound of formula (I). Conventional techniques for selecting and producing suitable prodrug derivatives are described, for example, in the following documents:
"Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985.

The present invention also includes active metabolites of the compounds of the present invention.

In addition, the compounds of the formula I according to the invention can be used in the treatment and / or prevention of conditions mediated by nuclear receptors, in particular peroxisome proliferator-activated receptors (PPAR).

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

In still further aspects, the invention relates to treating and / or treating type I or type II diabetes.
Or the use of one or more compounds of general formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention.

In a further aspect, the compounds of the present invention are useful in treating and / or preventing IGT.

[0103] In a further aspect, the compounds of the present invention are useful in treating and / or preventing type 2 diabetes.

In a further aspect, the compounds of the present invention are useful for delaying or preventing the progression of IGT to type 2 diabetes.

In a further aspect, the compounds of the present invention are useful for delaying or preventing progression from non-insulin demanding type 2 diabetes to insulin demanding type 2 diabetes.

In another aspect, the compounds of the present invention reduce blood sugar and triglyceride levels, and are therefore useful for treating and / or preventing diseases and disorders, such as diabetes and / or obesity.

In still other aspects, the compounds of the present invention can be used in insulin resistance (type 2 diabetes), impaired glucose tolerance, dyslipidemia, diseases related to Syndrome X, such as hypertension, obesity, insulin Useful in the treatment and / or prevention of tolerance, hyperglycemia, atherosclerosis, hyperlipidemia, coronary artery disease, myocardial infarction and other cardiovascular diseases.

In yet another aspect, the compounds of the invention are effective for reducing apoptosis in mammalian cells, eg, beta cells of the islets of Langerhans.

In yet another aspect, the compounds of the present invention are useful for treating certain kidney diseases, such as glomerulonephritis, glomerulosclerosis, nephrotic syndrome, and hypertensive renal sclerosis.

In still other aspects, the compounds of the invention also improve cognitive function in dementia, treat diabetic complications, psoriasis, polycystic ovary syndrome (PCOS), and reduce bone loss, eg, It may be effective for treating osteoporosis.

The present invention also provides, as an active ingredient, at least one compound of formula I or an optical or configurational isomer or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. And one or more pharmaceutically acceptable carriers or diluents.

Further, the present invention provides a method for preparing a pharmaceutical composition for treating and / or preventing a condition mediated by a nuclear receptor, in particular a peroxisome proliferator-activated receptor (PPAR), such as the aforementioned conditions. Compounds of I, their tautomers,
It relates to the use of their polymorphs, their pharmaceutically acceptable salts or pharmaceutically acceptable solvates.

The present invention also relates to the novel compounds described above, their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts or The present invention relates to a method for producing a pharmaceutically acceptable solvate.

The method comprises the following steps: a) converting a compound of formula (II), wherein A ¹ and A ² are as defined above, in a Homer Emmons reaction with a phosphonate ester.

[0115]

Embedded image

And reacting with a compound of formula III

[0117]

Embedded image

(A ¹ and A ² are as defined above) to produce a compound of formula III
Is reduced with diisobutylaluminum hydride to produce a compound of formula IV wherein A ¹ and A ² and n are as previously defined. Alternatively, a compound of formula IV can be prepared by reacting a compound of formula II with (Ph ₃ P) ₃ PCH ₂ (CH ₂ ) _n CH ₂ OH, Br and BuLi in a Wittig reaction:

[0119]

Embedded image

The alcohol group in the compound of formula IV can undergo a Mitsunobo reaction with the compound of formula V or can be converted to a suitable leaving group (mesyloxy, halide) and subjected to alkylation conditions. Formula V below

[0121]

Embedded image

Reacting with a compound of formula I wherein Q is OH, SH or amino and Ar, M, Y and R ⁵ -R ⁸ are as previously defined

[0123]

Embedded image

Compounds of the formula wherein k = 1 and A ¹ , A ² , Q, Ar, M, Y, n and R ⁵ -R ⁸ are as defined above can be produced.

The compound of formula (I) is ester deprotected according to standard hydrolysis techniques to give a compound of formula I (wherein
Y is O and k = 1 and A ¹ , A ² , Q, Ar, M, n and R ⁵ -R ⁸ are as defined above) can be produced.

Hydrogenation of a compound of formula IV over a palladium catalyst provides a compound of formula VI

[0127]

Embedded image

Wherein A ¹ , A ² and n are as defined above.

The compound of formula VI is subjected to a Mitsunovo reaction with a compound of formula V to give a compound of formula I

[0130]

Embedded image

Compounds of the formula wherein k = 2 and A ¹ , A ² , Q, Ar, M, Y, n and R ⁵ -R ⁸ are as defined above can be produced.

The compound of formula (I) is ester deprotected according to standard hydrolysis techniques to give a compound of formula I
Y is O and k = 2 and A ¹ , A ² , Q, Ar, M, n and R ⁵ -R ⁸ are as previously defined). Pharmacological methods In vitro activation activity of PPARalpha and PPARgamma Principle The PPAR gene transcriptional activation assay involves transient transfection of two plasmids encoding a chimeric test protein and a reporter protein into human HEK293 cells, respectively. based on. The chimeric test protein was a fusion of the DNA binding domain from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR protein. PPAR LBD contains a natural activation domain (activating function 2 = AF2) in addition to the ligand binding pocket, and the fusion protein
Enable to function as a PPAR ligand-dependent transcription factor. GAL4 DBD converts the fusion protein to a Gal4 enhancer (neither of which is present in HEK293 cells)
Will only bind against The reporter plasmid contains a Gal4 enhancer that drives expression of the firefly luciferase protein. After transfection, HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion protein subsequently binds to the Gal4 enhancer to control luciferase expression and does nothing in the absence of ligand. When the PPAR ligand is added to the cells, the luciferase protein will be produced in an amount corresponding to activation of the PPAR protein. After addition of the appropriate substrate, the amount of luciferase protein is measured by light emission. Methods Cell culture and transfection: HEK293 cells were transformed into DMEM + 10% FCS, 1%
Grew in PS. Cells were seeded in 96-well plates the day before transfection to 80% confluency at the time of transfection. 0.8 g DNA / well was transfected using FuGene transfection reagent according to the manufacturer's instructions (Boehringer Mannheim). After allowing the cells to express the protein for 48 hours, the compound was added.

Plasmid: PC using cDNA templates from liver, intestine and adipose tissue respectively
Human PPARα and γ were obtained by R amplification. The amplified cDNA was cloned into pCR2.1 and sequenced. LBD from each isoform PPAR is generated by PCR (PPAR
α: amino acids 167-C-terminal; PPARγ: amino acids 165-C-terminal), fused to GAL4-DBD by subcloning the fragment in frame into vector pM1 to generate plasmids pM1αLBD and pM1γLBD. Subsequent fusions were confirmed by sequencing. A reporter was constructed by inserting oligonucleotides encoding five repeats of the Gal4 recognition sequence into a pGL2 vector (Promega).

Compounds: All compounds were dissolved in DMSO and diluted 1: 1000 before adding to cells. Cells were treated with compound for 24 hours (diluted 1: 1000 in 200 μl growth medium with delipidated serum) and then a luciferase assay was performed.

Luciferase assay: The medium containing the test compound was aspirated, and 100 μl of PBS containing 1 mM Mg ²⁺ and Ca ²⁺ was added to each well. Manufacturer (Packard Instrume
The luciferase assay was performed using the LucLite kit according to the manufacturer's instructions. Light emission was quantified by counting the SPC mode with a top counter (Packard Instruments). In another aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, at least one compound of the general formula I:
Pharmaceutical compositions comprising the species or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent are included.

The compounds of the present invention may also be derived from one or more pharmacologically active substances, such as antiobesity agents, antidiabetic agents, antihypertensive agents, diabetes, or diabetes. For treating and / or preventing obesity-related complications and / or a substance selected from agents for treating and / or preventing obesity-related complications and / or diseases. Can be.

Thus, in a further aspect of the invention, the compounds of the invention can be administered in combination with one or more antiobesity agents or appetite regulating agents.

[0138] Such agents include CART (cocaine amphetamine-regulated transcription) agonists, NP
Y (neuropeptide Y) antagonist, MC4 (melanocortin 4) agonist, orexin antagonist, TNF (tumor necrosis factor) agonist, CRF (adrenocorticotropic hormone releasing factor) agonist, CRF BP (adrenocorticotropic hormone factor binding protein) antagonist , Urocortin agonist, β agonist, MSH (melanocyte stimulating hormone) agonist, MCH (melanocyte concentrating hormone) antagonist, CCK (cholecystokinin) agonist, serotonin reabsorption inhibitor, serotonin and noradrenaline reabsorption inhibitor, mixed serotonin and noradrenergic Compound, 5HT (serotonin) agonist, bombesin agonist, galanin antagonist, growth hormone, growth hormone releasing compound, TRH (threotropin releasing hormone) May be selected from the group consisting of agonists, UCP2 or 3 (uncoupled protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptine, doplexin), lipase / amylase inhibitors, RXR (retinoid X receptor) modulators or TRβ agonists it can.

[0139] In one embodiment of the invention, the antiobesity agent is leptin.

In another embodiment, the antiobesity agent is dexamphetamine or amphetamine.

[0141] In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

[0142] In still other embodiments, the antiobesity agent is sibutramine.

In a further embodiment, the antiobesity agent is orlistat.

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

Suitable antidiabetic agents are insulin, GLP-1 (glucagon-like peptide-1) derivatives, such as WO 98/08871 (Novo Nordisk A / S, herein incorporated by reference). As well as orally active hypoglycemic agents.

The active hypoglycemic agent is preferably a sulfonylurea, biguanide, meglitinide, glycosidase inhibitor, glucagon antagonist such as WO 99
/ 01423 (Novo Nordisk A / S and Agouron Pharmaceuticals, Inc.), GLP-1 agonists, potassium channel openers, such as
Those disclosed in WO 97/26265 and WO 99/03861 (Novo Nordisk A / S, which is incorporated herein by reference);
DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of liver enzymes involved in stimulating gluconeogenesis and / or glycogenolysis, modulators of glucose absorption, compounds that alter fat metabolism, such as antihyperlipidemic agents and antihyperlipidemic agents Includes lipemic agents such as HMG CoA inhibitors (statins), compounds that reduce food intake, RXR agonists, and factors that act on ATP-dependent potassium channels in β-cells.

In one embodiment of the invention, the compounds of the invention are administered in combination with insulin.

In a further embodiment, the compounds of the invention are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glicazide.

In another embodiment, the compounds of the invention are administered in combination with a biguanide, such as, for example, metformin.

In still other embodiments, the compounds of the present invention are administered in combination with a meglitinide, for example, repaglinide.

In a further embodiment, the compounds of the present invention are administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose.

In another embodiment, the compounds of the invention are administered in combination with an agent that acts on ATP-dependent potassium channels in β-cells, such as, for example, tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.

Additionally, the compounds of the present invention are administered in combination with nateglinide.

In still other embodiments, the compounds of the invention are antihyperlipidemic or antilipidemic agents such as cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or It is administered in combination with dextrothyroxine.

In a further embodiment, the compounds of the invention may be combined with two or more of the foregoing compounds, for example, sulfonylurea and metformin, sulfonylurea and acarbose, repaglinide and metformin, insulin and sulfonylurea, insulin and metformin, It is administered in combination with insulin and lovastatin, and the like.

Additionally, the compounds of the present invention can be administered in combination with one or more antihypertensive agents. Examples of anti-hypertensive agents are beta-blockers, such as alprenolol, atenolol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors, such as benazepri,
Captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, dithiazem and verapamil, and α-blockers such as doxazosin, urapidil, prazosin and terazosin They can be administered together. Further references can be found in Remington: The Science and Practice of Pharmacy, 19th Edition,
Gennaro Ed., Mack Publishing Company, Easton, PA, 1995.

The compounds according to the invention and one or more of the aforementioned compounds and optionally 1
It should be understood that suitable combinations with one or more other pharmacologically active substances are considered to be within the scope of the present invention.

Pharmaceutical compositions containing a compound of the present invention can be manufactured by conventional techniques, for example, as described in the following references: Remington: The Scie
nce and Practice of Pharmacy, 19th edition, 1995. The compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or topical applications.

A typical composition is associated with a pharmaceutically acceptable excipient that is a carrier or diluent, or diluted with a carrier, or in the form of a capsule, bag, paper or other container. It comprises a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof, surrounded by a possible carrier. In preparing the compositions, conventional techniques for preparing pharmaceutical compositions can be used. For example, the active compound can be mixed with a carrier, diluted with a carrier, or enclosed in a carrier, which can be in the form of a capsule, bag, paper, or other container. When the carrier acts as a diluent,
A carrier can be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a container of particulate solid, for example, a bag. Some examples of suitable carriers include water, saline,
Alcohol, polyethylene glycol, polyhydroxylated castor oil, peanut oil, olive oil, gelatin, lactose, porcelain clay, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia gum, stearic acid or cellulose Lower alkyl ethers, silicic acids, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent includes any art-known sustained release material such as glyceryl monostearate or glyceryl distearate alone or with a wax. The formulation may also include wetting, emulsifying and suspending agents, preservatives, sweetening or flavoring agents. The formulations of the present invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient, according to procedures well known in the art.

The pharmaceutical compositions can be sterilized and, if desired, mixed with adjuvants, emulsifiers, salts which affect osmotic pressure, buffers and / or coloring substances etc. which do not adversely react with the active compound. .

Routes of administration will effectively transport the active compound to the appropriate or desired site of action,
By any route, for example, oral, nasal, pulmonary, transdermal or parenteral, for example, rectal, storage, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or ointment route. it can. The oral route is preferred.

If a solid carrier is used for oral administration, the preparation is tabletted and placed in a hard gelatin capsule in powder or pellet form, or the preparation is in the form of a troche or lozenge. be able to. When using a liquid carrier,
The preparation can be a syrup, emulsion, soft gelatin capsule or sterile injectable solution, for example,
It can be in the form of an aqueous or non-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier can contain additives, for example, solubilizing agents, for example, polyethylene glycol, surfactants, absorption enhancers, for example, lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, for example, parabens.

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

Tablets, dragees or capsules with talc and / or carbohydrate carriers or diluents or other are particularly suitable for oral application. Preferred carriers for tablets, dragees, or capsules include lactose, corn starch, and / or potato starch. A syrup or elixir may be used when a vehicle with a sweetening agent is available.

A typical tablet that can be manufactured by conventional tableting techniques can contain the following ingredients: Core: Active compound (as free compound or salt thereof) 5 mg Colloidal silicon dioxide (Aerosil) 1.5mg Cellulose, microcrystal (Avicel) 70mg Modified cellulose gum (Ac-Di-Sol) 7.5mg Magnesium stearate Up to total amount Coating: HPMC Approx. 9mg Mywacett 9-40 T * Approx. Acylated monoglycerides used as

The compounds of the present invention can be administered to mammals, especially humans, in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood glucose.
Such mammals also include both livestock, eg, domestic pets, and non-livestock, eg, wildlife.

The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of an adult human, about 0.05 to about 100 mg / day, preferably about 0.1 to about 100 mg / day, can be used. Most preferred dosages are from about 0.1 to about 70 mg / day. Starting with a dosage of about 2 to about 70 mg / day in selecting a regimen for the patient, and reducing the dosage to as low as about 0.1 to about 10 mg / day when the symptoms are under control. Decreases may be frequently needed. The exact dosage will depend on the mode of administration, the desired therapy, the mode of administration, the subject to be treated, and the weight of the subject to be treated, and the preferences and experience of the attending physician or veterinarian.

Generally, the compounds of the present invention comprise from about 0.1 to about 100 mg of an active ingredient per unit dose,
And dispensed in unit dosage form comprising a pharmaceutically acceptable carrier.

Generally, suitable dosage forms for oral, nasal, pulmonary or transdermal administration are from about 0.001 mg to about 1 mg.
It comprises a mixture of 00 mg, preferably from about 0.01 mg to about 50 mg, of a compound of formula I and a pharmaceutically acceptable carrier or diluent.

Any novel feature or combination of features described herein is considered essential to the invention. The methods for preparing the compounds of the formula I and the preparations containing them are further illustrated in the enzymes below, but should not be construed as limiting.

The structure of the compound is confirmed by elemental analysis (MA), nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (d) are reported in parts per million (ppm) and only selected peaks are reported. mp is the melting point and is stated in ° C. WC Still et al., J. Org
Merck silica gel 6 according to the technique described in Chem. 1978, 43, 2923-2925.
Column chromatography was performed on 0 (Art 9385). The compounds used as starting materials are known compounds or compounds which can be easily prepared by methods known per se.

Abbreviations: TLC: thin layer chromatography DMSO: dimethyl sulfoxide CDCl ₃ : deuterated chloroform DMF: N, N-dimethylformamide min: min h: time Example 1 (E, Z) -2-ethoxy-3 -{3- [3-phenyl-3- (4-methylphenyl) -allyloxy] -phenyl} -propionic acid ethyl ester 3-Phenyl-3- (4-methylphenyl) -prop-2-ene- in THF 1-ol (150 mg, 0.6 mmol), triphenylphosphine (195 mg, 0.73 mmol) and 2-
Ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (19
(0 mg, 0.79 mmol) at an ice bath temperature, diethyl azodicarboxylate (0.11 ml, 0.73 mmol) was added and the reaction was stirred at this temperature for 1.5 hours and at room temperature for 16 hours. Ice water was added and the crude product was isolated by dichloromethane extraction and brine washing. Concentration under reduced pressure and flash chromatography gave the title compound (300 mg).

[0174]

(Equation 1)

[0175] MS: calcd for _{C 29 H 32 O 4: 444.6} ; Found: 444.2.

Example 2 (E, Z) -2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -allyloxy] -phenyl} -propionic acid (E, Z) -2 -Ethoxy-3- ｛4- [3-phenyl-3- (4-methylphenyl)
-Allyloxy] -phenyl} -propionic acid ethyl ester (Example 1) (80 m
g, 0.18 mmol) was hydrolyzed in 1N NaOH (0.35 ml) and ethanol (0.35 ml) for 4 hours at room temperature and 16 hours at 5 ° C. Water (1 ml) was added and the reaction mixture was neutralized with 6N HCl. The crude product was extracted with dichloromethane and concentrated under reduced pressure.
Flash chromatography provided the title compound (48 mg).

[0177]

(Equation 2)

[0178] MS: calcd for _{C 27 H 28 O 4: 416.5} ; Found: 416.3.

Example 3 (E, Z) -3- ｛4- [3- (2-chloro-phenyl) -3-phenyl-allyloxy
[S] -phenyl} -2-ethoxy-propionic acid ethyl ester 3- (2-chloro-phenyl) -3-phenyl-prop-2-ene- in benzene
A solution of 1-ol (370 mg, 1.5 mmol), tributylphosphine (0.5 ml, 1.6 mmol) and ethyl 2-ethoxy-3- (4-hydroxy-phenyl) -propionate (380 mg, 1.6 mmol) in an ice bath At temperature, azodicarboxylic acid dipiperidide (403 mg, 1.6 mmol) was added and the reaction was stirred for 1 hour. Workup and purification as in Example 1 yielded the title compound (490 mg).

[0180]

(Equation 3)

[0181] MS: calcd for _{C 28 H 29 ClO 4: 465.0} ; Found: 464.2.

Example 4 (E, Z) -3- {4- [3- (2-chloro-phenyl) -3-phenyl-allyloxy
[S] -phenyl} -2-ethoxy-propionic acid (E, Z) -3- {4- [3- (2-chloro-phenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid Ethyl ester (Example 3) (
Hydrolysis of 400 mg, 0.86 mmol) in the same manner as in Example 2 gives the title compound (353 m
g) was obtained.

[0183]

(Equation 4)

[0184] MS: calcd for _{C 26 H 25 ClO 4: 436.9} ; Found: 436.2.

Example 5 3- {4- [3,3-bis- (4-methoxy-phenyl) -allyloxy] -phenyl
Ru-2-ethoxy-propionic acid ethyl ester 3,3-bis- (4-methoxy-phenyl) -prop-2-en-1-ol (216
mg, 0.8 mmol), triphenylphosphine (240 mg, 0.9 mmol), 2-ethoxy-3
-(4-hydroxy-phenyl) -propionic acid ethyl ester (240 mg, 1.0 mmol
l) and diethyl azodicarboxylate (0.11 ml, 0.9 mmol) were reacted in the same manner as in Example 1 to give the title compound (90 mg).

[0186]

(Equation 5)

[0187] MS: calcd for _{C 30 H 34 O 6: 490.6} ; Found: 488.3.

Example 6 3- {4- [3,3-bis- (4-methoxy-phenyl) -allyloxy] -phenyl
Ethyl 2-ethoxy-propionic acid 3- {4- [3,3-bis- (4-methoxy-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester (Example 5) (80 mg , 0.16mm
ol) was hydrolyzed in the same manner as in Example 2 to obtain the title compound (29 mg).

[0189]

(Equation 6)

[0190] MS: calcd for _{C 28 H 30 O 6: 462.5} ; Found: 462.1.

Example 7 (E, Z) -3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy
[S] -phenyl} -2-ethoxy-propionic acid ethyl ester 3-phenyl-3- (biphenyl-4-yl) -prop-2-en-1-ol (2
50 mg, 0.66 mmol), triphenylphosphine (195 mg, 0.73 mmol), 2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (190 mg, 0.7 mg)
9 mmol) and diethyl azodicarboxylate (0.11 ml, 0.79 mmol) in Example 1.
The title compound (180 mg) was obtained in the same manner as described above.

[0192]

(Equation 7)

[0193] MS: calcd for _{C 34 H 34 O 4: 506.6} ; Found: 504.2.

Example 8 (E, Z) -3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy
[S] -phenyl} -2-ethoxy-propionic acid (E, Z) -3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid Ethyl ester (Example 7) (
70 mg, 0.13 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (25 mg)
was gotten.

[0195]

(Equation 8)

[0196] MS: calcd for _{C 32 H 30 O 4: 478.6} ; Found: 478.2.

Example 9 (E, Z) -2-ethoxy-3- {4- [3-phenyl-3- (thiophen-2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester 3-phenyl- 3- (thiophen-2-yl) -prop-2-en-1-ol (3
20 mg, 1.5 mmol), tributylphosphine (0.4 ml, 1.6 mmol), 2-ethoxy-3
-(4-hydroxy-phenyl) -propionic acid ethyl ester (380 mg, 1.6 mmol
l) and azodicarboxylic acid dipiperidide (403 mg, 1.6 mmol) were reacted in the same manner as in Example 3 to give the title compound (290 mg).

[0198]

(Equation 9)

[0199] MS: calcd for _{C 26 H 28 O 4 S:} 436.6; Found: 436.1.

Example 10 (E, Z) -2-ethoxy-3- {4- [3-phenyl-3- (thiophen-2-yl) -allyloxy] -phenyl} -propionic acid (E, Z)- 2-ethoxy-3- {4- [3-phenyl-3- (thiophen-2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester (Example 9) (2
(00mg, 0.45mmol) in the same manner as in Example 2 to give the title compound (94mg)
was gotten.

[0201]

(Equation 10)

[0203] MS: Calculated for _{C 24 H 24 O 4 S:} 408.5; Found: 408.2.

[0203] Example 11 2-ethoxy-3- {4- [3-phenyl-3- (pyridin-2-yl) - Ariruoki sheet] - phenyl} - propionic acid ethyl ester 3-phenyl-3- (pyridin - 2-yl) -prop-2-en-1-ol (320
mg, 1.5 mmol), tributylphosphine (0.42 ml, 1.6 mmol), 2-ethoxy-3-
(4-Hydroxy-phenyl) -propionic acid ethyl ester (380 mg, 1.6 mmol
) And azodicarboxylic acid dipiperidide (403 mg, 1.6 mmol) were reacted in the same manner as in Example 3 to give the title compound (650 mg).

[0204]

[Equation 11]

[0205] MS: calcd for _{C 27 H 29 O 4 N:} 431.5; Found: 431.3.

[0206] Example 12 2-ethoxy-3- {4- [3-phenyl-3- (pyridin-2-yl) - Ariruoki sheet] - phenyl} - propionic acid 2-ethoxy-3- {4- [3 -Phenyl-3- (pyridin-2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester (Example 11) (210 mg, 0.48 m
mol) was hydrolyzed in the same manner as in Example 2 to obtain the title compound (110 mg).

[0207]

(Equation 12)

[0208] MS: calcd for _{C 25 H 25 O 4 N:} 403.5; Found: 403.2.

Example 13 3- [4- (3,3-diphenyl-propoxy) -phenyl] -2-ethoxy-pro
Pionic acid ethyl ester 3,3-diphenyl-propan-1-ol (110 mg, 0.5 mmol), triphenylphosphine (145 mg, 0.55 mmol), 2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (140 mg, 0.6 mmol) and diethyl azodicarboxylate (0.09 ml, 0.55 mmol) were reacted in the same manner as in Example 1 to give the title compound (120 mg).

[0210]

(Equation 13)

[0211] MS: calcd for _{C 28 H 32 O 4: 432.6} ; Found: 432.3.

Example 14 3- [4- (3,3-diphenyl-propoxy) -phenyl] -2-ethoxy-pro
Hydrolysis of 3- [4- (3,3-diphenyl-propoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester of pionic acid (Example 13) (110 mg, 0.25 mmol) in the same manner as in Example 2. Then, the title compound (55 mg) was obtained.

[0213]

[Equation 14]

[0214] MS: calcd for _{C 26 H 28 O 4: 404.5} ; Found: 404.3.

Example 15 2-Ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -propoxy ] -phenyl} -propionic acid ethyl ester 3-phenyl-3- (4-methylphenyl ) -Prop-2-en-1-ol (210
mg, 0.88 mmol), tributylphosphine (0.25 ml, 1.0 mmol), 2-ethoxy-3
-(4-hydroxy-phenyl) -propionic acid ethyl ester (240 mg, 1.0 mmol
l) and azodicarboxylic acid dipiperidide (250 mg, 1.0 mmol) were reacted in the same manner as in Example 3 to give the title compound (160 mg).

[0216]

(Equation 15)

[0217] MS: calcd for _{C 29 H 34 O 4: 446.6} ; Found: 446.3.

Example 16 2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -propoxy ] -phenyl} -propionic acid 2-ethoxy-3- {4- [3-phenyl -3- (4-Methylphenyl) -propoxy] -phenyl} -propionic acid ethyl ester (Example 15) (130 mg, 0.30 mmol
l) was hydrolyzed in the same manner as in Example 2 to obtain the title compound (55 mg).

[0219]

(Equation 16)

[0220] MS: calcd for _{C 27 H 30 O 4: 418.5} ; Found: 418.3.

Example 17 3- {4- [3-phenyl-3- (biphenyl-4-yl) -propoxy] -phenyl
Ru-2-ethoxy-propionic acid ethyl ester 3-biphenyl-4-yl-3-phenyl-propan-1-ol (145 mg, 0.5 mm
ol), triphenylphosphine (145 mg, 0.55 mmol), 2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (140 mg, 0.6 mmol) and diethylazodicarboxylate (0.09 ml, 0.55 mmol) Was reacted in the same manner as in Example 1 to obtain the title compound (230 mg).

[0222]

[Equation 17]

[0223] MS: calcd for _{C 34 H 36 O 4: 508.7} ; Found: 508.3.

Example 18 3- {4- [3-Phenyl-3- (biphenyl-4-yl) -propoxy] -phenyl
3- {4- [3-Phenyl-3- (biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid ethyl ester of ru-2-ethoxy-propionic acid (Example 17) (200 mg) , 0.39
mmol) was hydrolyzed in the same manner as in Example 2 to obtain the title compound (70 mg).

[0225]

(Equation 18)

[0226] MS: calcd for _{C 32 H 32 O 4: 480.6} ; Found: 480.3.

Example 19 2- {4- [3,3-bis- (4-methoxy-phenyl) -allyloxy] -benzyl
Ru-malonic acid-dimethyl ester Under a nitrogen atmosphere, 3,3-bis- (4-methoxy-phenyl) -prop-2-en-1-ol (500 mg, 1.95 mmol), tributylphosphine (424 mg, 2.1 mmol) ) And 2- (4-hydroxy-benzyl) -malonic acid dimethyl ester (464 mg, 1.9 mg).
5 mmol) were successively dissolved in dry benzene (50 ml). Solid azodicarboxylic acid dipiperidide (ADDP) (530 mg, 2.1 mmol) was added to the solution with stirring at 0 ° C. After 10 minutes, the reaction mixture was brought to room temperature and stirring was continued for 16 hours. Heptane (10 ml) was added to the reaction mixture and the separated dihydro-ADDP was filtered. After evaporation of the solvent, the product was purified by chromatography, eluting with heptane / ethyl acetate (4: 1) to give 150 mg (16%) of the title compound.

[0228]

[Equation 19]

Example 20 (E)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl)
) -3-Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester (E) -3- (4-furan-2-yl-phenyl) -3-phenyl-prop-2-en-1-ol (475 mg, 1.72 mmol), tributylphosphine (0.63 ml, 2.58 mmol)
), (2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (451 mg, 1.89 mmol) and azodicarboxylic acid dipiperidide (650
(2.58 mmol) in benzene in the same manner as in Example 3 to give the title compound (450 mg, 53%).

[0230]

(Equation 20)

Example 21 (E)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl)
-3-Phenyl-allyloxy] -phenyl} -propionic acid (E)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl) -3-phenyl-allyloxy ] -Phenyl} -propionic acid ethyl ester (Example 20) (440 mg, 0.89 mmol) is hydrolyzed in the same manner as in Example 2.
The title compound (408 mg, 97%) was obtained.

[0232]

(Equation 21)

LCMS (electrospray): 491 (M + Na), 259 (100%).

[0234] Example 22 (E) - (2S) -3- [4- (3- biphenyl-4-yl-3-phenyl - Ariruoki sheet) - phenyl] -2-ethoxy - propionic acid ethyl ester (E) -3-Biphenyl-4-yl-3-phenyl-prop-2-en-1-ol (1.0 g, 3.49 mmol), tributylphosphine (1.3 ml, 5.24 mmol), (2S) -2-
Ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (0.
92 mg, 3.84 mmol) and azodicarboxylic acid dipiperidide (1.32 g, 5.24 mmol)
Was reacted in benzene in the same manner as in Example 3 to give the title compound (1.47 g).
, 83%).

[0235]

(Equation 22)

[0236] Example 23 (E) - (2S) -3- [4- (3- biphenyl-4-yl-3-phenyl - Ariruoki sheet) - phenyl] -2-ethoxy - propionic acid (E) - ( 2S) -3- [4- (3-Biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (Example 22)
(1.38 g, 2.72 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (1.2
(5 mg, 96%).

[0237]

(Equation 23)

Example 24 (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyl
Oxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (E, Z) -3-biphenyl-4-yl-3-phenyl-prop-2-en-1-ol (601 mg, 2.1 mmol), triphenyl Phosphine (606mg, 2.31mmol), (2S)
2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (601 mg, 2.52 mmol) and diethyl azodicarboxylate (402 mg, 2.31 mm
ol) was reacted in the same manner as in Example 1 to give the title compound (400 mg, 38%).

[0239]

(Equation 24)

Example 25 (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyl
(Oxy) -phenyl] -2-ethoxy-propionic acid (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy- Ethyl propionate (Example 2
4) (400 mg, 0.79 mmol) is hydrolyzed in the same manner as in Example 2 to give the title compound (
250 mg, 66%).

[0241]

(Equation 25)

Example 26 3- {4- [3,3-Bis- (3-methyl-thiophen-2-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester 3,3-bis- (3-Methylthiophen-2-yl) -prop-2-en-1-ol (1.0 mg, 3.99 mmol), tributylphosphine (0.91 mg, 4.5 mmol), 2-ethoxy-3- (4-hydroxy-phenyl ) -Propionic acid ethyl ester (1.07 mg
, 4.5 mmol) and azodicarboxylic acid dipiperidide (1.14 g, 4.5 mmol) were reacted in the same manner as in Example 3 to give the title compound (680 mg, 36%).

[0243]

(Equation 26)

Example 27 3- {4- [3,3-bis- (4-bromo-phenyl) -allyloxy] -phenyl
E-2-ethoxy-propionic acid ethyl ester 3,3-bis- (4-bromo-phenyl) -prop-2-en-1-ol (0.50 m
g, 1.36 mmol), triphenylphosphine (0.39 mg, 1.50 mmol), 2-ethoxy-
3- (4-hydroxy-phenyl) -propionic acid ethyl ester (0.39 mg, 1.63
mmol) and diethyl azodicarboxylate (0.26 g, 1.51 mmol) were reacted in the same manner as in Example 1 to give the title compound (450 mg, 56%).

[0245]

[Equation 27]

Example 28 3- {4- [3,3-bis- (4-bromo-phenyl) -allyloxy] -phenyl
{-2-ethoxy-propionic acid 3- {4- [3,3-bis- (4-bromo-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester (Example 27) (150 mg, 0.25mm
ol) was hydrolyzed in the same manner as in Example 2 to give the title compound (135 mg, 96%).

[0247]

[Equation 28]

Example 29 2-ethoxy-3- [4- (3-phenyl-3-pyridin-4-yl-allyloxy) -phenyl] -propionic acid ethyl ester 3-phenyl-3-pyridine-4-prop- 2-en-1-ol (0.50 mg, 2.37 m
mol), triphenylphosphine (0.68 mg, 2.61 mmol), 2-ethoxy-3- (4-
Hydroxy-phenyl) -propionic acid ethyl ester (0.68 mg, 2.84 mmol) and diethyl azodicarboxylate (0.46 g, 2.63 mmol) were reacted in the same manner as in Example 1 to give the title compound (435 mg, 43%) was gotten.

[0249]

(Equation 29)

Example 30 2-ethoxy-3- [4- (3-phenyl-3-pyridin-4-yl-allyloxy) -phenyl] -propionic acid 2-ethoxy-3- [4- (3-phenyl- 3-Pyridin-4-yl-allyloxy) -phenyl] -propionic acid ethyl ester (Example 29) (200 mg, 0.46 mmol
) Was hydrolyzed in the same manner as in Example 2 to give the title compound (50 mg, 27%).

[0251]

[Equation 30]

Example 31 (E, Z)-(2S) -2-ethoxy-3- {4- [3- (4-methoxyphenyl) -3- thiophen-2-yl-allyloxy] -phenyl} -propion Ethyl S
Ter- 3- (4-methoxyphenyl) -3-thiophen-2-yl-prop-2-ene-1
-Ol (271 mg, 1.10 mmol), triphenylphosphine (289 mg, 1.10 mmol),
(2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (238 mg 1.0 mmol) and diethyl azodicarboxylate (188 g, 1.
08 mmol) was reacted in the same manner as in Example 1 to give the title compound (80 mg, 17%
)was gotten.

[0253]

(Equation 31)

Example 32 (E, Z)-(2S) -2-ethoxy-3- {4- [3- (4-methoxyphenyl) -3- thiophen-2-yl-allyloxy] -phenyl} -propion Acid (E, Z)-(2S) -2-ethoxy-3- {4- [3- (4-methoxyphenyl) -3
-Thiophen-2-yl-allyloxy] -phenyl} -propionic acid ethyl ester (Example 31) (75 mg, 0.16 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (40 mg, 57%). Obtained.

[0255]

(Equation 32)

Example 33 (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyl
Oxy) -phenyl] -propionic acid ethyl ester (E, Z) -3-phenyl-p-tolyl-prop-2-en-1-ol (841 mg, 3
.75 mmol), triphenylphosphine (1.03 mg, 3.93 mmol), (2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (851 mg 3
.75 mmol) and diethyl azodicarboxylate (656 g, 3.94 mmol) in Example 1
Reaction in the same manner as afforded the title compound (0.64 g, 40%).

[0257]

[Equation 33]

Example 34 (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyl
Oxy) -phenyl] -propionic acid (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyloxy) -phenyl] -propionic acid ethyl ester (Example 33) ) (0.55mg,
1.24 mmol) is hydrolyzed in the same manner as in Example 2 to give the title compound (0.50 g, 97%)
was gotten.

[0259]

(Equation 34)

Example 35 (2S) -3- [4- (3,3-Diphenyl-allyloxy) -phenyl] -2-ethoxy
Xy-propionic acid ethyl ester 3,3-diphenyl-prop-2-en-1-ol (210 mg, 1.0 mmol), tributylphosphine (303 mg, 1.50 mmol), (2S) -2-ethoxy-3- (4- Hydroxy-phenyl) -propionic acid ethyl ester (250 mg, 1.05 mmol) and azodicarboxylic acid dipiperidide (378 g, 1.50 mmol) were reacted in the same manner as in Example 3 to give the title compound (290 mg, 67%). Was.

[0261]

(Equation 35)

Example 36 (2S) -3- [4- (3,3-diphenyl-allyloxy) -phenyl] -2-ethoxy
Xy-propionic acid (2S) -3- [4- (3,3-diphenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (Example 35) (215 mg, 0.50 mmol) was used as in Example 2. Hydrolysis in the same manner gave the title compound (180 mg, 90%).

[0263]

[Equation 36]

Example 37 (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-f
Enyl-allyloxy] -phenyl} -propionic acid ethyl ester (Z) -3- (4-fluorophenyl) -3-phenyl-prop-2-en-1-ol (200 mg, 0.88 mmol), triphenylphosphine (242 mg , 0.92 mmol), (2S
) -2-Ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (200 mg 0.84 mmol) and diethyl azodicarboxylate (160 g, 0.92 m
mol) was reacted in the same manner as in Example 1 to give the title compound (275 mg, 73%)
was gotten.

[0265]

(37)

Example 38 (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-f
Enyl-allyloxy] -phenyl} -propionic acid (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester (Example
37) (200 mg, 0.45 mmol) is hydrolyzed in the same manner as in Example 2 to give the title compound
(158 mg, 90%) was obtained.

[0267]

(38)

Example 39 (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-f
Enyl-allyloxy] -phenyl} -propionic acid ethyl ester (E) -3- (4-fluorophenyl) -3-phenyl-prop-2-en-1-ol (200 mg, 0.88 mmol), triphenylphosphine (242 mg , 0.92 mmol), (2S
) -2-Ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (200 mg 0.84 mmol) and diethyl azodicarboxylate (160 g, 0.92 m
mol) was reacted in the same manner as in Example 1 to give the title compound (320 mg, 85%)
was gotten.

[0269]

[Equation 39]

Example 40 (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-f
Enyl-allyloxy] -phenyl} -propionic acid (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester (Example
39) (225 mg, 0.50 mmol) is hydrolyzed in the same manner as in Example 2 to give the title compound
(245 mg, 95%) was obtained.

[0271]

(Equation 40)

Example 41 (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]-
Phenyl} -2-ethoxy-propionic acid ethyl ester 3,3-bis- (4-methoxyphenyl) -prop-2-en-1-ol (1.62 m
g, 5.99 mmol), triphenylphosphine (2.88 mg, 10.98 mmol), (2S) -2-
Ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (1.
19 mg, 4.99 mmol) and diethyl azodicarboxylate (1.92 g, 10.04 mmol)
Was reacted in the same manner as in Example 1 to give the title compound (0.434 mg, 17%).

[0273]

[Equation 41]

Example 42 (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]-
Phenyl} -2-ethoxy-propionic acid (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]
-Phenyl} -2-ethoxy-propionic acid ethyl ester (Example 41) (225 mg
, 0.495 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (150 mg, 71 mg).
%)was gotten.

[0275]

(Equation 42)

[0276] Example 43 (2S)-3-[4- (3,3-di -p- tolyl - allyloxy) - phenyl] -2-et butoxy - propionic acid ethyl ester 3,3-di - (4- Methylphenyl) -prop-2-en-1-ol (1.0 mg, 4.
20 mmol), tributylphosphine (1.27 mg, 6.30 mmol), (2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (1.10 g, 4.6
2 mmol) and azodicarboxylic acid dipiperidide (1.59 g, 6.30 mmol) in Example 3
Reaction in the same manner as afforded the title compound (0.76 g, 39%).

[0277]

[Equation 43]

[0278] Example 44 (2S) -3- [4- ( 3,3- di -p- tolyl - allyloxy) - phenyl] -2-et butoxy - propionic acid (2S) -3- [4- (3 , 3-Di-p-tolyl-allyloxy) -phenyl] -2-
Ethyl-propionic acid ethyl ester (Example 43) (0.76 mg, 1.66 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (0.696 mg, 98%).

[0279]

[Equation 44]

[0280] Example 45 (Z) - (2S) -3- [4- (3- biphenyl-4-yl-3-phenyl - Ariruoki sheet) - phenyl] -2-ethoxy - propionic acid propionic acid ethyl ester ( Z) -3-Biphenyl-4-yl-3-phenyl-prop-2-en-1-ol (171 mg, 0.60 mmol), triphenylphosphine (142 mg, 0.63 mmol), (2S)-
2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (149 mg, 0.63 mmol) and diethyl azodicarboxylate (95 mg, 0.55 mmol)
) Was reacted in the same manner as in Example 1 to give the title compound (160 mg, 83%).

[0281]

[Equation 45]

[0282] Example 46 (Z) - (2S) -3- [4- (3- biphenyl-4-yl-3-phenyl - Ariruoki sheet) - phenyl] -2-ethoxy - propionic acid (Z) - ( 2S) -3- [4- (3-Biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl propionate (Example 45) (0.36 mg, 0.71 mmol) When hydrolyzed in the same manner as in Example 2,
The title compound (0.345 mg, 86%) was obtained.

[0283]

[Equation 46]

[0284] Example 47 (Z) - (2S) -3- {4- [3- (4- bromophenyl) -3-phenyl - Ariruo alkoxy] - phenyl} -2-ethoxy - propionic acid ethyl ester 3- (4-bromophenyl) -3-phenyl-prop-2-en-1-ol (145
mg, 0.50 mmol), triphenylphosphine (144 mg, 0.55 mmol), (2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (119 m
g, 0.50 mmol) and diethyl azodicarboxylate (96 mg, 0.55 mmol) were reacted in the same manner as in Example 1 to give the title compound (110 mg, 43%).

[0285]

[Equation 47]

Microanalysis for C ₂₈ H ₂₉ BrO ₄ +0.1 H ₂ O: Calculated: 65.78% C, 5.76% H;
Found: 65.79% C, 5.91% H.

[0287] Example 48 (Z) - (2S) -3- {4- [3- (4- bromophenyl) -3-phenyl - Ariruo alkoxy] - phenyl} -2-ethoxy - propionic acid (Z) - (2S) -3- {4- [3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester (Example 47)
) (90 mg, 0.18 mmol) is hydrolyzed in the same manner as in Example 2 to give the title compound (60
mg, 71%).

[0288]

[Equation 48]

[0289] LCMS (electrospray): 503/505 (M + Na) , 498/500 (M + NH 4), 271/273
(100%).

Example 49 (2S) -3- {4- [3,3-Bis-biphenyl-4-yl-allyloxy) -fe
Nil] -2-ethoxy-propionic acid ethyl ester 3,3-bis-biphenyl-4-yl-prop-2-en-1-ol (363 mg, 1.
0 mmol), tributylphosphine (303 mg, 1.5 mmol), (2S) -2-ethoxy-3
-(4-Hydroxy-phenyl) -propionic acid ethyl ester (262 mg, 1.1 mmol
l) and azodicarboxylic acid dipiperidide (378 mg, 1.5 mmol) were reacted in the same manner as in Example 3 to give the title compound containing 0.8 equivalents of ethyl acetate (445 m
g, 76%).

[0291]

[Equation 49]

Example 50 (2S) -3- {4- [3,3-bis-biphenyl-4-yl-allyloxy) -fe
Nyl] -2-ethoxy-propionic acid (2S) -3- {4- [3,3-bis-biphenyl-4-yl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (Example 49) (560mg, 0.
96 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (450 mg, 84%).

[0293]

[Equation 50]

Example 51 (2S) -3- {4- [3,3-bis- (4-bromophenyl) -allyloxy] -f
Enyl} -2-ethoxy-propionic acid ethyl ester 3,3-bis- (4-bromophenyl) -prop-2-en-1-ol (2.60 mg
, 7.0 mmol), tributylphosphine (2.52 mg, 10.0 mmol), (2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (1.50 mg,
Reaction of 16.3 mmol) and azodicarboxylic acid dipiperidide (2.02 g, 10.0 mmol) in the same manner as in Example 3 gave the title compound (2.8 g, 75%) containing 0.8 equivalents of ethyl acetate.

[0295]

(Equation 51)

Example 52 (2S) -3- {4- [3,3-bis- (4-bromophenyl) -allyloxy] -f
Enyl} -2-ethoxy-propionic acid (2S) -3- {4- [3,3-bis- (4-bromophenyl) -allyloxy]-
Phenyl} -2-ethoxy-propionic acid ethyl ester (Example 51) (2.8 g, 4
(.76 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (2.3 g, 83%) containing approximately 0.25 equivalents of ethyl acetate.

[0297]

(Equation 52)

Example 53 (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl)
) -3-Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester (Z) -3- (4-furan-2-yl-phenyl) -3-phenyl-prop-2-en-1-ol (300 mg, 1.09 mmol), tributylphosphine (0.40 mg, 1.64 mmol)
), (2S) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (286 mg, 1.20 mmol) and azodicarboxylic acid dipiperidide (413
mg, 1.64 mmol) in benzene in the same manner as in Example 3 to give 0.8
The title compound (260 mg, 48%) containing an equivalent amount of ethyl acetate was obtained.

[0299]

(Equation 53)

[0300] LCMS (electrospray): 519 (M + Na) , 514 (M + NH 4), 259 (100%).

Example 54 (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl)
) -3-Phenyl-allyloxy] -phenyl} -propionic acid (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl) -3-phenyl- Allyloxy] -phenyl} -propionic acid ethyl ester (Example 53) (240 mg, 0.483 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (170 mg, 75%).

[0302]

(Equation 54)

[0303] LCMS (electrospray): 491 (M + Na) , 486 (M + NH 4), 259 (100%).

[0304] Example 55 (E) - (2S) -3- {4- [3- (4- bromophenyl) -3-phenyl - Ariruo alkoxy] - phenyl} -2-ethoxy - propionic acid ethyl ester (E ) -3- (4-Bromophenyl) -3-phenyl-prop-2-en-1-ol (0.37 mg, 1.5 mmol), tributylphosphine (0.37 mg, 1.5 mmol), (2S)-
2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (262 mg, 1.10 mmol) and azodicarboxylic acid dipiperidide (378 mg, 1.5 mmol)
) In benzene in the same manner as in Example 3 to give the title compound (460m
g, 90%).

[0305]

[Equation 55]

LCMS (electrospray): 531/533 (M + Na), 271/273 (100%).

[0307] Example 56 (E) - (2S) -3- {4- [3- (4- bromophenyl) -3-phenyl - Ariruo alkoxy] - phenyl} -2-ethoxy - propionic acid (E) - (2S) -3- {4- [3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester (Example 55)
) (382 mg, 0.75 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (3
(50 mg, 97%).

[0308]

[Equation 56]

[0309] LCMS (electrospray): 503/505 (M + Na) , 498/500 (M + NH 4), 271 /
273 (100%).

[0310] Example 57 (2S) -3- {4- [ 3,3- bis - (4-furan-2-yl-phenyl) - - Ariruo alkoxy] - phenyl} -2-ethoxy - propionic acid ethyl ester 3 , 3-Bis- (4-furan-2-yl-phenyl) -prop-2-en-1-ol (460 mg, 1.34 mmol), tributylphosphine (0.50 mg, 2.0 mmol), (2S)-
2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (320 mg, 1.34 mmol) and azodicarboxylic acid dipiperidide (504 mg, 2.0 mmol)
) In benzene in the same manner as in Example 3 to give the title compound (541m
g, 72%).

[0311]

[Equation 57]

[0312] Example 58 (2S) -3- {4- [ 3,3- bis - (4-furan-2-yl-phenyl) - - Ariruo alkoxy] - phenyl} -2-ethoxy - propionic acid (2S) -3- {4- [3,3-Bis- (4-furan-2-yl-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester (Example 57)
) (530 mg, 0.95 mmol) was hydrolyzed in the same manner as in Example 2 to give the title compound (4
00 mg, 79%).

[0313]

[Equation 58]

[0314] Example 59 (E, Z) - ( 2S) -3- [4- (3- biphenyl-4-yl -3-p-tolyl - allyl oxy) - phenyl] -2-ethoxy - ethyl propionate Ester (E, Z) -3-biphenyl-4-yl-3-p-tolyl-prop-2-en-1-ol (300 mg, 1.0 mmol), tributylphosphine (0.37 mg, 1.5 mmol), (2S)
2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (262 mg, 1.10 mmol) and azodicarboxylic acid dipiperidide (378 mg, 1.50 mm
ol) in benzene in the same manner as in Example 3 to give the title compound (39
(0 mg, 76%).

[0315]

[Equation 59]

[0316] LCMS (electrospray): 543 (M + Na) , 538 (M + NH 4), 283 (100%).

[0317] Example 60 (E, Z) - ( 2S) -3- [4- (3- biphenyl-4-yl -3-p-tolyl - allyl oxy) - phenyl] -2-ethoxy - propionic acid ( E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-p-tolyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester (Example 5
9) (370 mg, 0.71 mmol) is hydrolyzed in the same manner as in Example 2 to give the title compound (
310 mg, 89%).

[0318]

[Equation 60]

LCMS (electrospray): 515 (M + Na), 283 (100%).

Example 61 (E, Z)-(2R) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyl
Oxy) -phenyl] -2-ethoxy-propionic acid ethyl ester 4- (3-bromo-1-phenyl-prop-1-enyl) -biphenyl (0.35 g, 1.00 mmol) and (2R) in dry acetone (20 ml) To a stirred solution of) -2-ethoxy-3- (4-hydroxy-phenyl) -propionic acid ethyl ester (0.215 g, 0.90 mmol) was added potassium carbonate (0.25 g, 1.81 mmol) and the mixture was refluxed. Heated down at 60 ° C. for 18 hours. The resulting suspension was cooled to room temperature, filtered to remove inorganic products and the solvent was evaporated. The product was purified by chromatography on silica gel, eluting with 15% ethyl acetate in light petroleum to give the title compound as a colorless gum (0.40 g, 87%).

[0321]

[Equation 61]

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 3/04 A61P 3/04 4H006 3/06 3/06 3/10 3/10 13/12 13/12 17/06 17/06 19/10 19/10 25/28 25/28 43/00 111 43/00 111 C07C 69/736 C07C 69/736 C07D 213/30 C07D 213/30 307/42 307/42 333 / 16 333/16 // C07M 7:00 C07M 7:00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE) , LS, MW, SD, SL, SZ, TZ, UG, ZW), E (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN , CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, K P, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Petterson, Ingrid Denmark , Deko-1864 Frederiksberg, 2. Teho. , Grundby Gusby 18 (72) Inventor Brie, Paul Stanley Denmark, 2400 Kebenhaun Embeh, Jöltrums Alle 48 F-term (reference) 4C023 BA04 4C037 HA08 4C055 AA01 BA02 BA16 BB08 CA01 CA02 CA16 CB08 DA01 A02A03A03A BC17 MA01 MA04 MA52 MA55 MA56 MA57 MA59 NA05 NA14 ZA15 ZA70 ZA81 ZA89 ZA97 ZC02 ZC33 ZC35 4C206 AA01 AA03 DA21 DB20 KA01 MA01 MA04 MA72 MA75 MA76 MA77 MA79 MA83 NA14 ZA15 ZA81 ZA89 ZA97 ZC02 ZC30 ZC30 ZC30 ZC33 A30 BP30 BS10 BT12

Claims (51)

[Claims] 1. A compound of the following formula (I) or a pharmaceutically acceptable acid or
Include salts with bases, or any optical isomers, or racemic mixtures,
A mixture of optical isomers, or any tautomeric form:(Where A¹And A^TwoIs independently a 5- to 6-membered cyclic ring or a 9- to 10-membered bicyclic ring
And these may be optionally substituted by one or more of the following groups:
I: halogen, perhalomethyl, hydroxy, nitro, cyano, formyl, and
Is C_1-12Alkyl, (C_3-6Cycloalkyl) C_1-6Alkyl, C_4-12Alkenyl,
C_2-12Alkenyl, C_2-12Alkynyl, C_1-12Alkoxy, aryl, arylo
Xy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl
, Heteroarylalkyl, heteroaryloxy, heteroarylalkoxy
Si, acyl, acyloxy, hydroxy C_1-12Alkyl, amino, acylamino
, C_1-12Alkyl-amino, C_1-6Dialkylamino, arylamino, aryl
Alkylamino, amino C_1-12Alkyl, C_1-12Alkoxycarbonyl, alkyl
Aminocarbonyl, aryloxycarbonyl, arylalkoxycarbonyl
, C_1-12Alkoxy C_1-12Alkyl, aryloxy C_1-12Alkyl, aryla
Lucoxy C_1-12Alkyl, arylthio, C_1-12Alkylthio, Thio C_1-12Archi
, C_1-12Alkoxycarbonylamino, aryloxycarbonylamino,
Reel alkoxycarbonylamino, -COR¹, Or -SO_TwoR^Two, Where R¹And R ^Two Are independently selected from the following groups: hydroxy, halogen, perhalo
Methyl, C_1-6Alkoxy or amino; said amino is one or more C_1-6A
Alkyl, perhalomethyl or aryl.
Is one or more halogen, perhalomethyl, hydroxy, nitro or
May be substituted with ano; Z is C, CR^ThreeAnd where R^ThreeIs hydrogen, halogen, perhalomethyl, C_1-12Archi
, C_4-12Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl, C_1-12Alkoxy
, Aryloxy, arylalkoxy, heteroaryloxy, heteroaryl
Alkoxy, acyl, acyloxy, hydroxy C_1-12Alkyl, C_1-12Arco
Kiss C_1-12Alkyl, aryloxy C_1-12Alkyl, arylalkoxy C_1-12
Alkyl, Thio C_1-12Alkyl, -COR^Four, Or -SO_TwoR¹¹And where R^FourAnd
And R¹¹Are independently selected from the following groups: hydroxy, halogen, per
Halomethyl, C_1-6Alkoxy or amino; said amino is one or more C_{1- 6} Alkyl, perhalomethyl or aryl,
Is one or more halogen, perhalomethyl, hydroxy, nitro or
May be substituted with cyano; Q is O, S, NR¹²And where R¹²Is hydrogen, perhalomethyl, C_1-12Alkyl, C _4-12 Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl, aryl, arylua
Alkyl, heterocyclyl, heteroaryl, heteroarylalkyl, acyl,
Hydroxy C_1-12Alkyl, amino C_1-12Alkyl, C_1-12Alkoxycarbonyl
, Aryloxycarbonyl, arylalkoxycarbonyl, C_1-12Alkoki
C_1-12Alkyl, aryloxy C_1-12Alkyl, arylalkoxy C_1-12A
Lucil, Thio C_1-12Alkyl, -COR¹³, Or -SO_TwoR¹⁴And where R¹³And
And R¹⁴Are independently selected from the following groups: hydroxy, perhalomethyl
, C_1-6Alkoxy or amino; said amino is one or more C_1-6Alkyl
, Perhalomethyl or aryl, wherein said aryl is one or more
Or more halogen, perhalomethyl, hydroxy, nitro or cyano
Which may be substituted; Represents a single bond or a double bond; Ar is an arylene, a heteroarylene, or a divalent heterocyclic group;
Each is one or more halogen, C_1-6Alkyl, amino, hydroxy, C_{1- 6} Optionally substituted with alkoxy or aryl; R^FiveIs hydrogen, hydroxy, halogen, C_1-12Alkoxy, C_1-12Alkyl, C_4-12
Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl or arylalkyl
Said arylalkyl is one or more of halogen, perhalomethyl,
Optionally substituted with droxy, nitro or cyano, or R^FiveIs R⁶And one
To form a bond; R⁶Is hydrogen, hydroxy, halogen, C_1-12Alkoxy, C_1-12Alkyl, C_4-12
Alkenyl, C_2-12Alkenyl, C_2-12Alkynyl, acyl or arylal
Represents one or more halogen, perhalomethyl, hydroxy,
Optionally substituted with a nitro, cyano or cyano, or R⁶Is R^FiveCombined with
Form; M is OR⁷Where R⁷Is hydrogen, C_1-12Alkyl, C_4-12Alkenyl, C_2-12
Alkenyl, C_2-12Alkynyl, aryl, arylalkyl, C_1-12Alkoxy
C_1-12Alkyl, C_1-12Alkoxycarbonyl, aryloxycarbonyl, C_{1-1 Two} Alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl
Represents a lyi, heteroaryl or heteroarylalkyl group, wherein said group is
Is replaced by a further halogen, perhalomethyl, hydroxy, nitro or cyano.
Or M is COYR⁸Represents R⁸Is hydrogen, C_1-12Alkyl, C_4-12Alkenyl, C_2-12Alkenyl, C_2-12Al
Quinyl, aryl, arylalkyl, heterocyclyl, heteroaryl or
Represents a heteroarylalkyl group, said group comprising one or more halogen, per
Optionally substituted by halomethyl, hydroxy, nitro or cyano; Y is oxygen, sulfur or NR^TenWhere R^TenIs hydrogen, C_1-12Alkyl, Ally
, Hydroxy C_1-12Represents alkyl or arylalkyl, or Y is NR ^Ten , Then R⁸And R^TenCan form a 5- or 6-membered nitrogen-containing ring
Wherein said ring has one or more C_1-6May be substituted with alkyl; k is an integer in the range 1-2, n is an integer in the range 0-3, and m is 0-1
Range is an integer). 2. A ¹ and A ² are each independently a 5- to 6-membered cyclic ring or a 9- to 10-membered bicyclic ring, and these are optionally substituted with one or more of the following groups: The compound according to claim 1, which may be substituted: halogen, perhalomethyl, hydroxy, C _1-6 alkyl, (C _3-6 cycloalkyl) C _1-6 alkyl, C _4-6 alkenyl,
C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclyl, heteroaryl,
Heteroarylalkyl, heteroaryloxy, heteroarylalkoxy,
Acyl, hydroxy C _1-6 alkyl, C _1-6 alkyl-amino, C _1-6 dialkylamino, arylamino, arylalkylamino, amino C _1-6 alkyl, C _1-6 alkoxycarbonyl, alkylaminocarbonyl, aryl oxycarbonyl, aryl alkoxycarbonyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _{1 -6} alkyl or arylalkoxy C _1-6 alkyl. 3. A ¹ and A ² are each independently a 5- to 6-membered cyclic ring or a 9- to 10-membered bicyclic ring, and these are optionally substituted with one or more of the following groups: a compound according to any one of optionally substituted by the claims: halogen, perhalomethyl, hydroxy, C _1-6 alkyl, (C _3-6 cycloalkyl) C _1-6 alkyl, C _{4 -6} alkenynyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclyl,
Heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy, acyl, hydroxyalkyl C _1-6 alkyl, C _1-6 alkyl - amino, C _{1 -6} dialkylamino, arylamino, arylalkyl, amino C _{1- 6} alkyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, or arylalkoxy C _1-6 alkyl. 4. A¹And A^TwoAre independently of one another one or more halogens, C _1-6 Alkyl, C_1-65- to 6-membered optionally substituted with alkoxy or aryl
The compound according to any one of the preceding claims, which is a cyclic ring or a 9-10 membered bicyclic ring.
Compound. 5. A¹And A^TwoAre independently of one another one or more halogens, C _1-6 Alkyl, C_1-65- to 6-membered optionally substituted with alkoxy or aryl
The compound according to any one of the preceding claims, which is a cyclic ring. 6. Z is a terminal carbon atom of a double bond or Z is CR ³ wherein R ³ is hydrogen, halogen, perhalomethyl, C _1-12 alkyl, C _4-12 alkenyl, C _2-12 alkenyl, C _2-12 alkynyl, C _1-12 alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxy C _1-12 alkyl, C _1-12 alkoxy C _{1 -12} alkyl, aryloxy C _1-12 alkyl, arylalkoxy C _1-12 alkyl, thio C _1-12 alkyl, —COR ⁴ , or —SO ₂ R ¹¹ , wherein R ⁴ and R ¹¹ are independent of each other A compound according to any one of the preceding claims, wherein the compound is selected from the following groups: hydroxy, halogen, perhalomethyl, C _1-6 alkoxy or amino; said amino is one or more C _1-6 alkyl, Perha It may be substituted with romethyl or aryl, said aryl may be substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano. 7. Z is a terminal carbon atom of the double bond, or Z is CR ³ , wherein R ³ is hydrogen, halogen, perhalomethyl, C _1-6 alkyl, C _4-6 alkenyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryloxy,
Arylalkoxy, heteroaryloxy, heteroarylalkoxy, acyl, acyloxy, hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, arylalkoxy C _1-6 alkyl, thio A compound according to any one of the preceding claims, wherein C _1-6 alkyl, —COR ⁴ , or —SO ₂ R ¹¹ , wherein R ⁴ and R ¹¹ are independently selected from the following groups: : Hydroxy, halogen, perhalomethyl, C _1-6 alkoxy or amino; said amino may be substituted by one or more C _1-6 alkyl, perhalomethyl or aryl, said aryl is one or more halogen, It may be substituted with perhalomethyl, hydroxy, nitro or cyano. 8. Z is a terminal carbon atom of the double bond or Z is CR ³ , wherein R ³ is hydrogen, halogen, perhalomethyl, C _1-6 alkyl, C _4-6 alkenyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, aryloxy,
Arylalkoxy, heteroaryloxy, heteroarylalkoxy, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, or an arylalkoxy C _1-6 alkyl, in any one of the preceding claims A compound as described. 9. The compound according to any one of the preceding claims, wherein Z is the terminal carbon atom of the double bond, or Z is CR ³ , wherein R ³ is hydrogen. 10. Q is O, S or NR ^12,, wherein R ¹² is hydrogen, perhalomethyl, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl,
Aryl, arylalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, acyl, hydroxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxycarbonyl, aryloxycarbonyl, arylalkoxycarbonyl, C _1-6 alkoxy C _1-6 alkyl, aryloxy C _1-6 alkyl, arylalkoxy C _1-6 alkyl, thio C _1-6 alkyl, —COR ¹³ , or —SO ₂ R ¹⁴ , wherein R ¹³ and R ¹⁴ are is independently selected from the group below, the according to any one of claims compounds: hydroxy, perhalomethyl, C _1-6 alkoxy or amino; wherein amino is 1 or more C _1-6 alkyl May be substituted with perhalomethyl or aryl, wherein said aryl is substituted with one or more halogen or perhalo. Good. 11. The method of claim 1, wherein Q is O, S, or NR ¹² , wherein R ¹² is hydrogen, perhalomethyl, C _1-6 alkyl, aryl, arylalkyl, heteroarylalkyl, or acyl. A compound according to any one of the preceding claims. 12. The compound according to any one of the preceding claims, wherein Q is O or S. 13. The compound according to any one of the preceding claims, wherein Q is O. (14) A compound according to any one of the preceding claims, wherein represents a single or double bond. 15. Ar is an arylene, a heteroarylene, or a divalent heterocyclic ring.
Are formula groups, each of which is one or more halogen, C_1-6Alkyl or C _1-6 The compound according to any one of the preceding claims, which may be substituted with alkoxy.
Compound. 16. The compound according to any one of the preceding claims, wherein Ar is arylene or heteroarylene. 17. The compound according to any one of the preceding claims, wherein Ar is arylene. 18. R ⁵ represents hydrogen, hydroxy, halogen, C _1-6 alkoxy, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl or arylalkyl; the group may be substituted with 1 or more halogen or perhalomethyl, or R ⁵ forms a bond together with R ^6, a compound according to any one of the preceding claims. 19. R ⁵ is hydrogen, halogen, C _1-6 alkoxy, or represents C _1-6 alkyl or perhalomethyl, or R ⁵ forms a bond together with R ^6, any one of the preceding claims A compound according to claim 1. 20. or R ⁵ represents hydrogen, halogen, or R ⁵ forms a bond together with R ^6, A compound according to any one of the preceding claims. 21. A compound according to any one of the preceding claims, wherein R ⁵ represents hydrogen. 22. R ⁶ represents hydrogen, C _1-6 alkoxy, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, acyl or arylalkyl; the group A compound according to any one of the preceding claims, wherein the compound is substituted with one or more halogen or perhalomethyl, or wherein R ⁶ forms a bond with R ⁵ . 23. R ⁶ is hydrogen, halogen, or represents C _1-6 alkoxy, or
R ⁶ forms a bond together with R ^5, a compound according to any one of the preceding claims. 24. or R ⁶ represents hydrogen, a C _1-6 alkoxy, or R ⁶ forms a bond together with R ^5, a compound according to any one of the preceding claims. 25. The compound according to any one of the preceding claims, wherein R ⁶ represents hydrogen. 26. M represents OR ^7, wherein R ⁷ is hydrogen, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, arylalkyl, C _{1 -6} alkoxy C _1-6 alkyl, C _1-6 alkoxycarbonyl, aryloxycarbonyl, C _1-6 alkylaminocarbonyl, arylaminocarbonyl, acyl, heterocyclyl, heteroaryl or heteroarylalkyl group, wherein the group is 1 A compound according to any one of the preceding claims, optionally substituted with halogen, perhalomethyl, hydroxy, nitro or cyano. 27. M represents OR ^7, wherein R ⁷ is hydrogen, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, arylalkyl, C _{1 -6} alkoxy C _1-6 alkyl, represents heterocyclyl, heteroaryl or heteroarylalkyl group, the group may be substituted with 1 or more halogen or perhalomethyl, according to any one of the preceding claims Compound. 28. The method according to claim 1, wherein M represents OR ⁷ , wherein R ⁷ represents C _1-6 alkyl, or M represents COYR ⁸ , wherein R ⁸ is as defined in claim 1. A compound according to any one of the preceding claims. 29. M represents OR ⁷ wherein R ⁷ represents ethyl or M represents C
A compound according to any one of the preceding claims, wherein the compound represents OYR ⁸ , wherein R ⁸ is as defined in claim 1. 30. R ⁸ is hydrogen, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 represents alkenyl, C _2-6 alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl group The compound according to any one of the preceding claims, wherein said group is optionally substituted with one or more halogen, perhalomethyl, hydroxy, nitro or cyano. 31. R ⁸ represents hydrogen, C _1-6 alkyl, C _4-6 alkenynyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, arylalkyl, heterocyclyl, heteroaryl or heteroarylalkyl group The compound according to any one of the preceding claims, wherein said group is optionally substituted with one or more halogen or perhalomethyl. 32. A compound according to any one of the preceding claims, wherein R ⁸ represents hydrogen or C _1-6 alkyl. 33. A compound according to any one of the preceding claims, wherein R ⁸ represents hydrogen or ethyl. 34. Y represents oxygen, sulfur or NR ¹⁰ wherein R ¹⁰ represents hydrogen, C _1-6 alkyl, aryl, hydroxy C _1-6 alkyl or arylalkyl, or Y is NR ¹⁰ Wherein said R ⁸ and R ¹⁰ can form a 5- or 6-membered nitrogen-containing ring, wherein said ring is optionally substituted with one or more C _1-6 alkyl. The compound according to any one of the above. 35. When Y represents oxygen or NR ¹⁰ , wherein R ¹⁰ represents hydrogen, C _1-6 alkyl, aryl, or arylalkyl, or when Y is NR ¹⁰ , R ⁸ and R ¹⁰ Is capable of forming a 5- or 6-membered nitrogen-containing ring, wherein said ring is optionally substituted with one or more C _1-6 alkyl, according to any one of the preceding claims. Compound. 36. A compound according to any one of the preceding claims, wherein Y represents oxygen. 37. The compound according to any one of the preceding claims, wherein k is an integer in the range 1-2. 38. The compound according to any one of the preceding claims, wherein n and m are 1. 39. The compound of claim 1, which is the following compound: 2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -allyloxy] -phenyl} -propionic acid Ethyl ester, 2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -allyloxy] -phenyl} -propionic acid, 3- {4- [3- (2-chloro-phenyl) -3-Phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3- (2-chloro-phenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy- Propionic acid, 3- {4- [3,3-bis- (4-methoxy-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3,3-bis- (4-methoxy-phenyl) -A Ryloxy] -phenyl} -2-ethoxy-propionic acid, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid, 2-ethoxy-3- {4- [3-phenyl-3- (thiophene- 2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester, 2-ethoxy-3- {4- [3-phenyl-3- (thiophen-2-yl) -allyloxy] -phenyl} -propionic acid, 2 -Ethoxy-3- {4- [3-phenyl-3- (pyridin-2-yl) -allyloxy] -phenyl} -propionic acid ethyl ester, 2-ethoxy-3- {4- [3-phenyl-3- (Pyridine-2 -Yl) -allyloxy] -phenyl} -propionic acid, 3- [4- (3,3-diphenyl-propoxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, 3- [4- (3,3- Diphenyl-propoxy) -phenyl] -2-ethoxy-propionic acid, 2-ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -propoxy] -phenyl} -propionic acid ethyl ester, 2 -Ethoxy-3- {4- [3-phenyl-3- (4-methylphenyl) -propoxy] -phenyl} -propionic acid, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -Propoxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3-phenyl-3- (biphenyl-4-yl) -propoxy] -phenyl} -2-ethoxy-propionic acid, 2 − ｛4 -[3,3-bis- (4-methoxy-phenyl) -allyloxy] -benzyl} -malonic acid-dimethyl ester, (E)-(2S) -2-ethoxy-3- {4- [3- (4 -Furan-2-yl-phenyl) -3-phenyl-allyloxy] -phenyl} -propionic acid ethyl ester, (E)-(2S) -2-ethoxy-3- {4- [3- (4-furan- 2-Ethyl-phenyl) -3-phenyl-allyloxy] -phenyl} -propionic acid, (E)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl ] -2-ethoxy-propionic acid ethyl ester, (E)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-fe Nyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, (E, Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, 3- {4- [3,3-bis- (3-methyl-thiophen-2-yl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- ｛ 4- [3,3-bis- (4-bromo-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, 3- {4- [3,3-bis- (4-bromo-phenyl) ) -Allyloxy] -phenyl} -2-ethoxy-propionic acid, 2-ethoxy-3- [4- (3-phenyl-3-pyridin-4-yl-allyloxy) -phenyl] -propionic acid ethyl ester, 2- Ethoxy-3- [4- 3-phenyl-3-pyridin-4-yl-allyloxy) -phenyl] -propionic acid, (E, Z)-(2S) -2-ethoxy-3- {4- [3- (4-methoxyphenyl)- Three
-Thiophen-2-yl-allyloxy] -phenyl} -propionic acid ethyl ester, (E, Z)-(2S) -2-ethoxy-3- {4- [3- (4-methoxyphenyl) -3
-Thiophen-2-yl-allyloxy] -phenyl} -propionic acid, (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyloxy) -phenyl]- Ethyl propionate, (E, Z)-(2S) -2-ethoxy-3- [4- (3-phenyl-p-tolyl-allyloxy) -phenyl] -propionic acid, (2S) -3- [4 -(3,3-diphenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, (2S) -3- [4- (3,3-diphenyl-allyloxy) -phenyl] -2-ethoxy-propione Acid, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid, (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid ethyl ester, (E)-(2S) -2-ethoxy-3- {4- [3- (4-fluorophenyl) -3-
Phenyl-allyloxy] -phenyl} -propionic acid, (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]
-Phenyl} -2-ethoxy-propionic acid ethyl ester, (2S) -3- {4- [3,3-bis- (4-methoxyphenyl) -allyloxy]
-Phenyl} -2-ethoxy-propionic acid, (2S) -3- [4- (3,3-di-p-tolyl-allyloxy) -phenyl] -2-
Ethoxy-propionic acid ethyl ester, (2S) -3- [4- (3,3-di-p-tolyl-allyloxy) -phenyl] -2-
Ethoxy-propionic acid, (Z)-(2S) -3- [4- (3-biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (Z)-(2S ) -3- {4- [3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, (Z)-(2S) -3- {4- [ 3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid, (2S) -3- {4- [3,3-bis-biphenyl-4-yl-allyloxy) -Phenyl] -2-ethoxy-propionic acid ethyl ester, (2S) -3- {4- [3,3-bis-biphenyl-4-yl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (2S ) -3- ｛4- [3,3-Bis- (4-bromophenyl) -allyl Carboxy] -
Phenyl} -2-ethoxy-propionic acid ethyl ester, (2S) -3- {4- [3,3-bis- (4-bromophenyl) -allyloxy]-
Phenyl} -2-ethoxy-propionic acid, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl) -3-phenyl-allyloxy] -phenyl {-Propionic acid ethyl ester, (Z)-(2S) -2-ethoxy-3- {4- [3- (4-furan-2-yl-phenyl) -3-phenyl-allyloxy] -phenyl} -propion Acid, (E)-(2S) -3- {4- [3- (4-bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid ethyl ester, (E)-(2S ) -3- {4- [3- (4-Bromophenyl) -3-phenyl-allyloxy] -phenyl} -2-ethoxy-propionic acid, (2S) -3- {4- [3,3-bis- (4-furan-2-yl-phenyl) -allyloxy] -phenyl} -2-ethoxy-propio Acid ethyl ester, (2S) -3- {4- [3,3-bis- (4-furan-2-yl-phenyl) -allyloxy] -phenyl} -2-ethoxy-propionic acid, (E, Z) -(2S) -3- [4- (3-biphenyl-4-yl-3-p-tolyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, (E, Z)-(2S)- 3- [4- (3-biphenyl-4-yl-3-p-tolyl-allyloxy) -phenyl] -2-ethoxy-propionic acid, (E, Z)-(2R) -3- [4- (3 -Biphenyl-4-yl-3-phenyl-allyloxy) -phenyl] -2-ethoxy-propionic acid ethyl ester, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or Mixtures of optical isomers, including racemic mixtures, or any tautomers The body of the form. 40. A pharmaceutical composition comprising as an active ingredient a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 41. A unit dosage form comprising about 0.05 to about 100 mg, preferably about 0.1 to about 50 mg, of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof. 41. The pharmaceutical composition according to 40. 42. A nuclear receptor, in particular comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent as active ingredients. Peroxisome proliferator-activated receptor (PP
Pharmaceutical compositions useful in the treatment and / or prevention of conditions mediated by AR). 43. Diabetes and / or comprising as an active ingredient a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. A pharmaceutical composition useful in treating and / or preventing obesity. 44. A pharmaceutical composition according to any one of claims 40 to 43 for oral, nasal, transdermal, pulmonary or parenteral administration. 45. A subject to be treated with an effective amount of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 40-44. A method of treating a disease comprising administering to a subject. 46. A subject to be treated with an effective amount of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 40-44. A method for treating and / or preventing a condition mediated by a nuclear receptor, particularly a peroxisome proliferator-activated receptor (PPAR), comprising administering to a subject. 47. An effective amount of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, or a composition according to any one of claims 40-44 in need of treatment. A method of treating and / or preventing diabetes and / or obesity, comprising administering to a subject who does. 48. The effective amount of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt or ester thereof is about 0.05 to about 100 mg / day, preferably about 0.1 to about 50 mg / day. 48. The method of claim 45, 46 or 47. 49. Use of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. 50. A compound according to any one of the preceding claims for the manufacture of a medicament useful in the treatment and / or prevention of conditions mediated by nuclear receptors, in particular peroxisome proliferator-activated receptor (PPAR). Or the use of a pharmaceutically acceptable salt thereof. 51. Use of a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful in the treatment and / or prevention of diabetes and / or obesity.