New compounds and their use as ppar-modulators


FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula (I), in which X1 is phenyl, 9-member bicyclic heteroaryl, containing S or O as heteroatoms, or 5-member heteroaryl, containing S or O as heteroatoms, each of which is optionally substituted with one or more substitutes, chosen from halogen or C1-6alkyl, which is optionally substituted with one or more halogens. X2 is phenyl, which is optionally substituted with one or more substitutes, chosen from halogen, or 5-member heteroaryl, containing S or O as heteroatoms. Ar is phenylene, which is optionally substituted with one or more substitutes, chosen from halogen, or C1-6alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted with one or more halogens. Y1 is O or S, and Y2 represents O, Z represents -(CH2)n-, where n equals 1, 2 or 3. R1 is hydrogen or C1-6alkoxy and R2 is hydrogen, C1-6alkyl. The invention also relates to pharmaceutical salts of these compounds or any of their tautomeric forms, stereoisomers, stereoisomer mixtures, including racemic mixtures.

EFFECT: invention also pertains to use of these compounds as pharmaceutical compositions, with effect on receptors, activated by the peroxisome proliferator PPARδ subtype, and to pharmaceutical compositions, containing these compounds (I).

36 cl, 41 ex

 

The scope of the invention

The present invention relates to new compounds, to the use of these compounds as pharmaceutical compositions, to pharmaceutical compositions containing these compounds, and to a method of treatment, which use these compounds and compositions. More specifically, the compounds of the present invention can be used for the treatment and/or prevention of conditions oposredstvovanii receptors activated proliferation peroxisome (Peroxisome Proliferator-Activated Receptors) (PPAR), in particular PPARδ subtype.

Background of the invention

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

Hypolipidemic fibrates and antidiabetic preparations of thiazolidinediones separately demonstrated moderately effective, reducing triglycerides activity, although they are neither very efficient nor effective enough to use them as the only chosen therapy in dyslipidemia, which is often observed in patients with type II diabetes or in patients with metabolic Sindh is the Ohm. Preparations of thiazolidinediones also effectively reduce the levels of blood glucose in diabetes of the second type on animal models and in humans. However, the class fibrate compounds does not provide favorable effects when blood glucose levels. Studies on the action of these compounds at the molecular level shows that preparations of thiazolidinediones and fibrates appear to act through activation of specific transcription factor family receptor that is activated by proliferation peroxisome (PPAR), which leads to enhanced and attenuated the expression of specific enzymes and apolipoproteinb, respectively, and both play a key role in the regulation of content in plasma triglycerides. Fibrates, on the one hand, are activators of PPARαoperating mainly in the liver. Preparations of thiazolidinediones, on the other hand, are high affinity ligands for PPARγacting mainly on adipose tissue.

Adipose tissue plays a Central role in lipid homeostasis and the maintenance of energy balance in vertebrates. Adipocytes store energy in the form of triglycerides during periods of sufficient nutrients and excrete it in the form of free fatty acids during periods of nutritional deficiency. Development of white adipose tissue is the result of a continuous process of differentiation Avenue is within all life. Plenty of evidence points to the Central role of activation of PPARγ for the initiation and regulation of this cellular differentiation. Several highly specialized proteins induced during differentiation of adipocytes, and most of them involved in the processes of accumulation and lipid metabolism. Specific communication activation of PPARγ with changes in glucose metabolism, most notably in the reduction of insulin resistance in the muscles, still has not been clarified. Possible communication is a communication performed through the free fatty acids, such as activation of PPARγwhich induces lipoprotein lipase (LPL), a transport protein, fatty acids (FATP) and acyl-CoA a synthetase (ACS) in adipose tissue but not in muscle tissue. This, in turn, dramatically reduces the concentration of free fatty acids in plasma, and due to the competition of the substrate at the cellular level, skeletal muscle and other tissues with high speeds metabolism eventually switch oxidation fatty acid oxidation to glucose oxidation, resulting in a weakened resistance to insulin.

PPARα participate in stimulation β-oxidation of fatty acids. In rodents PPARα-mediated changes in the expression of genes involved in fatty acid metabolism that underlies the phenomenon of peroxisome proliferation, pleiotropy the mini-cell reactions limited, mainly by the liver and kidneys, which can lead to hepatocarcinogenesis in rodents. The phenomenon of peroxisome proliferation is not observed in humans. In addition to its role in peroxisome proliferation in rodents PPARα also participate in the control of the levels of HDL cholesterol in rodents and in humans. This effect is at least partially based on PPARα-mediated transcriptional regulation of major HDL of apolipoproteins, apo A-I and apo A-II. Hypotriglyceridemic action of fibrates and fatty acids also includes PPARα and can be summarized as follows: (I) enhanced lipolysis and clearance of residual particles due to changes in the levels of lipoprotein lipase and apo C-III, (II) stimulation of the uptake of fatty acids by the cells and their subsequent conversion to acyl-CoA derivatives by induction-type fatty acid binding protein and acyl-CoA synthase, (III) the induction of metabolic pathways β-oxidation of fatty acids, (IV) reduction in fatty acid synthesis and triglyceride levels and, finally, (V) the decrease in VLDL production. Therefore, as the increased catabolism of triglyceride-rich particles, and reduced secretion of VLDL particles comprise a mechanism that contributes to the hypolipidemic effect of fibrates.

It was initially reported that the activation of PPARδ not involved in modulating the levels of gluco is s or triglycerides. (Berger et al., J. Biol. Chem., 1999, Vol 274, p. 6718-6725). Later it was shown that activation of PPARδ leads to increased levels of HDL cholesterol in dbldb mice (Leibowitz et al. FEBS letters 2000, 473, 333-336). In addition, the agonist of PPARδbeing entered immune to insulin suffering from obesity makaka-RH middle age causes a sharp dose-dependent increase in the level of HDL cholesterol in serum and decrease LDL low density, triglycerides, glucose and insulin fasting (Oliver et al. PNAS 2001, 98, 5306-5311). In the same article it was shown that activation of PPARδ enhances ATP-binding cassette A1 reverse carrier of cholesterol and induces apolipoprotein A1-specific outflow of cholesterol. The involvement of PPARδ fatty acid oxidation in muscle was further confirmed in mice lacking PPARα. Muoio et al. (J. Biol. Chem. 2002, 277, 26089-26097) showed that high levels of PPARδ in skeletal muscle can compensate the deficiency of PPARα. Taken together, these observations suggest that activation of PPARδ benefits in the treatment and prevention of cardiovascular diseases and conditions, including atherosclerosis, hypertriglyceridemia and mixed dyslipidemia (WO 01/00603).

It was reported that a number of PPARδ connections can be used for the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (WO 02/59098, WO 01/603, WO 01/25181, WO 02/14291, WO 01/79197, WO 99/4815, WO97/28149, WO 98/27974, WO 97/28115, WO 97/27857, WO 97/28137, WO 97/27847).

Lower levels of glucose as the only approach does not allow to overcome the macrovascular complications associated with type II diabetes and metabolic syndrome. Therefore, new methods of treatment of type II diabetes and metabolic syndrome should be aimed at the reduction as an explicit hypertriglyceridemia associated with these syndromes, and facilitating conditions of hyperglycemia.

This indicates that the search for compounds that demonstrate different degrees of activation of PPARα, PPARγ and PPARδshould lead to the discovery of effective drugs that reduce the levels of triglycerides and/or cholesterol and/or glucose, which have high potential in the treatment of diseases such as type II diabetes, dyslipidemia, syndrome X (including the metabolic syndrome, i.e. impaired glucose tolerance, insulin resistance, hypertriglyceridemia and/or obesity), cardiovascular diseases (including atherosclerosis) and hypercholesterolemia.

In WO 97/48674 described various antimicrobial darily as anti-infective agents. The specified invention includes compounds of the formula:

where L is chosen from the group consisting of N, CH and C; G, E can be independently selected (along with others) from phenyl, replacing the military phenyl (substituents are halogen, alkyl or alkoxy), panels1-4of alkyl, substituted phenyls1-4of alkyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-tanila and 3-tanila; J may represent CH or O; X is selected from the group consisting of O, S, NR, and C(O)NR; Ar may represent aryl or substituted aryl (the substituents are halogen, alkyl or alkoxy); W can represent O or S; A is selected from the group consisting of (among others) NRR, amidino, COOH; CHRCOOH, CH=CHR, CH=C(COOH)2; m, n can be independently equal to 0 to 6; and q, p can be independently represent 0 or 1. In this application is not disclosed to any compounds in which p=1.

Definition

In the structural formulas presented below and throughout this description, the terms used have the following specified values:

The term "C1-6alkyl" in the sense as used herein, alone or in combination, represents a linear or branched saturated hydrocarbon chain containing the specified number of carbon atoms. Typical examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl etc.

The term "C1-6alkylsulphonyl" in the sense used in this description is "C1-6alkyl" group as defined above containing a specified number of carbon atoms is bound through a carbonyl group. Typical examples include, but are not limited to, methylcarbamyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, butylcarbamoyl, isobutylketone, second-butylcarbamoyl, tert-butylcarbamoyl, n-internabonal, isopentylamine, neopentylene, tert-internabonal, n-hexylcaine, isohexanol etc.

The term "C1-6alkylsulfonyl" in the sense used in this description, refers to a monovalent Deputy, including "1-6alkyl group, as defined above, linked through sulfonyloxy group. Typical examples include, but are not limited to, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, isobutylphenyl, second-butylsulfonyl, tert-butylsulfonyl, n-peterculter, isopentylamine, neopentylene, tert-peterculter, n-hexylsilane, isohexanol etc.

The term "C1-6alkylsulfonate" in the sense used in this description, refers to a monovalent Deputy, including "1-6alkyl group, as defined above, linked through sulfonyloxy group. Typical examples include, but are not limited to, methylsulfonylamino, ethylsulfonyl,

n-propylsulfonyl, isopropylphenoxy,

n-butylsulfonyl, isobutyronitrile,

p> Deut-butylsulfonyl, tert-butylsulfonyl,

n-pentylaniline, isopentylamine,

neopentanoate, tert-pentylaniline,

n-hexylaniline, isohexanoate etc.

The term "C1-6alkylamino", in the sense used in this description, refers to an acyl group, connected via the amino group. Typical examples include, but are not limited to, acetylamino, propionamido, bucillamine, isobutylamino, paulolino, Valeriano etc.

The term "C3-6cycloalkyl" in the sense as used herein, alone or in combination, is a saturated monocyclic hydrocarbon group containing the specified number of carbon atoms. Typical examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "C2-6alkenyl" in the sense used in this description, is refinancing branched or unbranched hydrocarbon group containing from 2 to the specified number of carbon atoms and at least one double bond. Typical examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, allyl, Isopropenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl etc.

The term "C2-6quinil" in the sense as used in Dan is th description is unsaturated branched or unbranched hydrocarbon group containing from 2 to the specified number of carbon atoms and at least one triple bond. Typical examples include, but are not limited to, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 1-pentenyl, 2-pentenyl etc.

The term "C4-6alkenyl" in the sense used in this description, is an unsaturated branched or unbranched hydrocarbon group containing 4 to the specified number of carbon atoms and at least one double bond and at least one triple bond. Typical examples include, but are not limited to, 1-penten-4-inyl, 3-penten-1-inyl, 1,3-hexadien-5-inyl etc.

The term "C1-6alkoxy" in the sense used in this description, separately or in combination, refers to an unbranched or branched structure, linked through ether oxygen, the free valency of which is represented by the relationship of essential oxygen. Examples of linear alkoxygroup are methoxy, ethoxy, propoxy, butoxy, pentox, hexose etc. are Examples of branched alkoxygroup serve isopropoxy, sec-butoxy, tert-butoxy, isopentylamine, etexilate etc.

The term "C3-6cycloalkane" in the sense used in this description, separately or in Combi is then, represents a saturated monocyclic hydrocarbon group containing the specified number of carbon atoms linked through an ether oxygen, the free valency of which is represented by the relationship of essential oxygen. Examples of cycloalkenyl serve cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy etc.

The term "C1-6alkylthio", in the sense used in this description, separately or in combination, refers to an unbranched or branched monovalent Deputy, including "1-6alkyl group, as defined above, linked through a divalent sulfur atom, the free valency of which is represented by the relationship sulfur atom, and containing 1-6 carbon atoms. Typical examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, pentylthio etc.

The term "C3-6cycloalkyl" in the sense used in this description, separately or in combination, is a saturated monocyclic hydrocarbon group containing the specified number of carbon atoms linked through a divalent sulfur atom, the free valency of which is represented by the relationship of the sulfur atom. Examples of cycloalkylation serve cyclopropylethyl, cyclobutyl, cyclopentyl, cyclohexylthio etc.

The term "C1-6alkylamino" in the sense as used in isolano in this description, separately or in combination, refers to an unbranched or branched monovalent Deputy, including "1-6alkyl group, as defined above, linked through the amino group, the free valency of which is represented by the relationship of the nitrogen atom. Typical examples include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, pentylamine etc.

The term "C1-6alkylaminocarbonyl" in the sense used in this description, refers to a monovalent Deputy, including1-6-monoalkylamines a group attached through a carbonyl group, such as, for example,

methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl,

isopropylaminocarbonyl, n-butylaminoethyl,

second-butylaminoethyl, isobutylparaben,

tert-butylaminoethyl, n-intramyocardial,

2-methylbutylamine, 3-methylbutylamine,

n-mexiletineciclovir, 4-methylbenzyloxycarbonyl,

neopentylglycol, n-mexiletineciclovir and

2.2-dimethylpropyleneurea etc.

The term "C3-6cyclooctylamino" in the sense used in this description, separately or in combination, is a saturated monocyclic hydrocarbon group containing the specified number of carbon atoms linked through the amino group, the free valency of which is represented by the relationship of the nitrogen atom. Typical examples include, but are not limited to, cyclopropylamino, cyclobutylamine, cyclopentylamine, cyclohexylamine etc.

The term "C1-6alkoxyl1-6alkyl" in the sense used in this description, separately or in combination, refers to "C1-6alkyl group, as defined above, is attached to "C1-6alkoxy" group as defined above. Typical examples include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl etc.

The term "aryl" in the sense used in this description, refers to an aromatic monocyclic or condensed aromatic bi -, or tricyclic hydrocarbon group. Typical examples include, but are not limited to, phenyl, naphthyl, anthracene, phenanthrene, azulene etc.

The term "arisen" in the sense used in this description, refers to a divalent monocyclic aromatic or a divalent condensed aromatic bi -, or tricyclic hydrocarbon group. Typical examples include, but are not limited to, phenylene, naftilan etc.

The term "arylcarbamoyl" in the sense used in this description, represents "aryl" group as defined above linked through a carbonyl group. Typical examples include, but are not ogranichivaut what they phenylcarbinol, afterburner, intracerebral, phenanthrenequinones, ashleykermani etc.

The term "arylsulfonyl" in the sense used in this description, refers to an "aryl" group as defined above linked through sulfonyloxy group. Typical examples include, but are not limited to, phenylsulfonyl, naphthylmethyl, anthracenesulfonic, phenanthridinone, Aslanishvili, etc.

The term "arylsulfonyl" in the sense used in this description, refers to an "aryl" group as defined above linked through sulfonyloxy. Typical examples include, but are not limited to, phenylsulfonyl,

naftiliaki, anthracenesulfonic,

phenanthrenequinone, Aslanishvili, etc.

The term "arylamino" in the sense used in this description, refers to arylcarbamoyl group, connected via the amino group. Typical examples include, but are not limited to, phenylcarbonylamino, nattermannallee,

intracerebrally, phenanthrenequinone,

aslanikasvili etc.

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

The term "perhalogenated" means trifluoromethyl, trichloromethyl, tribromoethyl or triacetyl.

The term "perhalogenated" means triptime the si, trichlormethane, tribromomethane or triacetoxy.

The term "C1-6-dialkylamino" in the sense used in this description, refers to the amino group in which two hydrogen atoms independently substituted unbranched or branched saturated hydrocarbon chain containing the specified number of carbon atoms. Typical examples include, but are not limited to, dimethylamino, N-ethyl-N-methylamino, diethylamino, dipropylamino, N-(n-butyl)-N-methylamino, di(n-pentyl)amino, etc.

The term "acyl" in the sense used in this description, refers to a monovalent Deputy, including "C1-6alkyl group, as defined above, linked through a carbonyl group. Typical examples include, but are not limited to, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl etc.

The term "heteroaryl" in the sense used in this description, separately or in combination, refers to a monovalent Deputy, including a 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolin, isoxazolyl, oxazolyl, oxadiazolyl ti is thiazolyl, chenail, ethanolic, hintline, honokalani, indolyl, benzimidazolyl, benzofuranyl, benzothiazol, pteridinyl and purines, etc.

The term "heteroaryl" in the sense used in this description, separately or in combination, refers to a divalent 5-7 membered monocyclic aromatic system or a 8-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, for example, fullen, tienlen, pyrroline, imidazoline, pyrazoline, triazoline, personalen, pyrimidine, pyridazine, isothiazoline, isoxazoline, oxazoline, oxadiazoline, thiadiazoline, chinoline, ethanallen, hintline, chynoxaline, indoline, benzimidazolyl, benzofuranyl, pteridinyl and phrenilin etc.

The term "heteroaromatic" in the sense used in this description, separately or in combination, refers to heteroaryl, as defined above, linked through the oxygen atom, the free valency of which is represented by the relationship of the oxygen atom, for example, pyrrolidone, imidazolidine, pyrazolinone, triazolinone, pyrazinone, pyrimidinone, pyridazinone, isothiazolinone, isoxazolidine, oxazolidine, oxadiazolidine, thiadiazolidine, hyalinelike, ethanolinduced, girasolereale, hinoksolinov, idoll the XI, benzimidazolinone, benzofuranyl, peridiniales, purinox etc.

The term "aralkyl" in the sense used in this description, refers to an unbranched or branched saturated carbon chain containing from 1 to 6 carbon atoms, substituted aromatic hydrocarbon. Typical examples include, but are not limited to, benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-(1-naphthyl)ethyl and the like,

The term "aryloxy" in the sense used in this description, refers to phenoxy, 1 naphthyloxy, 2-naphthyloxy etc.

The term "arakaki" in the sense used in this description, refers to C1-6alkoxygroup, substituted aromatic hydrocarbons, such as benzyloxy, venetucci, 3 phenylpropoxy, 1 aftermatket, 2-(1-naphthyl)ethoxy etc.

The term "heteroalkyl" in the sense used in this description, refers to an unbranched or branched carbon chain containing from 1 to 6 carbon atoms, a substituted heteroaryl group; such as (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl, etc.

The term "heteroaromatic" in the sense used in this description refers to heteroaromatic, as defined above, linked to the oxygen atom, the free valency of which the submission is and the relationship of the oxygen atom. Typical examples include, but are not limited to, (2-furyl)metiloksi, (3-furyl)metiloksi, (2-thienyl)metiloksi, (3-thienyl)metiloksi, (2-pyridyl)metiloksi, 1-methyl-1-(2-pyrimidyl)ethyloxy etc.

The term "aristeo" in the sense used in this description, separately or in combination, refers to an aryl group linked through a divalent sulfur atom, the free valency of which is represented by the relationship sulfur atom, and the aryl group may be optionally mono - or polyamidine C1-6by alkyl, halogen, hydroxy or With the1-6alkoxy. Typical examples include, but are not limited to, phenylthio, (4-were)thio, (2-chlorophenyl)thio etc.

Some of the above defined terms may occur in the structural formula more than once and in such case each of the terms must be defined independently of the other. The term "optionally substituted" in the sense used in this description, means that the group or is unsubstituted or substituted by one or more of these substituents. If the considered group substituted by more than one Deputy, these substituents may be the same or different.

Description of the invention

The present invention relates to compounds of General formula (I):

where X1predstavljaet aryl or heteroaryl, each of which is optionally substituted by one or more substituents selected from the

of halogen, hydroxy, cyano, amino or carboxy; or

C1-6of alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6the quinil, aralkyl, heteroalkyl, C1-6alkoxy, C3-6cycloalkane, aryloxy, Alcoxy, heteroaromatic, C1-6alkylthio, aaltio, C3-6cycloalkyl, C1-6alkylcarboxylic, arylcarbamoyl,1-6alkylsulfonyl, C1-6alkylsulfonate, arylsulfonate, arylsulfonate, C1-6alkylamino, arylamino,1-6alkylaminocarbonyl, C1-6alkylamino,1-6-dialkylamino or C3-6cyclooctylamino, each of which is optionally substituted by one or more halogen; and

X2represents aryl or heteroaryl, each of which is optionally substituted by one or more substituents selected from the

of halogen, hydroxy, cyano, amino or carboxy; or

C1-6of alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6the quinil, aralkyl, heteroalkyl, C1-6alkoxy, C3-6cycloalkane, aryloxy, Alcoxy, heteroaromatic, C1-6alkylthio, aaltio, C3-6cycloalkyl, C1-6alkylcarboxylic, arylcarbamoyl,1-6alkylsulfonyl, C1-6alkylsulfonate, arylsulfonate, arylsulfonate, C1-6alkylamino, and is ylamide, With1-6alkylaminocarbonyl, C1-6alkylamino,1-6-dialkylamino or C3-6cyclooctylamino, each of which is optionally substituted by one or more halogen; and

Ar represents arisen, which is optionally substituted by one or more substituents selected from the

halogen, hydroxy or cyano; or

C1-6of alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6the quinil, aryl, heteroaryl, aralkyl, heteroalkyl, C1-6alkoxy, C3-6cycloalkane, aryloxy, Alcoxy, heteroaromatic, C1-6alkylthio, aaltio or C3-6cycloalkyl, each of which is optionally substituted by one or more halogen; and

Y1represents O or S; and

Y2represents O or S; and

Z represents -(CH2)n-where n is 1, 2 or 3; and

R1represents hydrogen, halogen or Deputy, selected from

With1-6of alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6the quinil, aralkyl, heteroalkyl, C1-6alkoxy, C3-6cycloalkane, aryloxy, Alcoxy, heteroaromatic,1-6alkylthio, aaltio or C3-6cycloalkyl, each of which is optionally substituted by one or more halogen; and

R2represents hydrogen, C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6quinil, C4-6alkenyl or aryl; and

their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvate, or any tautomeric forms, stereoisomers, mixtures of stereoisomers including a racemic mixture, or polymorphs.

In one embodiment, the present invention relates to compounds of formula (I), where X1represents aryl, optionally substituted by one or more substituents selected from the

halogen or

C1-6of alkyl, C1-6alkoxy, C1-6alkylsulfonyl or1-6alkylsulfonate, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents aryl, optionally substituted by one or more substituents selected from the

halogen or

C1-6the alkyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents aryl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents phenyl, optionally substituted by one or more substituents selected from the

halogen or

C1-6of alkyl, C1-6alkoxy, C1-6alkylsulfonyl or1-6alcalali is aryloxy, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents phenyl, optionally substituted by one or more substituents selected from the

halogen or

With1-6the alkyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents phenyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1is heteroaryl, optionally substituted by one or more substituents selected from the

halogen or

With1-6of alkyl, C1-6alkoxy, C1-6alkylsulfonyl or1-6alkylsulfonate, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1is heteroaryl, optionally substituted by one or more substituents selected from the

halogen or

With1-6the alkyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1is heteroaryl, long is Ino substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents furyl, thienyl, benzothiazyl or benzofuranyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X1represents furyl, thienyl, benzothiazyl or benzofuranyl, optionally substituted by one or more1-6alkilani, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents aryl, optionally substituted by one or more substituents selected from the

halogen or

With1-6of alkyl, C1-6alkoxy, C1-6alkylsulfonyl or1-6alkylsulfonate, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents aryl, optionally substituted by one or more substituents selected from the

halogen or

With1-6the alkyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents aryl, optionally substituted by one or more Halogens.

In other variations the ones the present invention relates to compounds of formula (I), where X2represents phenyl, optionally substituted by one or more substituents selected from the

halogen or

C1-6of alkyl, C1-6alkoxy, C1-6alkylsulfonyl or C1-6alkylsulfonate, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents phenyl, optionally substituted by one or more substituents selected from the

halogen or

C1-6the alkyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents phenyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2is heteroaryl, optionally substituted by one or more substituents selected from the

halogen or

C1-6of alkyl, C1-6alkoxy, C1-6alkylsulfonyl or1-6alkylsulfonate, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2is heteroaryl, not necessarily for ewenny one or more substituents, selected from the

halogen or

C1-6the alkyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2is heteroaryl optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents furyl, thienyl, benzothiazyl or benzofuranyl, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where X2represents furyl, thienyl, benzothiazyl or benzofuranyl, optionally substituted by one or more C1-6alkilani, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more substituents selected from the

halogen, hydroxy or cyano; or

With1-6of alkyl, C3-6cycloalkyl, C2-6alkenyl, C2-6the quinil, aryl, heteroaryl, aralkyl, heteroalkyl,1-6alkoxy, C3-6cycloalkane, aryloxy, Alcoxy, heteroaromatic, C1-6alkylthio, aaltio or C3-6cycloalkyl, each of which is optionally substituted by one or more Halogens is.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more substituents selected from the

halogen or

With1-6of alkyl, aryl, C1-6alkoxy, aryloxy or Alcoxy, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more C1-6alkilani, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more C1-6alkoxy, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more Allami, optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which neo is Astelin replaced by stands or ethyl.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by methoxy.

In another embodiment, the present invention relates to compounds of formula (I), where Ar is phenylene, which is optionally substituted by one or more fenelli.

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

In another embodiment, the present invention relates to compounds of formula (I), where Y1represents O.

In another embodiment, the present invention relates to compounds of formula (I), where Y1is S.

In another embodiment, the present invention relates to compounds of formula (I), where Y2represents O.

In another embodiment, the present invention relates to compounds of formula (I), where Y2is S.

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

In another embodiment, the present invention relates to compounds of formula (I), where R1represents hydrogen or Deputy, is selected from C1-6of alkyl, aralkyl, C1-6alkoxy, aryloxy, Alcoxy, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula is (I), where R1represents hydrogen or a Deputy selected from C1-6of alkyl, C1-6alkoxy, each of which is optionally substituted by one or more Halogens.

In another embodiment, the present invention relates to compounds of formula (I), where R1represents hydrogen.

In another embodiment, the present invention relates to compounds of formula (I), where R1represents methoxy or ethoxy.

In another embodiment, the present invention relates to compounds of formula (I), where R2represents hydrogen.

In another embodiment, the present invention relates to compounds of formula (I), where R2represents methyl or ethyl.

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

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

In another embodiment, the present invention relates to compounds of formula I, where quinil is 1-PROPYNYL.

In another embodiment, the present invention relates to compounds of formula I, where alkenyl is 1-penten-4 in.

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

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

In another embodiment, the present invention relates to compounds of formula I, where Allen is phenylene.

In another embodiment, the present invention relates to compounds of formula I, where the halogen is bromine, fluorine or chlorine.

In another embodiment, the present invention relates to compounds of formula I, where perhalogenated represents trifluoromethyl.

In another embodiment, the present invention relates to compounds of formula I, where perhalogenated is triptoreline,

In another embodiment, the present invention relates to compounds of formula I, where heteroaryl is furyl or thienyl.

In another embodiment, the present invention relates to compounds of formula I, where aralkyl represents benzyl.

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

In another embodiment, the present invention relates to compounds of formula I, where arakaki is benzyloxy.

In another embodiment, the present invention relates to compounds of formula I where the substituents R1and X2are in the TRANS configuration.

In another embodiment, the present invention relates to compounds of formula I where the substituents R1and X2are in the CIS-configuration.

In others the d variant, the present invention relates to compounds of the formula I, which are agonists of PPARδ.

In another embodiment, the present invention relates to compounds of the formula I, which are selective agonists of PPARδ.

Examples of specific compounds of the present invention are:

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

ethyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2,6-diphenylmethoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)allyloxy]-2,6-diphenylmethoxy}acetic acid, or

their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvate, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.

Other examples of specific compounds of the present invention are:

methyl ester {4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid,

4-[3,-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-m is Difenoxin}acetic acid

or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvate, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.

Other examples of specific compounds of the present invention are:

(E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(4-bromophenyl)-3-(5-methylthiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(furan-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(5-methylthiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(benzo[b]thiophene-3-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

{4-[3,3-bis-(4-chlorophenyl)allyloxy]phenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-triptoreline}acetic acid,

{4-[3,3-bis-(3-methylthiophene-2-yl)arylsulfonyl]-2-triptoreline}acetic acid,

[4-(3,3-difuran-2-intellisurvey)-2-triptoreline]acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

(E/Z)-[4-[3-(5-Bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid, or

their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvate, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.

Other examples of specific compounds of the present invention are:

{4-[3-(2-forfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylethylamine is]phenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]phenoxy}acetic acid,

4-[3-(2-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4[3-(2-trifloromethyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-methylphenoxy}acetic to the slot,

{4-[3-(2-were)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-generally sulfanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenyl who lilangeni]-2-chlorophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-iodophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-2-chlorphenol and}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylal sulfanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-2-bromophenoxy}vinegar is Aya acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylal ylsulphonyl]-2-iodinate}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-trifter terphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

20 {4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenyl who lilangeni]-3-methylphenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-Trifluoromethyl-phenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-methylphenoxy}vinegar is Aya acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid the acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-f is lalallalala]-3-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-3-chlorophenoxy}of uksosn the I acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-generallyrally the l]-3-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-trifloromethyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenyl who lilangeni]-3-iodinate}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-methoxyphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-methoxyphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-methoxyphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-ethoxyphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-ethoxyphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-ethoxyphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-trifloromethyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-trifloromethyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-trifloromethyl)-3-generallya hanil]-3-iodinate}acetic acid,

{4-[3-(2-methanesulfonylaminoethyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-methanesulfonylaminoethyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-methanesulfonylaminoethyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]Fe is oxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-methylphenoxy}of the criminal code of Usna acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-itfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-itfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-itfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-2-methylphe the oxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-torfin the l)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-2-glorf is noxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-bromophenoxy}is kasna acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-iodinate}acetic sour is a,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-itfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-itfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-itfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-2-iodinate}uksu the Naya acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-methylphenoxy}acetic Ki the lot,

{4-[3,3-bis-(2-itfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-itfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-itfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-atok iphenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-3-chlorophenoxy}acetic to the slot,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-tripto the methoxyphenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-itfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-itfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-itfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-methylphen the l)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-3-bromophenoxy}UKS is SNA acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-itfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-itfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-itfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-were)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-were)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-were)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-ethylphenyl)arylsulfonyl]-3-iodinate}acetic who Isleta,

{4-[3,3-bis-(3-ethylphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-ethylphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-triptoreline)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-triptoreline)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-methoxyphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-methoxyphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-methoxyphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-ethoxyphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-ethoxyphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-ethoxyphenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-trifloromethyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-trifloromethyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-trifloromethyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-methanesulfonylaminoethyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-methysulfonylmethane)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-methysulfonylmethane)arylsulfonyl]-3-iodf is noxy}acetic acid

or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvate, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture, or polymorphs.

The present invention also includes pharmaceutically acceptable salts of the compounds of the present invention. Such salts include pharmaceutically acceptable salts of joining acids, pharmaceutically acceptable salts joining bases, pharmaceutically acceptable metal salts, ammonium salts and salts of alkylated ammonium. Salt accession acids include inorganic salts as well as salts of organic acids.

Typical examples of suitable inorganic acids include hydrochloric, Hydrobromic, yodiewonderdog, phosphoric, sulphuric, nitric acid, etc. are Typical examples of suitable organic acids include formic, acetic, trichloroacetic, triperoxonane, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, almond, oxalic acid, picric acid, pyruvic acid, salicylic, succinic, methansulfonate, econsultancy, tartaric, ascorbic, Paveway, biotranslation, etanislao, gluconic, citraconate, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic the th, glutamic, benzosulfimide, p-toluensulfonate acid. Examples of salts include sulfates, nitrates, phosphates, perchlorates, borates, acetates, benzoate, hydroxynaphthoate, glycerophosphate, Ketoglutarate etc. are Other examples of pharmaceutically acceptable inorganic or organic salts accession acids include pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is included in this description by reference. Examples of metal salts include salts of lithium, sodium, potassium, magnesium, zinc, calcium, etc. are Examples of amines and organic amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, Propylamine, butylamine, tetramethylene, ethanolamine, diethanolamine, triethanolamine, meglumine, Ethylenediamine, choline, N,N'-dibenziletilendiaminom, N-benzylpenicillin, N-methyl-D-glucamine, guanidine and the like, Examples of the cationic amino acids include lysine, arginine, histidine, etc.

Pharmaceutically acceptable salts are obtained by interaction of the compounds of formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, tert-piperonyl potassium, calcium hydroxide, magnesium hydroxide and the like, in solvents such as ether, THF, methanol, tert-butanol, dioxane, isopropanol, ethanol, etc. Can be used solvent mixtures. You can also use the organization of the institutions of the base, such as lysine, arginine, diethanolamine, choline, guanidine and derivatives thereof, etc. In another embodiment, the salt of the accession acids obtained by treatment with acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluensulfonate acid, methanesulfonate acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzolsulfonat acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. you Can also use a mixture of solvents.

The stereoisomers of the compounds forming part of the present invention, can be obtained using the reagents in the form of individual enantiomers in any way in which this is possible, or carrying out the reaction in the presence of reagents or catalysts in the form of individual enantiomers, or separating a mixture of stereoisomers by conventional methods. Some of the preferred methods include the use of microbiological separation, enzymatic separation, separation diastereoisomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, m is lachna acid, and so, where possible, or chiral bases such as brucine, (R)- or (S)-phenylethylamine, Hinn alkaloids and their derivatives, etc. are Usually used methods collected Jaques et. al. in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically the compound of formula I can be converted to a mixture of 1:1 diastereoisomeric amides processing of chiral amines, aminoacids, aminoalcohols derived from aminoacids; and to convert the acids into amides you can use normal reactions; diastereoisomer you can share or fractional crystallization or chromatography and the stereoisomers of the compounds of formula I can be obtained gidrolizu clean diastereoisomeric amide.

Different polymorphs of the compounds of formula I, form part of the present invention, can be obtained by crystallization of the compounds of formula I in various conditions. For example, using commonly used various solvents or their mixtures for recrystallization; crystallization at different temperatures, different types of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting compounds with subsequent gradual or fast cooling. The presence of polymorphs may be determined using solid state NMR spectrum is the scopy, Infrared spectroscopy, differential scanning calorimetry, powder x-ray diffraction analysis or other similar methods.

The present invention also includes prodrugs of the compounds of the present invention that after administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. Typically, such prodrugs will be functional derivatives of the compounds of the present invention, which easily undergo transformation in vivo into the required compound of formula (I). The usual methods of selecting and obtaining the appropriate proletarienne derivatives disclosed, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

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

The present invention relates also to pharmaceutical compositions containing as active ingredient at least one compound of formula I, or any optical or geometric isomer or tautomeric form, including mixtures thereof, or their pharmaceutically acceptable salts, together with one or more pharmaceutically acceptable carriers or diluents.

In addition, the present invention relates to the use of compounds of General formula I or its tautomeric form, stereoisomer is in, their polymorphs, their pharmaceutically acceptable salts, or pharmaceutically acceptable solvate to obtain pharmaceutical compositions for the treatment and/or prevention of conditions oposredstvovanii nuclear receptors, especially the receptors activated proliferation peroxisome (PPAR)such as the above condition.

In another aspect, the present invention relates to a method of treatment and/or prevention of diabetes the first or second types.

In another aspect, the present invention relates to the use of one or more compounds of General formula I or their pharmaceutically acceptable salts to obtain a pharmaceutical composition for the treatment and/or prevention of diabetes, the first or second types.

In another aspect, the compounds of the present invention are useful for the treatment and/or prophylaxis of impaired glucose tolerance (IGT).

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

In another aspect, the compounds of the present invention is useful for delaying or preventing the development of diseases from IGT to diabetes of the second type.

In another aspect, the compounds of the present invention is useful for delaying or preventing the development of non-insulin dependent type II diabetes is insulin-dependent diabetes W is of which type.

In another aspect, the compounds of the present invention reduce the levels of glucose and triglycerides in the blood, and, accordingly, useful for treatment and/or prevention of diseases and disorders such as diabetes and/or obesity.

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

In another aspect the compounds of the present invention effective to reduce apoptosis in mammalian cells such as beta cells of the islets of Langerhans.

In another aspect the compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

In another aspect, the compounds of the present invention can also be used for improving cognitive functions in dementia, for the treatment of diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS) and for the prevention and treatment of loss of bone tissue, is the example of osteoporosis.

In another aspect the present invention relates also to the use of compounds of the present invention, which, after their introduction reduce the amount of biomarkers of atherosclerosis like (but not limited to, C-reactive protein (CRP), TNFα and IL-6.

Compounds of the present invention can also type in combination with one or more other pharmacologically active substances, for example selected from anti-obesity, diabetes, hypertension, for the treatment and/or prevention of complications resulting from diabetes or associated with diabetes and for the treatment and/or prevention of complications and disorders resulting from obesity or obesity-related.

Thus, in another aspect of the present invention compounds of the present invention can be introduced in combination with one or more means preventing obesity, or a means of regulating the appetite.

Such means can be selected from the group consisting of agonists CART (transcript, adjustable cocaine amphetamine), antagonists of NPY (neuropeptide Y), agonists of MC4 (melanocortin 4), antagonists of orexin, agonists of TNF (tumor necrosis factor)agonists, CRF (factor release corticotropin), antagonists of CRF BP (binding protein factor release corticotropin), agonists of oracort is on, agonists β3, agonists, MSH (melanocyte-stimulating hormone), antagonists of MCH (concentrating hormone melanocytes), CCK agonists (cholecystokinin), inhibitors of serotonin reuptake, inhibitors of reuptake of serotonin and norepinephrine, mixtures of serotonin and noradrenergic compounds, 5HT agonists (serotonin)agonists of bombezin, antagonists Galanina, growth hormones compounds, releasing growth hormone, TRH agonists (the hormone that stimulates tireotropina), modulators of the UCP 2 or 3 (uncoupling protein 2 or 3), leptin agonists, DA agonists (bromocriptin, depressin), inhibitors of lipase/amylase, RXR modulators (X receptor retinoids) or agonists TRβ.

In one embodiment of the present invention remedy against obesity is leptin.

In another embodiment, anti-obesity are dexamfetamine or amphetamine.

In another embodiment, anti-obesity are fenfluramine or dexfenfluramin.

In another embodiment, the tool against obesity is sibutramine.

In yet another embodiment, the tool against obesity is orlistat.

In another embodiment, the means against obesity is mazindol or phentermine.

Suitable anti-diabetic agents include insulin, GLP-1 (like peptide-1) derivatives such as disclosed in WO 98/0881 from Novo Nordisk A/S, which is incorporated in this description by reference, as well as active when orally administered hypoglycemic agents.

Active when orally administered hypoglycemic agents preferably include sulfonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists, such as disclosed in WO 99/01423 from Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., agonists GLP-1 agents, the opening of potassium channels, such as disclosed in WO 97/26265 and WO 99/03861 from Novo Nordisk A/S, which are included in this description by reference, inhibitors of DPP-IV (dipeptidyl peptidase-IV)inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of the seizure of glucose, compounds modifying the lipid metabolism such as antihyperlipidemic tools and antilipidemics tools, such as inhibitors of HMG CoA (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP-dependent potassium channels β-cells.

In one embodiment of the present invention compounds of the present invention is administered in combination with insulin.

In another one embodiment of the present invention compounds of the present invention is administered in combination with a sulfonylurea, for example, tolbutamide, glibenclamide, glipizide or glicazide.

Still one of the option is in the present invention the compounds of the present invention is administered in combination with biguanides, for example, Metformin.

In another one embodiment of the present invention compounds of the present invention is administered in combination with meglitinides, for example, Repaglinide or singledom.

In another one embodiment of the present invention compounds of the present invention is administered in combination with an inhibitor α-glucosidase, for example, miglitol or acarbose.

In another one embodiment of the present invention compounds of the present invention is administered in combination with an agent acting on the ATP-dependent potassium channels β-cells, for example, tolbutamide, glibenclamide, glipizide or Repaglinide.

In addition, the compounds of the present invention can be introduced in combination with nateglinide.

In another one embodiment of the present invention compounds of the present invention is administered in combination with an antihyperlipidemic agent or antilipidemic means, for example, cholestyramine, holestipol, clofibrate, gemfibrozil, fenofibrate, bezafibrat, tesaglitazar, EML-4156, LY-518674, LY-519818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, cerivastin, acipimox, ezetimiba, probucol, dextrothyroxine or nicotinic acid.

In another one embodiment of the present invention compounds of the present invention is administered in combination with what diazolidinyl, for example, troglitazone, ciglitazone, pioglitazone or rosiglitazone.

In another one embodiment of the present invention compounds of the present invention is administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and Metformin, a sulfonylurea and acarbose, Repaglinide and Metformin, insulin and a sulfonylurea, insulin and Metformin, insulin, insulin and lovastatin, etc.

In addition, the compounds of the present invention can be introduced in combination with one or more anti-hypertensive agents. Examples of anti-hypertensive funds are β-blockers, such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE inhibitors (the enzyme that converts angiotensin), such as benazepril, captopril, enalapril, fosinopril, lisinopril, inapril and ramipril, calcium channel blockers, such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and α-blockers, such as doxazosin, urapidil, prazosin and terazosin. As other links, you can specify Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

It should be understood that any suitable combination of the compounds in accordance with the present invention with one or more of the above-mentioned compounds and optionally with one or more pharmacologically active substances are considered as included in the scope of the present invention.

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

The PHARMACEUTICAL COMPOSITION

Compounds of the present invention can be entered separately or in combination with pharmaceutically acceptable carriers or excipients, in the form of single dose or multiple doses. Pharmaceutical compositions in accordance with the present invention can be obtained with pharmaceutically acceptable carriers or diluents as well as any other known adjuvantly and excipients in accordance with conventional techniques, such as disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The composition can be in conventional forms, for example, in the form of capsules, tablets, aerosols, solutions, suspensions or drugs for local use.

Typical compositions include a compound of formula I or its pharmaceutically acceptable salt accession acids, in Association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent, or the composition may be diluted by a carrier, or may be enclosed within a carrier which may be in the form maintain the, sachet, paper or other container. When creating songs, you can use the usual methods to obtain pharmaceutical compositions. For example, the active compound is usually mixed with a carrier, or diluted by a carrier, or enter into the inside of the carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier, excipient or medium for the active connection. The active compound may be absorbed on a granular solid container, for example, in the sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, peanut oil, olive oil, gelatine, lactose, white clay, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkalemia ethers of cellulose, silicic acid, fatty acids, amines, fatty acids, monoglycerides and diglycerides of fatty acids, fatty acid esters and pentaerythritol, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any well-known specialists in the field of substance, ensure is it slow release such as glycerylmonostearate or glycerylmonostearate, separately or in mixture with wax. The composition may also include wetting agents, emulsifying and suspendresume agents, preservatives, sweeteners or flavoring agents. Compositions of the present invention can be designed to provide rapid, prolonged or delayed release of the active ingredient after administration to the patient, using techniques well known in the field.

The pharmaceutical compositions can be sterilized and mixed, if necessary, with auxiliary agents, emulsifiers, salts to adjust osmotic pressure, buffers and/or coloring substances and the like which do not react in a harmful way with the active compounds.

The method of administration may be any method that provides efficient transport of the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, with an eye solutions or ointments, and the preferred method is oral.

If for oral administration use solid media, the preparations can be in the form of tablets, can be p medeni in hard gelatin capsules in the form of powders or granules, or may be in the form of beads or pastilles. If using liquid media, the preparations can be in the form of a syrup, emulsion, soft gelatin capsule or sterile water for injection such as aqueous or non-aqueous liquid suspension or solution.

For nasal injection preparations may contain the compound of formula I dissolved or suspended in a liquid medium, especially in aqueous media, for use in aerosols. The carrier may contain additives, such as contributing to the dissolution agents, for example, propylene glycol, surface-active substances, substances that increase the absorption, such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives, such as parabens.

For parenteral administration are especially suitable solutions or suspensions for injection, preferably aqueous solutions with the active compound dissolved in polyhydroxyalkane castor oil.

Tablets, coated tablets or capsules containing as a carrier talc and/or carbohydrate, or binder, or the like, particularly suitable for oral administration. Preferred carriers for tablets, coated tablets or capsules include lactose, corn starch and/or potato starch. A syrup or elixir can be used in cases when you can use sweetened media.

A typical tablet is a, which can be manufactured using conventional tabletting methods may include:

Core:

The active compound (compound in free form or its salt)5 mg
Colloidal silicon dioxide (Aerosil)1.5 mg
Microcrystalline cellulose (Avicel)70 mg
Modified cellulose resin (Ac-Di-Sol)7.5 mg
Magnesium stearateAd.

Floor:

HPMC approximately9 mg
*Mywacett 9-40 T approximately0.9 mg
*The acylated monoglyceride used as plasticizer for film coating.

Optionally, the pharmaceutical composition of the present invention may contain the compound of formula (I) in combination with other pharmacologically active substances, such as described above.

Compounds of the present invention it is possible to enter a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or weakening of diseases associated with the regulation of blood sugar levels.

Such mammals include so the e animals such as Pets, for example, Pets, and domestic animals like wild animals.

Compounds of the present invention is effective in a wide range of dosages. Interval typical dose for oral administration is from about 0.001 to about 100 mg/kg of body weight per day, preferably from about 0.01 to about 50 mg/kg body weight / day and, more preferably, from about 0.05 to about 10 mg/kg of body weight per day, administered in one or in several doses, for example, in 1-3 doses. The exact dose depends on the frequency and route of administration, sex, age, weight and General condition of the subject treated of the subject, the nature and severity of the subject to treatment status and any related conditions, be treated and other factors evident to a person skilled in this field.

Designs are usually conveniently presented in unit dosage form by methods known to experts in this field. Typical unit dosage form for oral administration one or more times a day, for example, 1-3 times a day, can contain from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferably, from about 0.5 mg to about 200 mg

Any ideas disclosed in this description of new signs or combinations of signs are considered essential for this izopet the deposits.

EXAMPLES

The following examples and common procedures refer to intermediate compounds and final products specified in the description and in the synthesis schemes. Obtaining the compounds of the present invention disclosed in detail using the following examples. In some cases, the reaction may be unacceptable, as described to each compound included within the disclosed scope of the present invention. Connection for which this is true can be easily recognized by a person skilled in the art. In these cases, the reaction can be carried out using conventional modifications known to specialists in this field, that is, using the appropriate methods of protection of interfering groups, by replacing other conventional reagents, or by modification of the reaction conditions. Alternatively, other disclosed herein or known from other sources, reactions can be used to obtain the corresponding compounds of the present invention. In all preparative methods, all of the original substance or known, or can easily be obtained from known starting materials. Structures of the compounds are confirmed by the data of nuclear magnetic resonance (NMR). Chemical shifts NMR (δ) are given in ppm (ppm). TPL is melting point and is contained in ଌ.

Abbreviations used in the examples have the following meanings:

THF: tetrahydrofuran

DMSO: dimethyl sulfoxide

CDCl3: deuterated chloroform

DMF: N,N-dimethylformamide

min: minutes

hours: hours

General method (A)

Stage A:

Carry out the reaction of the compound of formula (II)

where X1and X2have the above values, using a method similar to the Wittig reaction, for example, with (EtO)2PO(CHR1)COOR3(where R3represents alkyl group), in the presence of a base such as sodium hydride, EtONa and the like, receiving the compound of formula (III)

where X1X2, R1and R3have the above values.

Stage B:

Restore the connection of the formula (III), where X1X2, R1and R3have the above values, a suitable reagent, such as diisobutylaluminium, receiving the compound of formula (IV)

where X1X2and R1have the above values.

Stage C:

Interact the compounds of formula (IV), where X1X2and R1have the above values (except that if X1or X2substituted by hydroxy, this functional groups which should be protected) with the compound of the formula (V)

where Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen, under conditions Mitsunobu, using a reagent such as triphenylphosphine/diethylazodicarboxylate etc., receiving the compound of formula (I), where X1X2, Y1, Y2, Ar, Z, R1and R2have the above values, except that R2is not hydrogen.

General method (B)

Stage A:

Carry out the transformation of the-OH functional group in the compound of formula (IV), where X1X2and R1have the above values, the corresponding tsepliaeva group (L), such as p-toluensulfonate, methanesulfonate, halogen (for example, by methods according to: Houben-Weyl, Methods der organischen Chemie, Alkohole III, 6/1b, Thieme-Verlag 1984, 4th Ed., pp. 927-939; Comprehensive Organic Transformations. A guide to functional group preparations, VCH Publishers, 1989, 1st Ed., pp. 353-363 and J. Org. Chem., Vol. 36 (20), 3044-3045, 1971), triplet etc., receiving the compound of formula (VI)

where, X1X2, R1and L have the above values.

Stage B:

Interact the compounds of formula (VI), where L is tsepliaeva group, such as p-toluensulfonate, methanesulfonate, halogen, triflate etc., and where X1X2and R1have the above meanings, with a compound of formula (V), where Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen, receiving compound of formula (I), where X2, Y1, Y2, Ar, Z, R1and Rhave the above values, except that R2is not hydrogen.

General method (C)

Stage A:

As a result of chemical or enzymatic saponification of compounds of formula (I), where X1X2, Y1, Y2, Ar, Z, R1and R2have the above values, except that R2is not hydrogen, obtain the connection formula (I), where X1X2, Y1, Y2, Ar, Z, R1and R2have the above values, except that R2represents hydrogen.

General procedure (D)

Stage A:

Interact the compounds of formula (VII)

where X1has the above values, with cetarehhloristam carbon and triphenylphosphine, receiving the compound of formula (VIII)

where X1has the above values.

Stage B:

Interact the compounds of formula (VIII), where X1has the above values, with paraformaldehyde in the presence of a strong base, such BuLi, receiving the connection is of the formula (IX)

where X1has the above values.

Stage C:

Restore the connection of the formula (IX), where X1has the above values using LiAlH4in the presence of a base such as sodium methoxide, process then dimethylcarbonate and iodine, receiving compound of formula (X)

where X1has the above values.

Stage D:

Turn the hydroxyl functional group of compounds of formula (X) in tsepliaeva group (L)as described in the General methods B, receiving the compound of formula (XI)

where X1and L have the above values.

Stage E:

Interact the compounds of formula (XI), where L is tsepliaeva group, such as p-toluensulfonate, methanesulfonate, halogen, triflate etc., and where X1has the above meanings, with a compound of formula (V), where Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen, receiving compound of formula (XII)

where Y2, Ar, Z, and R2have the above values, except that R2is not hydrogen.

Stage F:

Interact joint is of the formula (XII), where X1, Y1, Y2, Ar, Z, and R2have the above values, except that R2is not hydrogen, X2-tributiloltin in the presence of a palladium catalyst such as Pd2(dba)3and three(tert-butyl)phosphine, receiving the compound of formula (I), where X1X2, Y1, Y2, Ar, Z, R1and R2has the above values, except that R1is hydrogen and R2is not hydrogen.

The General procedure (E)

Stage A:

Interact the compounds of formula X1-halogen, where X1has the above values in the same conditions of the Heck reaction with propargilovyh alcohol in the presence of palladium catalyst such as Pd2(dba)3and cubber(I), obtaining the compound of formula (IX), where X1has the above values.

The General procedure (F)

Stage A:

Interact the compounds of formula (X), where X1has the above values, with X2-tributiloltin in the presence of a palladium catalyst such as Pd2(dba)3and three(tert-butyl)phosphine, receiving the compound of formula (IV), where X1and X2have the above significance, and R1represents hydrogen.

The General procedure (G)

Stage A:

Implementation of interaction is the compounds of formula (XIV)

with the compound of the formula (V), where Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen, receiving compound of formula (XV)

where Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen.

Stage B:

Carry out the reaction cross-combination between a compound of formula (XV), where Y1, Y2, Ar, Z, and R2have the above values, except that R2is not hydrogen, for example, with the appropriate Bronevoy acid X1-B(OH)2(cross combination Suzuki), or alternatively, for example, X1-SnBu3(cross combinations for Stille), gives compound of formula (XVI)

where X1, Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen.

Stage C:

Carry out the reaction cross-combination between a compound of formula (XVI), where X1, Y1, Y2, Ar, Z, and R2have the above values, except that R2is not hydrogen, for example, with the appropriate Bronevoy acid X2-B(OH)2(in the conditions of cross-combination Suzuki), or alternatively, for example, X2-SnBu3(cross combinations for Stille), obtaining the compound of formula (I), where X1X2, Y1, Ar, Y2, Z and R2have the above values, except that R2is not hydrogen.

Using a combination of the above techniques or similar methods, you can get various connections in the scope of the present invention.

Further, the present invention is illustrated in the following examples, which illustrate the formation of compounds in accordance with the present invention. However, these examples are in no way intended to limit the scope of the present invention.

Example 1(General procedure (A))

Methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

To a solution of NaH (3,53 g, 88,2 mmol) in dry toluene (300 ml) at 0°C added dropwise a solution of triethylphosphate (13,2 g, 58.8 mmol) in toluene (100 ml).

The reaction mixture was stirred for 30 min, then add a solution of 4,4-dibromobenzophenone (10.0 g, 29.4 mmol) in THF (100 ml). The reaction mixture is stirred for 48 hours. Add ethanol (10 ml) and water (300 ml) and the mixture is extracted with a mixture of ethyl acetate-methanol (2%, 2×150 ml). The combined organic phases are washed with asystem salt solution, dried over MgSO4, filtered and evaporated. The residue is purified column chromatography (eluent: ether)to give ethyl-3,3-bis-(4-bromophenyl)acrylate resin. Crystallization from hexanol gives white crystals with a yield 8,77 g (73%).

1H NMR (CDCl3, 300 MHz); δ of 1.20 (3H, t), of 4.05 (2H, square), 6.35mm (1H, s), to 7.0, and 7.1 (4H, DM), 7,40-7,52 (4H, DM).

Stage B:

Ethyl-3,3-bis-(4-bromophenyl)acrylate (of 8.75 g of 21.3 mmol) dissolved in dry THF (35 ml). DIBAL-H (1.5 m in toluene, 43 ml, 64,0 mmol) is added at -15°C and the reaction mixture is stirred for 30 minutes Add a solution of ammoniaand in water and the mixture extracted with ethyl acetate (3×50 ml). The combined organic phases are washed with saturated salt solution, dried over MgSO4, filtered and evaporated, obtaining 3,3-bis-(4-bromophenyl)Pro-2-EN-1-ol to yield 6.0 g (76%).

1H NMR (CDCl3, 300 MHz); δ to 1.15 (1H, USS), 4,16-4,20 (2H, DD), and 6.25 (1H, t), of 7.0, and 7.1 (4H, DM), 7,40-7,52 (4H, DM).

Stage C:

3,3-bis-(4-bromophenyl)Pro-2-EN-1-ol (2,98 g, 8.1 mmol) and tributylphosphine (2.4 g, 12.1 mmol) dissolved in dry THF (150 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (3.1 g, 12.1 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 min) methyl ester of (4-mercapto-2-methylphenoxy)acetic acid (to 2.06 g, 9.7 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) and stirring is continued for 2 hours is ri 0° C. Add water (100 ml) and the mixture extracted with dichloromethane (2×150 ml). The combined organic phases are dried over MgSO4, filtered and evaporated. The residue is purified column chromatography (eluent: dichloromethane)to give 4.0 g (88%) specified in the connection header.

1H NMR (CDCl3, 300 MHz); δ of 2.20 (3H, s), 3,44 (2H, d), of 3.78 (3H, s), with 4.64 (2H, s), 6,11 (1H, t), 6,55 (1H, d), of 6.73 (2H, d), 6,98 (2H, d), 7,10 (2H, USS), 7,38 (2H, d), the 7.43 (2H, d).

Example 2(General procedure (C))

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

A solution of methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid (example 1) (530 mg, of 0.94 mmol) in ethanol (20 ml) and 1M NaOH (2.0 ml, 2.0 mmol) was stirred at room temperature for 2 hours. To the reaction mixture are added water (20 ml) and 1N. HCl (3.0 ml). The aqueous phase is extracted with dichloromethane (2×50 ml), the combined organic phases are dried over MgSO4, filtered and evaporated, getting 482 mg (93%) specified in the connection header.

1H NMR (CDCl3, 300 MHz); δ of 2.20 (3H, s), of 3.45 (2H, d), and 4.68 (2H, s), 6,10 (1H, t), to 6.58 (1H, d), of 6.75 (2H, d), 6,98 (2H, d), 7,10-7,13 (2H, m), 7,38 (2H, d), the 7.43 (2H, d).

Example 3(General procedure (A))

Ethyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2,6-diphenylmethoxy}acetic acid

<> Stage C:

a) a Mixture of 4-acetoxy-2,6-diphenylphenol (6,1 g, 20 mmol; obtained as described in Ber. 101, 2519 (1968)), ethylbromoacetate (4.0 g, 24 mmol), potassium carbonate (3.3 g, 24 mmol) and 2-butanone (150 ml) is refluxed for 24 hours, then filtered and the solvent is evaporated. The residue is purified column chromatography on silica gel (120 g, eluent: benzene)to give 7.2 g (92 %) of oily ethyl-4-acetoxy-2,6-diphenylquinoxaline.

1H NMR (CDCl3, 300 MHz): δ to 7.64 (m, 4H); 7,37 (m, 6N); was 7.08 (s, 2H); 3,93 (sq, J=7,1, 1H); 3,79 (s, 2H); of 1.07 (t, J=7,1, 3H).

b) ethyl-4-acetoxy-2,6-diphenylquinoxaline (7.2 g, 18.5 mmol) was dissolved in wet toluene (400 ml) and add the catalyst (25 g SiO2treated with a solution of 2 g of 4-toluensulfonate acid in 10 ml of acetone and evaporated in vacuum). The mixture is stirred and heated at 100°C for 6 hours, cooled and filtered through a column of silica gel (50 g). Elution with benzene gives 3.6 g (56 %) of ethyl ether (2,6-diphenyl-4-hydroxyphenoxy)acetic acid as white crystals, which are recrystallized from a mixture of benzene/petroleum ether. TPL 91-93°C.

1H NMR (250 MHz, CDCl3): δ of 1.05 (t, J=7,2, 3H); 3,92 (sq, J=7.2 Hz, 2H); to 3.73 (s, 2H); PC 6.82 (s, 2H); of 7.60 (m, 4H); 7,35 (m, 6N).

c) 3,3-bis-(4-bromophenyl)Pro-2-EN-1-ol (example 1, stage (B) (184 mg, 0.5 mmol) dissolved in dry THF (5 ml) and under nitrogen atmosphere add to these the new ether (2,6-diphenyl-4-hydroxyphenoxy)acetic acid (209 mg, 0.6 mmol) and tributylphosphine (150 mg, 0.7 mmol). The reaction mixture was cooled to 0°C and added 1,1'-(azodicarbon)dipiperidino (ADDP) (185 mg, 0.7 mmol). The reaction mixture is stirred for 2 hours at 0°C. Add water (10 ml) and the mixture extracted with dichloromethane (3×15 ml). The combined organic phases are dried over MgSO4, filtered and evaporated. The residue is purified column chromatography (eluent: heptane/ethyl acetate (6:1))to give 170 mg specified in the connection header.

1H NMR (CDCl3, 300 MHz); δ of 1.05 (3H, t), and 3.72 (2H, s), 3,90 (3H, square), 4,58 (2H, d), 6,32 (1H, t), is 6.78 (2H, s), 7,02 (2H, d), 7,10 (2H, d), 7,20-the 7.43 (8H, m), 7,45 (2H, d), 7,58 (4H, d).

Example 4(General procedure (C))

{4-[3,3-bis-(4-bromophenyl)allyloxy]-2,6-diphenylmethoxy}acetic acid

Stage A:

A solution of methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid (example 3) (102 mg, 0.15 mmol) in ethanol (4 ml) and 1M NaOH (1.0 ml, 1.0 mmol) was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, add 1N. HCl (1.2 ml) and the product extracted with dichloromethane (2×15 ml). The combined organic phases are dried over MgSO4, filtered and evaporated, getting mentioned in the title compound in the form of oil. The residue is precipitated in the form of salts of L-arginine. Yield 117 mg (95%).

1H NMR (CDCl3 , 300 MHz); δ 3,74 (2H, s), of 4.57 (2H, d), of 6.31 (1H, t), 6,79 (2H, s), 7,03 (2H, d), 7,10 (2H, d), 7,35 is 7.50 (10H, m), 7,53 (4H, d).

Example 5(General procedure (A))

Methyl ester {4-[3,3-bis-(4-itfinal)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

When 0°C to a solution of triethylphosphate (11,7 g, a 52.4 mmol) in THF (230 ml) is added over 5 minutes a solution of NaH (60% in oil, 2.6 g; 109 mmol). The reaction mixture was stirred for 30 min, then add 4,4-Diocleziano (18,8 g, 42,4 mmol; Bull. Chem. Soc. Jpn. 1999, 72, 115-120) for 10 minutes, the Reaction mixture is stirred over night at room temperature. Add water (5 ml), then dekalim. The mixture is evaporated and the solid residue extracted with dichloromethane (3×200 ml). The combined organic phase is evaporated, obtaining the crude product with a yield of 17.9 g (80%). The product was then purified column chromatography (eluent: dichloromethane)to give ethyl-3,3-bis-(4-itfinal)acrylate in the form of an oil with a yield of 9.6 g (43%).

1H NMR (CDCl3, 300 MHz); δ to 1.15 (3H, t)4,07 (2H, square), 6.35mm (1H, s), 6.90 to-7,02 (4H, m), 7,63 to 7.75 (4H, m).

Stage B:

To a solution of ethyl-3,3-bis-(4-itfinal)acrylate (706 mg, 1.4 mmol) in THF (1.5 ml) is added over 45 min a solution of DIBAL-H (1.5 m in toluene, 6.3 ml, 9.5 mmol) at -20°C. the Reaction mixture is stirred for 1 hour. Add a solution of ameriglide and add to the mixture this is latitat (40 ml) and dekalim. The mixture is filtered and the filter washed with ethyl acetate (100 ml). The combined filtrate is evaporated and the residue purified column chromatography (eluent: dichloromethane:THF (8:3))to give 3,3-bis-(4-itfinal)Pro-2-EN-1-ol with the release of 541 mg (84%).

1H NMR (CDCl3, 300 MHz); δ and 1.60 (1H, USS), 4,20 (2H, d), 6,23 (1H, t), 6,84-to 7.00 (4H, m), EUR 7.57 to 7.75 (4H, m).

Stage C:

3,3-bis-(4-itfinal)Pro-2-EN-1-ol (540 mg, 1.1 mmol) and tributylphosphine (354 mg, 1.7 mmol) dissolved in dry THF (30 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (442 mg, 1.7 mmol) and the reaction mixture is stirred for 5 minutes, Slowly add the methyl ester of (4-mercapto-2-methylphenoxy)acetic acid (298 mg, 1.4 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) (5 min) and stirring is continued for 4 hours at a temperature of from 0°C to 10°C. Add water (50 ml) and the mixture extracted with dichloromethane (2×150 ml). The combined organic extracts dried and evaporated. The residue is purified column chromatography (eluent: heptane:ethyl acetate (10:1)), getting mentioned in the title compound with a yield 302 mg (39%).

1H NMR (CDCl3, 300 MHz); δ of 2.20 (3H, s), of 3.45 (2H, d), of 3.78 (3H, s), with 4.64 (2H, s), 6,11 (1H, t), 6,55 (1H, d), 6,60 (2H, d), 6,86 (2H, d), 7,11 (2H, s), EUR 7.57 (2H, d), a 7.62 (2H,d).

Example 6(General procedure (C))

{4-[3,3-bis-(4-itfinal)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid (342 mg, 0.5 mmol) was dissolved in warm ethanol (20 ml). At room temperature add 1H. NaOH, the reaction mixture is stirred for 1 hour and then evaporated. The residue is treated with 1H. HCl (1.0 ml) and extracted with dichloromethane (3×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield 320 mg (96%).

1H NMR (CDCl3, 300 MHz) δ; to 2.18 (3H, s), of 3.45 (2H, d), of 4.67 (2H, s), 6,10 (1H, t), 6,60 (3H, m), 6,85 (2H, d), 7,10 (2H, BC), of 7.55 (2H, d), to 7.61 (2H, d).

Example 7(General procedure (A))

Methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

When 0°C to a solution of triethylphosphate (18,5 g of 82.5 mmol) in THF (375 ml) is added over 5 minutes a solution of NaH 60% in oil (7.6 g; 320 mmol). The reaction mixture was stirred for 30 min, then add 4,4-fermentation (15 g, of 68.7 mmol) for 10 minutes, the Reaction mixture was stirred for 12 h at room temperature. Carefully add water (100 ml) and the reaction mixture is extracted with ethyl acetate (2×250 ml). The combined extracts dried and evaporated. The residue is purified using the device Horizon Flashcollector (eluent: heptane:ethyl acetate (98,5:1,5)), getting the -3,3-bis-(4-forfinal)acrylate to yield 11.6 g (59%).

1H NMR (400 MHz, CDCl3) δ; to 1.15 (3H, t)4,06 (2H, square), 6,30 (1H, s), of 6.96-7,30 (7,5H, m), 7,83 (0,5H, m).

Stage B:

To a solution of ethyl-3,3-bis-(4-forfinal)acrylate (11.6 g, of 40.3 mmol) in THF (215 ml) is added over 45 min a solution of DIBAL-H (1.5 m in toluene, 165 ml of 247.5 mmol) at -20°C. the Reaction mixture was stirred for additional 12 hours. Add a solution of ameriglide and to the mixture are added ethyl acetate (100 ml) and dekalim. The mixture is filtered and the filter washed with ethyl acetate (2×200 ml). The combined filtrate is evaporated and the residue purified using the device Horizon Flashcollector (eluent: dichloromethane)to give 3,3-bis-(4-forfinal)Pro-2-EN-1-ol with a yield equal to 6.05 g (61%).

1H NMR (400 MHz, CDCl3) δ; of 1.55 (1H, USS), 4,18 (2H, d), 6,16 (1H, t), 6,92-7,33 (8H, m).

Stage C:

3,3-bis-(4-forfinal)Pro-2-EN-1-ol (7.5 g, 30,5 mmol) and tributylphosphine (15,4 g, with 76.1 mmol) dissolved in dry THF (500 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (15,4 g, 76,2 mmol) and the reaction mixture is stirred for 5 minutes, Slowly add the methyl ester of (4-mercapto-2-methylphenoxy)acetic acid (7,8 g of 36.5 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) (5 min) and stirring is continued for 2 hours at 0°C. Add water (100 ml) and the mixture extracted with dichloromethane (2×150 ml). The combined organic extracts dried and evaporated. The remainder will maternalistic with ether (2× 100 ml), filtered and evaporated. The residue is purified column chromatography (eluent: dichloromethane), getting mentioned in the title compound with a yield of 9.6 g (72%).

1H NMR (400 MHz, CDCl3) δ; of 2.20 (3H, s), of 3.45 (2H, d), of 3.77 (3H, s), with 4.64 (2H, s), the 6.06 (1H, t), 6,55 (1H, d), 6,84-7,14 (10H, m).

Example 8(General procedure (C))

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid (of 10.05 g of 22.8 mmol) was dissolved in warm ethanol (400 ml). At room temperature add 1H. NaOH (35,5 ml, 35.5 mmol), the reaction mixture is stirred for 2 hours and then evaporated. The residue is treated with water (350 ml) and 1N. HCl (41,5 ml) and extracted with dichloromethane (2×750 ml). The combined organic phases are dried and evaporated, receiving specified in the header of the connection to the output 9,23 g (95%).

1H NMR (400 MHz, CDCl3) δ; to 2.18 (3H, s), 3,48 (2H, d)and 4.65 (2H, s), equal to 6.05 (1H, t), to 6.57 (1H, d), 6,85-to 7.15 (10H, m), 10,4 (1H, DS).

Example 9(General procedure (A))

Methyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid

Stage C:

3,3-bis-(4-bromophenyl)Pro-2-EN-1-ol (1.5 g, 4.1 mmol; example 1, stage B), tributylphosphine (2.1 g, or 10.3 mmol) and methyl ester (4-hydroxy-2-methylphenoxy)uksu the Noah acid (1.7 g, 9.1 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) was dissolved in dry THF (500 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (2.6 g, or 10.3 mmol) and the reaction mixture is stirred for 2 hours. Add water (100 ml) and the mixture extracted with dichloromethane (2×150 ml). The combined organic extracts dried and evaporated. The residue is triturated with ether (2×25 ml), filtered and the filtrate is evaporated. The residue is purified column chromatography (eluent: dichloromethane), getting mentioned in the title compound with a yield of 1.9 g (84%).

1H NMR (400 MHz, CDCl3) δ; and 2.26 (3H, s), of 3.77 (3H, s), to 4.46 (2H, d), of 4.57 (2H, s), 6,30 (1H, t), 6,55-6,70 (3H, m), 7,07 (2H, d), 7,10 (2H, d), 7,41 (2H, d), 7,53 (2H, d).

Example 10(General procedure (C))

{4-[3,3-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid (1.9 g, 3.5 mmol) was dissolved in warm ethanol (100 ml). Add 1H. NaOH (7 ml, 7 mmol), the reaction mixture is stirred for 2 hours at 60°C and then evaporated. The residue is treated with water (50 ml) and 1N. HCl (8 ml) and extracted with dichloromethane (2×250 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 1.8 g (99%).

1H NMR (CDCl3, 300 MHz) δ; 2,6 (3H, C)4,48 (2H, d), to 4.62 (2H, s), 6,30 (1H, t), 6,55-6,70 (3H, m), 7,02-7,13 (4H, m), 7,42 (4H, d), 7,53 (4H, d).

Example 11(General procedure (A))

Methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

To a solution of triethylphosphate (8,1 g, 36 mmol) in THF (150 ml) is added over 5 minutes a solution of NaH 60% in oil (1.2 g; 50 mmol). The reaction mixture was stirred for 30 min, then add 4,4-chlorobenzophenone (7.5 g, 30.0 mmol) for 10 minutes, the Reaction mixture is stirred for 1 hour at room temperature. Carefully add water (50 ml) and the reaction mixture is extracted with ethyl acetate (2×150 ml). The combined extracts are dried and evaporated, receiving ethyl-3,3-bis-(4-chlorophenyl)acrylate to yield 8 g (83%). The connection used in the next stage without further purification.

Stage B:

To a solution of ethyl-3,3-bis-(4-chlorophenyl)acrylate (8.0 g, 24,9 mmol) in THF (200 ml) is added over 15 min a solution of DIBAL-H (1.5 m in toluene, 110 ml, 165 mmol) at -20°C. the Reaction mixture is stirred for an additional 1 hour. To the reaction mixture is carefully added methanol (50 ml), then 1N. HCl (500 ml). The mixture is extracted with dichloromethane (3×150 ml) and washed with water. The organic phase is dried and evaporated. The residue is dissolved in methanol (50 ml), washed with heptane and evaporated, getting neocidin the th 3,3-bis-(4-chlorophenyl)Pro-2-EN-1-ol to yield 8 g (about 100%).

1H NMR (CDCl3, 300 MHz) δ; of 1.55 (1H, USS), 4,20 (2H, d), from 6.22 (1H, t), 7,05-7,38 (8H, m).

Stage C:

3,3-bis-(4-chlorophenyl)Pro-2-EN-1-ol (279 mg, 1 mmol) and tributylphosphine (404 mg, 2 mmol) dissolved in dry THF (15 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (504 mg, 2 mmol) and the reaction mixture is stirred for 5 minutes, Slowly add the methyl ester of (4-mercapto-2-methylphenoxy)acetic acid (212 mg, 1 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) (5 min) and stirring is continued for 0.5 hour at 0°C. Add water (10 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified HPLC, getting mentioned in the title compound with a yield of 150 mg (32%).

1H NMR (CDCl3, 400 MHz) δ; of 2.20 (3H, s), 3,47 (2H, d), of 3.77 (3H, s), with 4.64 (2H, s), 6,12 (1H, t), 6,55 (1H, d), 6,79 (2H, d), 7,02-7,29 (8H, m).

Example 12(General procedure (C))

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid (100 mg, 0,218 mmol) dissolved in ethanol (10 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours at 5°C, then treated with 1N. HCl (3 ml) and extracted with dichlor the tan (2× 20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 50 mg (10%).

1H NMR (CDCl3, 300 MHz) δ; to 2.18 (3H, s), 3,47 (2H, d), and 4.68 (2H, s), 6,10 (1H, t), to 6.58 (1H, d), at 6.84 (2H, d), 7.03 is-7,28 (8H, m), 10,1 (1H, DS).

Example 13(General procedure (A))

Methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid

Stage A:

To a solution of triethylphosphate (7,4 g, 36 mmol) in THF (150 ml) for 5 minutes and add a solution of NaH (60% in oil (1.3 g; 54 mmol). The reaction mixture is stirred for 30 minutes, then for 10 min add 3,3-dateformatlength (9.5 g, 30 mmol). The reaction mixture was stirred over night at room temperature. Add water (200 ml) and the mixture extracted with ethyl acetate (3×200 ml). The combined organic phase is evaporated, obtaining the crude product. Purification of column chromatography (eluent: heptane:ethyl acetate (4:1)) to give ethyl-3,3-bis-(3-triptoreline)acrylate in the form of an oil with a yield of 8 g (69%).

1H NMR (CDCl3, 300 MHz) δ; of 1.12 (3H, t)4,07 (2H, square), of 6.45 (1H, s), 7,37-7,72 (8H, m).

Stage B:

To a solution of ethyl-3,3-bis-(3-triptoreline)acrylate (8.0 g, to 20.6 mmol) in THF (400 ml) for 15 minutes, add a solution of DIBAL-H (1.5 m in toluene, 100 ml, 150 mmol) at -20°C. the Reaction mixture paramashiva the t for an additional 1 hour at a temperature of from 0° C to room temperature. To the reaction mixture is carefully added methanol (50 ml), then 1N. HCl (500 ml). The mixture is extracted with ethyl acetate (3×250 ml) and the organic phase is washed with water. The organic phase is dried and evaporated. The residue is purified column chromatography (eluent: heptane:ethyl acetate (2:1))to give the crude 3,3-bis-(3-triptoreline)Pro-2-EN-1-ol to yield 5 g (72%).

1H NMR (CDCl3, 300 MHz) δ; of 1.55 (1H, USS), 4,24 (2H, d), 6,36 (1H, t), 7,32-to 7.67 (8H, m).

Stage C:

3,3-bis-(3-triptoreline)Pro-2-EN-1-ol (346 mg, 1 mmol) and tributylphosphine (404 mg, 2 mmol) dissolved in dry THF (15 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (504 mg, 2 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 min) methyl ester of (4-mercapto-2-methylphenoxy)acetic acid (212 mg, 1 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) and stirring is continued for 0.5 hour at 0°C. Add water (10 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified HPLC, getting mentioned in the title compound with a yield of 150 mg (27%).

1H NMR (CDCl3, 300 MHz) δ; of 2.20 (3H, s), 3,47 (2H, d), a 3.87 (3H, s), with 4.64 (2H, s), 6,24 (1H, t), to 6.57 (1H, d), 7,02-of 7.60 (10H, m).

Example 14(General procedure (C))

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-IU is elfenix}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid (100 mg, 0.23 mmol) dissolved in ethanol (10 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours at 5°C, then treated with 1N. HCl (3 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 20 mg (5%).

1H NMR (CDCl3, 300 MHz) δ; are 2.19 (3H, s), 3,48 (2H, d), of 4.67 (2H, s), 6,24 (1H, t), is 6.61 (1H, d), 7.03 is-of 7.60 (10H, m).

Example 15(General procedure (A))

Methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage C:

a) a Solution of 2-ethylphenol (24.4 g, 200 mmol), potassium carbonate (up 41.4 g, 300 mmol) and ethylbromoacetate (36,7 g, 220 mmol) in 2-butanone (250 ml) was stirred at 100°C for 24 hours. The reaction mixture is filtered and evaporated. The residue is dissolved in benzene (100 ml), washed with sodium bicarbonate (5%, 25 ml), dried and evaporated. The residue is dissolved in dichloromethane (100 ml) and at a temperature of -5°C slowly added chlorosulfonic acid (34,9 g, 300 mmol). The reaction mixture was stirred at room temperature for 6 hours. Add ice water (25 ml) and the mixture extragear who have dichloromethane (3× 100 ml). The combined organic phases are washed with water, dried and evaporated, obtaining the crude ethyl ester (4-chlorosulfonyl-2-ethylenoxy)acetic acid in the form of oil. Crystallization from heptane (500 ml) gives the desired product with a yield of 31.6 g (52%).

1H NMR (CDCl3, 300 MHz) δ; of 1.27 (t, 3H), of 1.32 (t, 3H), 2,78 (square, 2H), 4,29 (square, 2N), of 4.77 (s, 2H), PC 6.82 (d, 1H), 7,86 (m, 2H).

b) To boiling under reflux the solution PH3(4.3 g, 126,5 mmol) and (I2(0.7 g, 2.6 mmol) in glacial acetic acid (30 ml) is added slowly a solution of ethyl ester (4-chlorosulfonyl-2-ethylenoxy)acetic acid (15 g, for 48.9 mmol) in glacial acetic acid (20 ml). The reaction mixture is refluxed for 24 hours. Carefully add water (10 ml), the mixture is refluxed for an additional 1 hour, after cooling, the reaction mixture is filtered and the filtrate is diluted with water (100 ml). The mixture is extracted with dichloromethane (3×100 ml) and the organic phase washed with water. After drying the dichloromethane phase is evaporated, obtaining the crude (2-ethyl-4-mercaptobenzoic)acetic acid to yield 10 g (96%). The crude acid was dissolved in methanol (30 ml) and 10°C slowly add a solution of acetylchloride (10 g, 47 mmol) in methanol (20 ml). The reaction mixture is stirred for 1 hour. The reaction mixture is evaporated, the residue is purified count the night chromatography, getting pure methyl ether (2-ethyl-4-mercaptobenzoic)acetic acid to yield 2.2 g (21%).

1H NMR (CDCl3, 300 MHz) δ; to 1.19 (t, 3H), 2.66 per (square, 2H), 3,36 (s, 1H), of 3.77 (s, 3H), with 4.64 (s, 2H), return of 6.58 (d, 1H), 7,05-7,16 (m, 2H).

c) 3,3-bis-(4-forfinal)Pro-2-EN-1-ol (246 mg, 1 mmol, example 7 stage B) and tributylphosphine (404 mg, 2 mmol) dissolved in dry THF (15 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (504 mg, 2 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 minutes) methyl ester of (4-mercapto-2-ethylenoxy)acetic acid (212 mg, 1 mmol) and stirring is continued for 1 hour at 10°C. Add water (10 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified using Gilson PREP-1, and get mentioned in the title compound with a yield of 130 mg (28%).

1H NMR (CDCl3, 300 MHz) δ; to 1.14 (3H, t), 2,63 (2H, square), 3,47 (2H, d), and 3.7 (3H, s), with 4.64 (2H, s), 6,13 (1H, t), to 6.57 (1H, d), 6,77 (d, 2H), 7,02-7,29 (8H, m).

Example 16(General procedure (C))

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid (100 mg, 0.22 mmol, example 15) was dissolved in ethanol (10 ml). At room temperature add 1H. NOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours at 5°C, then treated with 1N. HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 10 mg

1H NMR (CDCl3, 300 MHz) δ; to 1.15 (3H, t), 2,61 (2H, square), 3,47 (2H, d), 4,69 (2H, s), 6,13 (1H, t), only 6.64 (1H, d), PC 6.82 (2H, d), 7.03 is-7,28 (8H, m).

Example 17(General procedure (A))

Methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage C:

3,3-bis-(4-chlorophenyl)Pro-2-EN-1-ol (246 mg, 1 mmol, example 11 stage B) and tributylphosphine (404 mg, 2 mmol) dissolved in dry THF (15 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (504 mg, 2 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 minutes) methyl ester of (4-mercapto-2-ethylenoxy)acetic acid (212 mg, 1 mmol, example 15 stage C (b)) and stirring is continued for 1 hour at 10°C. Add water (10 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified using Gilson PREP-1, and get mentioned in the title compound with a yield of 130 mg (28%).

1H NMR (CDCl3, 300 MHz) δ; of 1.13 (3H, t), 2,63 (2H, square), 3,47 (2H, d), of 3.77 (3H, s), with 4.64 (2H, s), and 6.25 (1H, t), to 6.57 (1H, d), 00-7,57 (10H, m).

Example 18(General procedure (C))

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid (100 mg, 0.22 mmol, example 17) dissolved in ethanol (10 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours at 5°C, then treated with 1N. HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 10 mg

1H NMR (CDCl3, 300 MHz) δ; of 1.13 (3H, t), 2,63 (2H, square), 3,47 (2H, d), and 4.68 (2H, s), and 6.25 (1H, t), only 6.64 (1H, d), 7.03 is-7,63 (10H, m).

Example 19(General procedure (A))

Methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage C:

3,3-bis-(3-triptoreline)Pro-2-EN-1-ol (246 mg, 1 mmol, example 13, step B) and tributylphosphine (404 mg, 2 mmol) dissolved in dry THF (15 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (504 mg, 2 mmol) and the reaction mixture is stirred for 5 minutes, Slowly add the methyl ester of (4-mercapto-2-ethylenoxy)acetic acid (212 mg, 1 mmol, example 15, step C (b)) (5 min) and stirring about oleaut for 1 hour at 10° C. Add water (10 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified using Gilson PREP-1, and get mentioned in the title compound with a yield of 130 mg (23%).

1H NMR (CDCl3, 300 MHz) δ; to 1.15 (3H, t), 2,63 (2H, square), 3,47 (2H, d), of 3.75 (3H, s)and 4.65 (2H, s), 6,07 (1H, t), to 6.57 (1H, d), 6,78-to 7.32 (10H, m).

Example 20(General procedure (C))

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid (100 mg, 0.22 mmol, example 19) was dissolved in ethanol (10 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours. at 5°C, then treated with 1N. HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 10 mg

1H NMR (CDCl3, 300 MHz) δ; to 1.15 (3H, t), 2,63 (2H, square), of 3.48 (2H, d), and 4.68 (2H, s), 6,07 (1H, t), 6,62 (1H, d), 6,83-7,33 (10H, m).

Example 21(General procedure (A))

Methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage C:

3,3-bis-(4-bromophenyl)Pro-2-EN-1-ol (2.0 g, 5.5 mmol, example 1, stage B) and tribes shall tilloston (1.7 g, 8.5 mmol) dissolved in dry THF (50 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (2.1 g, 8.5 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 minutes) methyl ester of (4-mercapto-2-ethylenoxy)acetic acid (970 mg, 4.2 mmol, example 15, step C (b)) and stirring is continued for 1 hour at 10°C. Add water (20 ml) and the mixture extracted with ethyl acetate (2×100 ml). The combined organic extracts dried and evaporated. The residue is purified using Gilson PREP-1, and get mentioned in the title compound with a yield of 2.1 g (87%).

1H NMR (CDCl3, 300 MHz) δ; of 1.13 (3H, t), 2,63 (2H, square), of 3.45 (2H, d), of 3.77 (3H, s)and 4.65 (2H, s), 6,13 (1H, t), 6,55 (1H, d), 6,72 (2H, d), of 6.99 (2H, d), 7,08-7,44 (6N, m).

Example 22(General procedure (C))

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid (350 mg, 0.6 mmol, example 21) was dissolved in ethanol (10 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours at 5°C, then treated with 1N. HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 130 mg (68%)

1H NMR (CDCl3, 300 MHz) δ; of 1.13 (3H, t), 2,63 (2H, square), 3,47 (2H, d), 4,69 (2H, s), 6,13 (1H, t), to 6.58 (1H, d), 6,74 (2H, d), of 6.99 (2H, d), 7,08-7,44 (6N, m), 10,4 (1H, USS).

Example 23(General procedure (A))

Methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid

Stage C:

a) a Solution of 2-chlorophenol (25,7 g, 200 mmol), potassium carbonate (up 41.4 g, 300 mmol) and ethylbromoacetate (35.1 g, 210 mmol) in 2-butanone (240 ml) was stirred at 100°C for 24 hours. The reaction mixture is filtered and evaporated. The residue is dissolved in toluene (100 ml), washed with water (3×25 ml), dried and evaporated. The remainder (37 g, 172 mmol) dissolved in dichloromethane (50 ml) and -10°C slowly added chlorosulfonic acid (93 g, 800 mmol). The reaction mixture was stirred at room temperature for 1 hour. Carefully add ice water (25 ml) and the mixture extracted with dichloromethane (3×100 ml). The combined organic phases are washed with water, dried and evaporated, obtaining the crude ethyl ester (4-chlorosulfonyl-2-chlorophenoxy)acetic acid in the form of oil output, 47,5

1H NMR (CDCl3, 300 MHz) δ; of 1.32 (3H, t), 4,32 (2H, square), is 4.85 (2H, s), 6,98 (1H, d), 7,86-8,07 (2H, m).

b) To boiling under reflux the solution PH3(17 g, 500 mmol) and (I2(2.4 g, 9.4 mmol) in glacial acetic acid (100 ml) is added slowly R is the target ethyl ester (4-chlorosulfonyl-2-chlorophenoxy)acetic acid (47,5 g, 151 mmol) in glacial acetic acid (1000 ml). The reaction mixture is refluxed for 24 hours. Carefully add water (20 ml) and the mixture refluxed for an additional 1 hour. After cooling, the reaction mixture is filtered and the filtrate is diluted with water (500 ml). The mixture is extracted with dichloromethane (3×100 ml) and the organic phase washed with water. After drying the dichloromethane phase is evaporated, obtaining the crude (2-chloro-4-mercaptobenzoic)acetic acid with the release of 17,

The crude acid was dissolved in methanol (50 ml) and 10°C slowly add a solution of acetylchloride (24 g, 310 mmol) in methanol (200 ml). The reaction mixture is stirred for 2 hours. The reaction mixture is evaporated and the residue purified column chromatography (eluent: ethyl acetate:heptane (4:1))to give pure methyl ether (2-chloro-4-mercaptobenzoic)acetic acid with the release of 17,

1H NMR (CDCl3, 300 MHz) δ; 3,44 (1H, s), and 3.72 (3H, s), 4,70 (2H, s), of 6.75 (1H, d), to 7.15 (1H, DD), of 7.48 (1H, d).

c) 3,3-bis-(4-bromophenyl)Pro-2-EN-1-ol (2.1 mg, 5.5 mmol, example 1, stage B) and tributylphosphine (1.7 g, 8.6 mmol) dissolved in dry THF (50 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (2.1 g, 8.6 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 min) methyl ester of (4-mercapto-2-chlorphen the XI)acetic acid (1 g, 4.2 mmol) and stirring is continued for 12 h at 5°C. Add water (10 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified using Gilson PREP-1, and get mentioned in the title compound with a yield of 2.9 g

1H NMR (CDCl3, 300 MHz) δ; 3,49 (2H, d), of 3.78 (3H, s), 4,70 (2H, s), 6,11 (1H, t), 6,69 (1H, d), 6,79 (2H, d), 6,98 (2H, d), 7,12-to 7.50 (5H, m).

Example 24(General procedure (C))

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid (350 mg, 0.6 mmol, example 23) was dissolved in ethanol (10 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture is stirred for 18 hours at 5°C, then treated with 1N. HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield 230 mg (68%).

1H NMR (CDCl3, 300 MHz) δ; 3,50 (2H, d), and 4.75 (2H, s), 6,13 (1H, t), of 6.73 (1H, d), 6,83 (2H, d), of 6.99 (2H, d), 7,10-7,55 (6N, m), for 9.95 (1H, USS).

Example 25(General procedure (A))

Methyl ester {4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-methylphenoxy}acetic acid

Stage A:

To rest the ru triethylphosphine-2-ethoxyacetic (3.2 g, to 11.9 mmol) and 4,4-bromobenzophenone (2.7 g, 7.9 mmol) in THF (20 ml) add a solution of NaH 60% in oil (800 mg, 33 mmol). The reaction mixture is stirred for 24 hours at room temperature. Carefully add water (10 ml) and the reaction mixture is extracted with ethyl acetate (2×25 ml). The combined extracts are dried and evaporated, obtaining the crude ethyl-3,3-bis-(4-bromophenyl)-2-ethoxyacrylate with the release of 3.5 g (97%).

1H NMR (CDCl3, 400 MHz) δ; and 0.98 (3H, t), of 1.28 (3H, t)to 3.92 (2H, square), a 4.03 (2H, square), 7,03 (2H, d), to 7.15 (2H, d), the 7.43 (4H, m).

Stage B:

To a solution of ethyl-3,3-bis-(4-bromophenyl)-2-ethoxyacrylate (500 mg, 1.1 mmol) in THF (20 ml) is added slowly a solution of DIBAL-H (1.5 m in toluene, 625 mg, 4.4 mmol) at -20°C. the Reaction mixture was stirred for additional 12 h at 0°C. To the mixture is added methanol, water and 1N. HCl. The mixture is extracted with ethyl acetate (2×200 ml). The combined extracts are evaporated and the residue purified column chromatography (eluent: ethyl acetate:heptane (1:5))to give 3,3-bis-(4-bromophenyl)-2-ataxia-2-EN-1-ol with a yield of 400 mg

1H NMR (CDCl3, 300 MHz) δ; of 1.23 (3H, t), is 2.05 (1H, USS), a-3.84 (2H, square), 4,17 (2H, s), 7,03 (2H, d), 7,14 (2H, d), 7,35-7,47 (4H, m).

Stage C:

3,3-bis-(4-bromophenyl)-2-ataxia-2-EN-1-ol (495 mg, 1.2 mmol) and tributylphosphine (485 mg, 2.4 mmol) dissolved in dry THF (20 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)di is hypericin (ADDP) (605 mg, 2.4 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 minutes) methyl ester of (4-mercapto-2-methylphenoxy)-acetic acid (217 mg, 1.0 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517) and stirring is continued for 2 hours at 0°C. Add water (100 ml) and the mixture extracted with ethyl acetate (2×50 ml). The combined organic extracts dried and evaporated. The residue is purified column chromatography (eluent: ethyl acetate:heptane (1:3)), getting mentioned in the title compound with a yield 170 mg (23%).

1H NMR (CDCl3, 300 MHz) δ; of 1.23 (3H, t), 2,22 (3H, s), of 3.54 (2H, s), of 3.77 (3H, s), a 3.87 (2H, square), with 4.64 (2H, s), to 6.57 (1H, d), to 6.67 (2H, d), to 7.09 (2H, d), 7,12-7,47 (6N, m).

Example 26(General procedure (C))

{4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-methylphenoxy}acetic acid

Stage A:

Methyl ester {4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-methylphenoxy}acetic acid (170 mg, 0.3 mmol, example 25) was dissolved in ethanol (5 ml). At room temperature add 1H. NaOH (3 ml, 3 mmol), the reaction mixture was stirred at room temperature for 30 minutes, then treated with 1N. HCl (15 ml) and extracted with ethyl acetate (2×20 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield of 150 mg (90%) output.

1H NMR (CDCl3, 300 MHz) δ; 1,22 3H, t), 2,22 (3H, s), of 3.56 (2H, d), 3,86 (2H, square), and 4.68 (2H, s), 6,59 (1H, d), of 6.68 (2H, d), was 7.08 (2H, d), 7,15-7,40 (6N, m).

Example 27(General procedure (D))

(E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy]acetic acid

Stage A, 1-bromo-4-(2,2-dibromovinyl)benzene:

Tetrabromomethane (21,5 g, 65,9 mmol) are added to a chilled solution of 4-bromobenzaldehyde (10.0 g, 54.0 per mmol) and triphenylphosphine (30.0 g, 130 mmol) in dry methylene chloride (100 ml). The reaction mixture is stirred for 3 hours at room temperature. Then add a saturated solution of sodium bicarbonate (50 ml), the organic layer washed with water (150 ml), dried over anhydrous magnesium sulfate and evaporated in vacuum. The triphenylphosphine oxide is removed from the residue by crystallization from ethyl acetate and hexane. Evaporation of the mother liquor gives an 18.4 g of a yellowish oil. Crude yield: 18,4 g (85%).

RF(SiO2, hexane)=0,70.

Stage B, 3-(4-bromophenyl)prop-2-in-1-ol:

The above bromo derivatives (8.0 g, 23 mmol) is dissolved in dry tetrahydrofuran (120 ml) and cooled to -78°C in an inert atmosphere. To the reaction mixture are added dropwise 2M solution sitedisability in tetrahydrofuran (38 ml, 75 mmol) and the mixture is stirred for 2 hours while cooling. Finely ground powder paraformaldehyde (7.0 g, 230 IMO the b) add to the mixture and stirred for additional 3 h, slowly warming the reaction mixture to room temperature. Add a saturated solution of salt (50 ml) and the mixture extracted with ether (4×50 ml). The combined organic layers dried over anhydrous magnesium sulfate and then evaporated in vacuum. The residue is pre-purified column chromatography (silica gel Fluka 60, hexane/ethyl acetate 1:0 to 3:1) and the obtained crude product is optionally purified by crystallization from ethyl acetate and hexane, obtaining 3.0 g of the desired product. Yield: 3.0 g (66%).

RF=0,10 (SiO2, hexane/ethyl acetate 9:1).

1H NMR (250 MHz, CDCl3): 7,24-7,49 (m, 4H); 4,48 (s, 2H).

Stage C, (Z)-3-(4-bromophenyl)-3-hotprop-2-EN-1-ol:

The solution obtained above alkyne (2.0 g, 10 mmol) in dry tetrahydrofuran (25 ml) was added dropwise to a cooled with ice to a solution of sociallyengaged (600 mg, 15 mmol) and sodium methoxide (2 mg, 0.5%) in dry tetrahydrofuran (10 ml). The reaction mixture is stirred for 3 hours in nitrogen atmosphere, are added dropwise at 0°C solution dimethylcarbonate (1.2 g, 20 mmol) in dry tetrahydrofuran (10 ml) and the reaction mixture stirred for an additional 1 hour. Then add a solution of iodine (5.0 g, 20 mmol) in tetrahydrofuran (20 ml) and the mixture is left to stand overnight in the refrigerator. Add methanol (10 ml) and the reaction mixture is stirred for additional is but 0.5 hour. Add a saturated solution of sodium thiosulfate (50 ml) and then saturated salt solution (150 ml) and the mixture extracted with ether (4×150 ml). The combined organic solutions are dried over anhydrous magnesium sulfate and then evaporated in vacuum. The residue is purified column chromatography (silica gel Fluka 60, hexane/methylene chloride 9:1→methylene chloride→methylene chloride/methanol 3:1)to give 2.7 g of product. Yield: 2.7 g (84%).

RF=0,50 (SiO2, hexane/ethyl acetate 8:2).

Stage D-E, Ethyl-(Z)-[4-(3-(4-bromophenyl)-3-totallyconfused-2-methylphenoxy]acetate:

A solution of tetrabromomethane (2.1 g, 6.6 mmol) in dry methylene chloride (20 ml) was added dropwise to a cooled with ice to a solution of 3-(4-bromophenyl)-3-hotprop-2-EN-1-ol (1.5 g, 4.4 mmol) and triphenylphosphine (2.4 g, 9.0 mmol) in dry methylene chloride (50 ml). The reaction mixture was stirred at room temperature for 2 hours and the solvent is evaporated in vacuum. To the residue in the atmosphere of nitrogen is added N,N-diisopropylethylamine (1.2 g, 9.0 mmol) and ethyl(4-mercapto-2-methylphenoxy)acetate (1.5 g, 6.6 mmol; Bioorg. Med. Chem. Lett. 2003, 13, 1517). The reaction mixture is stirred for 3 hours, filtered through a short column of silica gel and the filtrate is evaporated in vacuum. The residue is purified column chromatography (silica gel Merck 60, hexane /ethyl acetate 1:0-9:1)to give 0,80 complex ester. Output: 0,80 g (40%).

RF=0,55 (SiO2 , hexane/ethyl acetate 8:2).

Stage F, Ethyl-(Z)-[4-(-[3-benzo[b]thiophene-2-yl)-3-(4-bromophenyl)arylsulfonyl-2-methylphenoxy]acetate:

To a solution of ethyl-(Z)-[4-[3-(4-bromophenyl)-3-totallyconfused]-2-methylphenoxy]acetate (369,2 mg, 0,675 mmol) and (benzo[b]thiophene-2-yl)anti (571,3 mg, 1.35 mmol, obtained according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (3 ml) is added Pd2 (dba)3.CHCl3(21,0 mg, at 0.020 mmol). Remove trace amounts of moisture and oxygen in nitrogen atmosphere add 0,20M solution three(tert-butyl)phosphine in cyclohexane (of 0.44 ml, 0,088 mmol) and the whole mixture was stirred at 50°C for 1.5 hour. The dark solution was poured into 10% aqueous solution of potassium fluoride (20 ml) and added ethyl acetate (30 ml). The layers separated, the aqueous layer washed with ethyl acetate (2×10 ml) and the combined organic layers washed with saturated salt solution (10 ml), 10% solution of potassium fluoride (20 ml), water (20 ml) and saturated salt solution (20 ml). The organic solution is dried over anhydrous sodium sulfate, receiving the oil, which is purified column chromatography (silica gel Fluka 60, hexane/ethyl acetate 9:1), receiving 235,3 mg of ester. Output: 235,3 mg (32%).

RF=0,40 (SiO2, hexane/ethyl acetate 9:1).

General method (C):

Stage A, (E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy]acetic acid:

To the solution obtained above of ester (235,3 mg, 0,425 mmol) in a mixture of tetrahydrofuran/ethanol (1:1, 18 ml) was added 1,M solution of the monohydrate of lithium hydroxide (0,247 ml, 0,482 mmol). The resulting solution was stirred for 3 h and then evaporated in vacuum. The residue was diluted with water (10 ml), acidified with 1M hydrochloric acid to pH 2-3 and extracted with ether (40+15 ml). The combined organic layers washed with water (25 ml) and saturated salt solution (30 ml) and dried over anhydrous magnesium sulfate. Obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, chloroform+1-15% methanol), receiving 126,6 mg of a mixture of both isomers indicated in the title acid. Output: 126,6 mg (57%).

RF=0,20 (SiO2, chloroform+15% methanol).

The above acid (126,6 mg, 0,241 mmol) dissolved in minimum amount of dry methylene chloride (about 1.4 ml), the resulting solution was diluted with absolute methanol (10 ml) and add L-lysine (a 30.7 mg, 0.21 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, evaporated in vacuo and the residue triturated with anhydrous ether (2×10 ml), receiving 74,4 mg L-lysinate indicated in the title acid. Output: 74,4 mg (46%).

TPL: 130-139°C (amorphous).

1H NMR (250 MHz, DMSO-d6): 7,94-6,62 (m, N); 6,27+of 6.26 (t, 1H); 4,24 (USS, 2H); 3,69+3,40 (d, 2H); 3,18 (m, 1H); 2,71 (who, 2H); 2,07+2,04 (s, 3H); 1,72 to 1.31 (m, 6N).

Example 28(General procedure (D))

(E/Z)-[4-[3-(4-bromophenyl)-3-(5-methylthiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid

Stage F, Ethyl-(Z)-[4-[3-(4-bromophenyl)-3-(5-methylthiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetate

To a solution of ethyl-(Z)-[4-[3-(4-bromophenyl)-3-totallyconfused]-2-methylphenoxy]acetate (418 mg, 0,764 mmol; example 27, step D-E) and tributyl(5-methylthiophene-2-yl)tin (585 mg and 1.51 mmol, obtained in 86% yield according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (9 ml) is added Pd2 (dba)3.CHCl3(25.0 mg, 0,024 mmol). Trace amounts of moisture and oxygen are removed, add in an atmosphere of nitrogen 0,20M solution three(tert-butyl)phosphine in cyclohexane (of 0.43 ml, 0,086 mmol) and the whole mixture was stirred at room temperature for 30 min and for an additional 150 minutes at 50°C. the Dark solution was poured into 10% aqueous solution of potassium fluoride (15 ml) and add ethyl acetate (50 ml). The layers separated, the aqueous layer washed with ethyl acetate (2×10 ml) and the combined organic layers washed with saturated salt solution (2×15 ml), 10% solution of potassium fluoride (15 ml), water (2×15 ml) and saturated salt solution (2×15 ml). The organic solution is dried over anhydrous magnesium sulfate and evaporation gives an oil which is purified column is cromatografia (silica gel Fluka 60, hexane/ethyl acetate 10:1)to give 304 mg of ester. Output: 304 mg (77%) (oil).

RF=0,25 (SiO2, hexane/ethyl acetate 10:1).

General method (C):

Stage A, (E/Z)-[4-[3-(4-bromophenyl)-3-(5-methylthiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid:

To the solution obtained above ester (304 mg, 0,587 mmol) in a mixture of tetrahydrofuran/methanol (1:3, 5 ml) add a solution of the monohydrate of lithium hydroxide (36 mg, 0,858 mmol) in distilled water (0.5 ml). The resulting solution was stirred for 60 min and then evaporated in vacuum. The residue was diluted with water (20 ml), neutralized with acetic acid (51 mg, 0,849 mmol) and extracted with ether (3×20 ml). The combined organic layers washed with water (2×10 ml) and saturated salt solution (3×10 ml) and dried over anhydrous magnesium sulfate. Obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, chloroform+4-12% methanol)to give 190 mg of a mixture of both isomers (ratio about 2:1) indicated in the title acid. Yield: 198 mg (69%). TPL: 53-56°C.

RF=0,30 (SiO2, chloroform/methanol 85:15).

1H NMR (250 MHz, DMSO-d6): 7,55-7,51 (m, 2H); 7,17? 7.04 baby mortality (m, 2H); 6,83-6,63 (m, 4H); 6,36 (d, 1H); 6,04 (t, 1H); 4,57 and of 4.54 (s, 2H); 3.72 points and 3,37 (d, 2H); 2,45 and 2,40 (USS, 3H); 2.13 and and are 2.11 (s, 3H).

The above acid (190 mg, 0,388 mmol) dissolved in minimum amount of dry methylene chloride (okolo,5 ml), the resulting solution was diluted with absolute methanol (5 ml) and add L-lysine (52 mg, 0,355 mmol). The reaction mixture was stirred at room temperature for 90 min, evaporated in vacuo and the residue triturated with anhydrous ether (2×8 ml)to give 184 mg L-lysinate indicated in the title acid. Output: 184 mg (74%). TPL: 129-134°C (amorphous).

1H NMR (250 MHz, DMSO-d6): EUR 7.57-6,36 (m, N); 6,05 (t, 1H); and 4.26 to 4.28 (s, 2H); 3,71 and to 3.36 (d, 2H); 3,26 (m, 1H); 2,73 (m, 2H); 2,45 and is 2.40 (s, 3H); to 2.13 and 2.10 (s, 3H); 1,76-of 1.29 (m, 6N).

Example 29(General procedure (D))

(E/Z)-[4-[3-(furan-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid

Stage A, 1,1-dibromo-2-(4-triptoreline)Ethan:

A solution of 4-triftormetilfullerenov (13.3 ml; 0.1 mol), chetyrehpostovye carbon (36,2 g; 0.11 mol) and triphenylphosphine (28.8 g; 0.11 mol) in anhydrous dichloromethane (250 ml) is stirred over night. The solid precipitate is filtered off and washed with a small amount of dichloromethane. The solution is concentrated and the solid is again filtered off and washed with a small amount of dichloromethane. The solvent is evaporated and the product purified by distillation in vacuo provided an oil pump

(84-99°C ˜1 Torr)to give 28 g (84%) of liquid.

Stage B, 3-(4-(trifluoromethyl)prop-3-in-1-ol:

In the reaction flasks is with a rubber septum was placed 1,1-dibromo-2-(4-triptoreline)ethane (21.1 g; 64 mmol) and dissolved in anhydrous THF. The reaction mixture was cooled to -78°C and slowly add utility (106 ml, 1.5m solution in hexane; 0.16 mol). The reaction mixture was stirred at -78°C for an additional 0.5 hour and add paraformaldehyde (4.8 g, 0.16 mmol). The reaction mixture is stirred without cooling until the temperature reaches room temperature, poured into water and extracted with ethyl acetate (3×). The combined organic layers are dried over magnesium sulfate and evaporated. Chromatographic processing on silica gel (250 g, gradient elution hexane-acetic acid ethyl ester 9:1, 8:2, 7:3) give 5.49 g (42 %) of product.

Stage C, (Z)-3-iodine-3-(4-trimetilfenil)prop-2-EN-1-ol:

The solution sociallyengaged in THF (33 ml, 1M solution in THF, 33 mmol), sodium methoxide (54 mg, 1 mmol) and THF (30 ml) cooled to 0°C. Slowly add a solution of 3-(4-(trifluoromethyl)prop-3-in-1-ol (5.49 g; 27.5 mmol) in THF (20 ml) and stirred for 2 hours at 0°C. for 5 minutes add dimethylcarbonate (2,78 ml, 33 mmol). After 10 min the mixture is cooled to -78°C and add iodine (10 g, 40 mmol). The reaction mixture is stirred without cooling until the temperature reaches room temperature, and add methanol (10 ml). After 1 hour the mixture was poured into water, acidified with HCl and extracted with ethyl acetate (3×). The combined organic layers Susitna magnesium sulfate and evaporated. Chromatographic processing on silica gel (hexane-ethyl acetate, gradient 9:1 to 8:2-7:3) gives 6.42 per g (71%) of the connection.

Stage D-E, Ethyl-(Z)-(4-(3-iodine-3-(4-trimetilfenil)PoWPA-2-EN-1-ylsulphonyl)-2-methylphenoxy)acetate:

A solution of (Z)-3-iodine-3-(4-trimetilfenil)prop-2-EN-1-ol (3.28 g, 10 mmol), chetyrehpostovye carbon (3.98 g, 12 mmol) and triphenylphosphine (3,14 g, 12 mmol) in methylene chloride is stirred overnight at room temperature in a nitrogen atmosphere. Add a solution of diisopropylethylamine (20 ml, 116 mmol), water (4 ml, 222 mmol) in THF (40 ml) and the reaction mixture was kept under nitrogen atmosphere. Add ethyl(4-mercapto-2-methylphenoxy)acetate (2,94 g, 13 mmol) (clean). The reaction mixture was stirred overnight, diluted with ethyl acetate and filtered through silica. The solvent is evaporated and the mixture chromatographic on silica gel (100 g, hexane-ethyl acetate, gradient 95:5 to 80:20), receiving of 3.96 g (76%).

1H NMR (300 MHz, CDCl3): 7,4-7,6 (m, 4H); 7,21-7,33 (m, 2H); 6,62 (d, J=8.5 Hz, 1H); 6,00 (d, J=7,28,5 Hz, 1H); 4,22 (sq, J=7,28,5 Hz, 2H); 3,70 (d, 2H); and 2.26 (s, 3H); 1.27mm (s, J=7,28,5 Hz, 3H).

Stage F, Ethyl-(Z)-[4-[3-(furan-2-yl)-3-(4-triptoreline)arylsulfonyl-2-methylphenoxy]acetate:

To a solution of ethyl-(Z)-[4-[3-iodine-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate (417 mg, 0,777 mmol) and tributyl(furan-2-yl)tin (277 mg, 0,776 mmol; obtained with a yield of 78% in accordance with Mrimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (5 ml) is added Pd2 (dba)3.CHCl3(20.2 mg, at 0.020 mmol). Trace amounts of moisture and oxygen is removed in a nitrogen atmosphere add 0,20M solution three(tert-butyl)phosphine in cyclohexane (0,38 ml, 0,076 mmol) and the whole mixture was stirred at 50°C for 90 minutes the Dark solution was poured into 10% aqueous solution of potassium fluoride (15 ml) and then added ethyl acetate (50 ml). The layers separated, the aqueous layer washed with ethyl acetate (2×15 ml) and the combined organic layers washed with saturated salt solution (2×20 ml), 10% solution of potassium fluoride (2×10 ml), water (2×10 ml) and saturated salt solution (2×10 ml). The organic solution is dried over anhydrous sodium sulfate and obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, hexane/ethyl acetate 10:1+0.1% triethylamine)to give 306 mg of ester. Crude yield: 306 mg (83%) (oil).

RF=0,35 (SiO2, hexane/ethyl acetate 10:1).

General method (C):

Stage A, (E/Z)-[4-[3-(furan-2-yl)-3-(4-triptoreline)arylsulfonyl-2-methylphenoxy]acetic acid:

To the solution obtained above ester (306 mg, 0,642 mmol) in a mixture of tetrahydrofuran/methanol (1:3, 8 ml) add a solution of the monohydrate of lithium hydroxide (46 mg, 1.10 mmol) in distilled water (0.5 ml). The resulting solution was stirred for 30 m and then evaporated in vacuum. The residue was diluted with water (30 ml), neutralized with acetic acid (66 mg, 1.10 mmol) and extracted with ether (3×25 ml). The combined organic layers washed with water (10 ml) and saturated salt solution (2×20 ml) and dried over anhydrous sodium sulfate. Obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, chloroform+4-12% methanol)to give 163 mg approximately equimolar mixture of both isomers indicated in the title acid. Yield: 163 mg (57%) (oil).

RF=0,30 (SiO2, chloroform/methanol 85:15).

1H NMR (250 MHz, DMSO-d6): 7,72-of 6.71 (m, 8H); 6,55 and to 6.43 (m, 1H); of 6.31 and of 5.83 (d, 1H); 6,28 and to 5.93 (t, 1H); 4,67 and br4.61 (s, 2H); 3,92 and 3.38 (d, 2H); 2,10 and to 2.06 (s, 3H).

The above acid (153 mg, 0,341 mmol) dissolved in minimum amount of dry methylene chloride (0.5 ml), the resulting solution was diluted with absolute methanol (5 ml) and add L-lysine (50 mg, 0,342 mmol). The reaction mixture was stirred at room temperature for 3 hours, evaporated in vacuo and the residue triturated with anhydrous ether (2×8 ml)to give 144 mg L-lysinate indicated in the title acid. Yield: 144 mg (71 %). TPL: 133-143°C (amorphous).

1H NMR (250 MHz, DMSO-d6): 7,73-of 6.61 (m, 8H); 6,55 and 6.42 per (DD, 1H); 6,33 and of 5.83 (d, 1H); 6,28 and 5,94 (t, 1H); 4,28 and to 4.23 (s, 2H); 3.89 and to 3.38 (d, 2H); 3,23 (m, 1H); 2,72 (m, 2H); 2,08 and 2,04 (s, 3H); 1.77 in-1,22 (m, 6N).

Example 30(General procedure(D))

(E/Z)-[4-[3-(5-methylthiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid

Stage F, Ethyl-(Z)-[4-(5-methylthiophene-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate:

To a solution of ethyl-(Z)-[4-[3-iodine-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate (413 mg, 0,770 mmol; example 29, step D-E) and tributyl(5-methylthiophene-2-yl)tin (306 mg, 0,790 mmol, obtained with a yield of 86% according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (8 ml) is added Pd2(dba)3.CHCl3(24.6 mg, 0,024 mmol). Trace amounts of moisture and oxygen is removed in a nitrogen atmosphere add 0,20M solution three(tert-butyl)phosphine in cyclohexane (of 0.48 ml, 0,096 mmol) and the whole mixture was stirred at room temperature for 15 min and for an additional 100 min at 50°C. the Dark solution was poured into 10% aqueous solution of potassium fluoride (15 ml) and then added ethyl acetate (50 ml). The layers separated, the aqueous layer washed with ethyl acetate (2×10 ml) and the combined organic layers washed with saturated salt solution (2×15 ml), 10% solution of potassium fluoride (15 ml), water (2×15 ml) and saturated salt solution (2×15 ml). The organic solution is dried over anhydrous sodium sulfate and obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, hexa is/ethyl acetate 10:1), getting 380 mg of the ether. Yield: 380 mg (97%) (oil).

RF=0,30 (SiO2, hexane/ethyl acetate 9:1).

General method (C):

Stage A, (E/Z)-[4-[3-(5-methylthiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid:

To the solution obtained above ester (380 mg, 0,750 mmol) in a mixture of tetrahydrofuran/methanol (1:4, 5 ml) add a solution of the monohydrate of lithium hydroxide (47 mg, to 1.14 mmol) in distilled water (0.5 ml). The resulting solution was stirred for 30 min, neutralized with acetic acid (67 mg, 1.12 mmol) and then evaporated in vacuum. The residue was diluted with water (20 ml), acidified with additional portion of acetic acid (about 20 mg) and extracted with ether (3×20 ml). The combined organic layers washed with water (2×10 ml) and saturated salt solution (3×10 ml) and dried over anhydrous magnesium sulfate. Obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, chloroform+3-8% methanol)to give 247 mg of the mixture of both isomers (ratio about 3:1) indicated in the title acid. Output: 247 mg (69%) (oil).

RF=0,30 (SiO2, chloroform/methanol 85:15).

1H NMR (250 MHz, DMSO-d6): 7,69-6,63 (m, 8H); 6,55 and of 6.31 (d, 1H); 6,13 and between 6.08 (t, 1H); 4.72, and of 4.67 (s, 2H); 3.75 to and to 3.34 (d, 2H); 2,43 and 2,39 (s, 3H); 2,12 and 2.07 (s, 3H).

The above acid (232 mg, 0,485 mmol) dissolved in minimum amount of dry the stands who chloride (0.5 ml), the resulting solution was diluted with absolute methanol (5 ml) and add L-lysine (68 mg, 0,465 mmol). The reaction mixture was stirred at room temperature for 1 hour, evaporated in vacuo and the residue triturated with anhydrous ether (2×8 ml)to give 241 mg L-lysinate indicated in the title acid. Output: 241 mg (80 %). TPL: 131 -138°C (amorphous).

1H NMR (250 MHz, DMSO-d6): 7,72-6,33 (m, N); 6,16 and 6,10 (t, 1H); 4 : 31 and to 4.28 (s, 2H); 3,74 and the 3.35 (d, 2H); 3.27 to (m, 1H); to 2.75 (m, 2H); 2,46 and 2.41 (s, 3H); 2.13 in and of 2.08 (s, 3H); 1,81-1,22 (m, 6N).

Example 31(General procedure (D))

(E/Z)-[4-[3-(benzo[b]thiophene-3-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid

Stage F, Ethyl-(Z)-[4-[3-(benzo[b]thiophene-3-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate:

To a solution of ethyl-(Z)-[4-[3-iodine-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate (410,9 mg, 0,766 mmol; example 29, step D-E) and (benzo[b]thiophene-3-yl)anti (330,9 mg, 0,782 mmol, obtained from 71% yield according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (3 ml) is added Pd2(dba)3.CHCl3(23,8 mg, is 0.023 mmol). Trace amounts of moisture and oxygen is removed in a nitrogen atmosphere add 0,20M solution three(tert-butyl)phosphine in cyclohexane (0,50 ml, 0.1 mmol) and the whole mixture was stirred at 90°C for 7.5 hours. So the initial solution is poured into 10% aqueous solution of potassium fluoride (20 ml) and then added ethyl acetate (30 ml). The layers separated, the aqueous layer washed with ethyl acetate (2×15 ml) and the combined organic layers washed with saturated salt solution (10 ml), 10% solution of potassium fluoride (20 ml), water (20 ml) and saturated salt solution (20 ml). The organic solution is dried over anhydrous sodium sulfate and obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, hexane/ethyl acetate 9:1), receiving 282,2 mg of ester. Output: 282,2 mg (67%). RF=0,30 (SiO2, hexane/ethyl acetate 9:1).

General method (C):

Stage A, (E/Z)-[4-[3-(benzo[b]thiophene-3-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid:

To the solution obtained above ester (282,2 mg, 0,520 mmol) in a mixture of tetrahydrofuran/ethanol (1:1, 15 ml) was added 1,M solution of the monohydrate of lithium hydroxide (0,331 ml, to 0.645 mmol). The resulting solution was stirred for 2 hours and then evaporated in vacuum. The residue was diluted with water (10 ml), acidified with 1M hydrochloric acid to pH 2-3 and extracted with ether (40+15 ml). The combined organic layers washed with water (25 ml) and saturated salt solution (30 ml) and dried over anhydrous magnesium sulfate. Obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, chloroform+1-15% methanol), receiving 86,6 mg of a mixture of both isomers indicated in the title acid. Output: 86,6 mg (33%).

RF =0,10 (SiO2, chloroform+15% methanol).

The above acid (86,6 mg, 0,1683 mmol) dissolved in absolute methanol (5 ml) and add L-lysine (23,6 mg, 0,161 mmol). The reaction mixture was stirred at room temperature for 2 hours, evaporated in vacuo and the residue triturated with anhydrous ether (2×5 ml), receiving 65,3 mg L-lysinate indicated in the title acid. Output: 65,3 mg (59 %). TPL: 139-141°C

1H NMR (250 MHz, DMSO-d6): 8,12-of 6.78 (m, N); 6,53+6,16 (t, 1H); 4,30+4,28 (s, 2H); 3,70+3,43 (m, 2H); 3,17 (m, 1H); 2,69 (m, 2H); 2,13+2,11 (s, 3H); 1,72-of 1.27 (m, 6N).

Example 32(General procedure (D))

(E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid

Stage F, Ethyl-(Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate:

To a solution of ethyl-(Z)-[4-[3-iodine-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetate (407,1 mg, 0,759 mmol; example 29, step D-E) and (benzo[b]thiophene-2-yl)anti (327,2 mg, 0,773 mmol, obtained according to Morimoto et al.: J.Med.Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (3 ml) is added Pd2(dba)3.CHCl3(24,1 mg, is 0.023 mmol). Trace amounts of moisture and oxygen is removed in a nitrogen atmosphere add 0,20M solution three(tert-butyl)phosphine in cyclohexane (0,49 ml, 0,098 mmol) and the whole mixture was stirred at 60°St for 5 hours. The dark solution was poured into 10% aqueous solution of potassium fluoride (20 ml) and then added ethyl acetate (30 ml). The layers separated, the aqueous layer washed with ethyl acetate (2×15 ml) and the combined organic layers washed with saturated salt solution (10 ml), 10% solution of potassium fluoride (20 ml), water (20 ml) and saturated salt solution (20 ml). The organic solution is dried over anhydrous sodium sulfate and obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, hexane/ethyl acetate 9:1), receiving 318,6 mg of ester. Output: 318,6 mg (76%).

RF=0,35 (SiO2, hexane/ethyl acetate 9:1).

General method (C):

Stage A, (E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-triptoreline)arylsulfonyl-2-methylphenoxy]acetic acid:

To the solution obtained above ester (318,6 mg, 0,587 mmol) in a mixture of tetrahydrofuran/ethanol (1:1, to 15.4 ml) was added 1,M aqueous solution of the monohydrate of lithium hydroxide (0,373 ml, 0,7281 mmol). The resulting solution was stirred for 3 h and then evaporated in vacuum. The residue was diluted with water (10 ml), acidified with 1M hydrochloric acid to pH 2-3 and extracted with ether (40+15 ml). The combined organic layers washed with water (25 ml) and saturated salt solution (30 ml) and dried over anhydrous magnesium sulfate. Obtained after evaporation of the oil is purified column chromatography (silica gel Fluka 60, chloroform-15% methanol), getting 191 mg of a mixture of both isomers indicated in the title acid. Yield: 191 mg (63%).

RF=0,16 (SiO2, chloroform+15% methanol).

1H NMR (250 MHz, CDCl3): 7,80-7,01 (m, 11N); of 6.31+6,23 (t, 1H); 4,56+of 4.54 (s, 2H); to 3.73+3,35 (d, 2H); 2,15+2,13 (s, 3H).

The above acid (177,2 mg, 0,344 mmol) dissolved in absolute methanol (5 ml) and add L-lysine (48,5 mg of 0.332 mmol). The reaction mixture was stirred at room temperature for 1 hour, evaporated in vacuo and the residue triturated with anhydrous ether (2×10 ml), getting to 40.1 mg L-lysinate indicated in the title acid. Output: 40,1 mg (20%). TPL: 121-132°C (amorphous).

1H NMR (250 MHz, DMSO-d6): to $ 7.91-of 6.61 (m, N); 6,39+of 6.31 (t, 1H); 4,23+is 4.21 (s, 2H); 3.72 points+3,38 (d, 2H); 3.15 in (m, 1H); 2.71 to (m, 2H); 2,04 (s, 3H); 1,71-of 1.29 (m, 6N).

Example 33(General procedure (A))

{4-[3,3-bis-(4-chlorophenyl)allyloxy]phenoxy}acetic acid

Stage C:

A solution of 3,3-bis-(4-chlorophenyl)prop-2-EN-1-ol (200 mg, to 0.72 mmol; example 11, step B) and tributylphosphine (361 mg, to 1.79 mmol) in dry THF (10 ml) is stirred under nitrogen atmosphere at 0°C. Add ADDP (451 mg, to 1.79 mmol) and the reaction mixture is stirred for 5 minutes for 5 min add ethyl ester (4-hydroxyphenoxy)acetic acid (169 mg, 0.86 mmol) and the reaction mixture stirred for 2 hours at 0°C. To the reaction mixture, water is added 10 ml) and the mixture is extracted with methylene chloride (3× 15 ml). The combined organic phases are dried (MgSO4), filtered and evaporated. The residue is triturated with ether (3×10 ml) and the ether phase is evaporated, obtaining the crude product. Purification of column chromatography using methylene chloride as eluent gives the pure ethyl ester {4-[3,3-bis-(4-chlorophenyl)allyloxy]phenoxy}acetic acid to yield 140 mg (43%).

1H NMR (CDCl3, 400 MHz) δ; of 1.27 (t, 3H), 4,25 (square, 2H), 4,48 (d, 2H), 4,56 (s, 2H), 6,28 (t, 1H), 6,77 (d, 2H), at 6.84 (d, 2H), 7,14 (d, 2H), 7,17 (d, 2H), 7,26 (d, 2H), 7,37 (d, 2H).

General method (C):

Stage A.

A solution of ethyl ester {4-[3,3-bis-(4-chlorophenyl)allyloxy]phenoxy}acetic acid (140 mg, 0.3 mmol) in 1H. NaOH (1 ml) and ethanol (10 ml) was stirred at room temperature for 18 hours. The reaction mixture is evaporated and the residue is dissolved in water (5 ml) and 1N. HCl (1.2 ml). The aqueous phase is extracted with ethyl acetate (3×15 ml), dried (MgSO4) and evaporated, getting mentioned in the title compound with a yield of 130 mg (99%).

1H NMR (CDCl3, 300 MHz) δ; 4,50 (d, 2H), to 4.62 (s, 2H), 6.30-in (t, 1H), 6,77 (d, 2H), 6,85 (d, 2H), 7,09-7,20 (m, 4H), 7,27 (m, 2H), 7,37 (d, 2H).

Example 34(General procedure (A))

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid

Stage C:

A solution of 3,3-bis-(4-chlorophenyl)prop-2-EN-1-ol (200 mg, to 0.72 mmol; example 11, a hundred the Oia B) and tributylphosphine (361 mg, to 1.79 mmol) in dry THF (10 ml) is stirred under nitrogen atmosphere at 0°C. Add ADDP (451 mg, to 1.79 mmol) and the reaction mixture is stirred for 5 minutes for 5 min add ethyl ester (2-chloro-4-mercaptobenzoic)acetic acid (212 mg, 0.86 mmol; example 23) and the reaction mixture is stirred for 2 hours at 0°C. To the reaction mixture are added water (10 ml) and the mixture is extracted with methylene chloride (3×15 ml). The combined organic phases are dried (MgSO4), filtered and evaporated. The residue is triturated with ether (3×10 ml) and the ether phase is evaporated, obtaining the crude product. Purification of column chromatography using methylene chloride as eluent, to give pure ethyl ester of {{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid to yield 100 mg (27%).

1H NMR (CDCl3, 400 MHz) δ; of 1.26 (t, 3H), 3,49 (d, 2H), 4,24 (square, 2H), and 4.68 (s, 2H), between 6.08 (t, 1H), 6,69 (d, 1H), 6,86 (d, 2H), 7,05 (d, 2H), 7,12-7,33 (m, 6N).

General methods C:

Stage A:

A solution of ethyl ester {{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid (100 mg, 0.2 mmol) in 1H. NaOH (1 ml) and ethanol (10 ml) was stirred at room temperature for 18 hours. The reaction mixture is evaporated and the residue is dissolved in water (5 ml) and 1N. HCl (1.2 ml). The aqueous phase is extracted with ethyl acetate (3×15 ml), dried (MgSO4) and evaporated, receiving is shown in the title compound with a yield of 95 mg (100%).

1H NMR (CDCl3, 300 MHz) δ; 3,51 (d, 2H), 4.72 in (s, 2H), 6,09 (t, 1H), 6.73 x (d, 1H), 6.87 in (d, 2H), 7,00 to 7.75 (m, 8H), 9,7 (USS, 1H).

Example 35(General procedure (A))

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-triptoreline}acetic acid

Stage C:

A solution of 3,3-bis-(4-chlorophenyl)prop-2-EN-1-ol (200 mg, to 0.72 mmol; example 11, step B) and tributylphosphine (361 mg, to 1.79 mmol) in dry THF (10 ml) is stirred under nitrogen atmosphere at 0°C. Add ADDP (451 mg, to 1.79 mmol) and the reaction mixture is stirred for 5 minutes for 5 min add ethyl ester (2-trifluoromethyl-4-mercaptobenzoic)acetic acid (241 mg, 0.86 mmol; obtained analogously to example 23) and the reaction mixture is stirred for 2 hours at 0°C. To the reaction mixture are added water (10 ml) and the mixture is extracted with methylene chloride (3×15 ml). The combined organic phases are dried (MgSO4), filtered and evaporated. The residue is triturated with ether (3×10 ml) and the ether phase is evaporated, obtaining the crude product. Purification of column chromatography, using as eluent methylene chloride, gives the pure ethyl ester of {{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-trimethylpentane}acetic acid to yield 135 mg (35%).

1H NMR (CDCl3, 400 MHz) δ; of 1.26 (t, 3H), 3,49 (d, 2H), 4,24 (square, 2H), 4,70 (s, 2H), 6,10 (t, 1H), 6,74 (d, 1H), PC 6.82 (d, 2H), 7,05 (d, 2H), 7.23 percent (d 2H), 7,29 (d, 2H), 7,42 (d, 1H), 7,56 (s, 1H).

General methods C:

Stage A:

A solution of ethyl ester {{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-triptoreline}acetic acid (135 mg, 0.25 mmol) in 1H. NaOH (1 ml) and ethanol (10 ml) was stirred at room temperature for 18 hours. The reaction mixture is evaporated and the residue is dissolved in water (5 ml) and 1N. HCl (1.2 ml). The aqueous phase is extracted with ethyl acetate (3×15 ml), dried (MgSO4) and evaporated, getting mentioned in the title compound with a yield of 130 mg (100%).

1H NMR (CDCl3, 300 MHz) δ; to 3.52 (d, 2H), 4,74 (s, 2H), 6,10 (t, 1H), 6,76 (d, 1H), at 6.84 (d, 2H), 7,05 (d, 2H), 7,17 was 7.45 (m, 5H), 7,55 (s, 1H), 9,6 (USS, 1H).

Example 36(General procedure (A))

{4-[3,3-bis-(3-methylthiophene-2-yl)arylsulfonyl]-2-triptoreline}acetic acid

Stage A:

To a solution of triethylphosphate (4,48 g, 19,97 mmol) in ethanol (100 ml) add a solution of sodium (689 mg, 30 mmol) in ethanol (3 ml) at room temperature. The reaction mixture is stirred for 15 minutes In an atmosphere of nitrogen was added bis(3-methyl-2-thienyl)ketone (2,22 g, 9,98 mmol) and the reaction mixture stirred at 90°C for 72 hours. The reaction mixture was added to 1N. HCl (pH 2) and extracted with methylene chloride (4×50 ml). The combined organic phases are dried, filtered and evaporated, obtaining the crude product. Cleaning the column chromatography, using a mixture of toluene:heptane:THF (2:1:5%), gives the ethyl ester of 3,3-bis-(3-methylthiophene-2-yl)acrylic acid with the release 2,11 g (72%).

1H NMR (CDCl3, 400 MHz) δ; of 1.17 (t, 3H), 2.50 each (C, 6N), 4,10 (square, 2H), 6,29 (s, 1H), 6,86 (m, 2H), 7,28 (m, 2H).

Stage B:

To a solution of ethyl ester of 3,3-bis-(3-methylthiophene-2-yl)acrylic acid (2,12 g, 7,27 mmol) in THF (20 ml) is added a solution of DIBAL-H (1.5 m in toluene, 33 ml, a 49.5 mmol) at -20°C. the Reaction mixture is stirred for an additional 2 hours. Add a solution of ameriglide, then methylene chloride (150 ml) and dekalim. The mixture is filtered and the filter washed with additional amount of methylene chloride (500 ml). The combined organic phase is evaporated, obtaining the crude product. Purification of column chromatography gives 3,3-bis-(3-methylthiophene-2-yl)prop-2-EN-1-ol with the release of 376 mg (21%).

1H NMR (CDCl3, 400 MHz) δ; 2,02 (d, 6N), 4,18 (d, 2H), 6,21 (t, 1H), 6,78 (d, 1H), 6,85 (d, 1H), was 7.08 (d, 1H), 7.23 percent (d, 1H).

Stage C:

To a solution of 3,3-bis-(3-methylthiophene-2-yl)prop-2-EN-1-ol (110 mg, 0.44 mmol) and triphenylphosphine (220 mg, 0.88 mmol) in THF at room temperature under nitrogen atmosphere add DEAD (153 mg, 0.88 mmol). The reaction mixture is stirred for 5 minutes, then for 15 min add ethyl ester (2-trifluoromethyl-4-mercaptobenzoic)acetic acid (70 mg, 0.25 mmol). The reaction mixture was stirred at room temperature in them is giving 100 hours. The reaction mixture is evaporated and the crude residue purified using the Horizon and gradient elution with a mixture of methylene chloride:heptane. The desired ethyl ester {4-[3,3-bis-(3-methylthiophene-2-yl)arylsulfonyl]-2-triptoreline}acetic acid allocate with a yield of 75 mg (59%).

1H NMR (CDCl3, 400 MHz) δ; of 1.25 (t, 3H), of 1.88 (s, 3H), of 1.94 (s, 3H), 3,57 (d, 2H), 4,24 (square, 2H), and 4.68 (s, 2H), equal to 6.05 (t, 1H), 6,72-6,85 (m, 3H), 7,07 (d, 1H), 7,22 (d, 1H), 7,46 (m, 1H), to 7.61 (s, 1H).

General method (C):

Stage A:

A solution of ethyl ester {4-[3,3-bis-(3-methylthiophene-2-yl)arylsulfonyl]-2-triptoreline}acetic acid (75 mg, 0.15 mmol) in 1H. NaOH (0,02 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours. The reaction mixture is evaporated and the residue is dissolved in 1N. HCl (0,03 ml). The aqueous phase is extracted with methylene chloride (3×25 ml), dried (MgSO4) and evaporated, getting mentioned in the title compound with a yield 70 mg (99%).

1H NMR (CDCl3, 400 MHz) δ; of 1.88 (s, 3H), of 1.94 (s, 3H), 3,57 (d, 2H), with 4.64 (s, 2H), 6,04 (t, 1H), 6,70-6,84 (m, 3H), 7,05 (d, 1H), of 7.70 (d, 1H), 7,44 (DD, 1H), 7,58 (s, 1H), 8,50 (USS, 1H).

Example 37(General procedure (A))

[4-(3,3-difuran-2-intellisurvey)-2-triptoreline]acetic acid

Stage A:

To a solution of triethylphosphate (4,48 g, 19,97 mmol) in ethanol (100 ml) add a solution of sodium (689 mg, 30 mmol) in ethane is Le (3 ml) at room temperature. The reaction mixture is stirred for 15 minutes In an atmosphere of nitrogen was added bis(2-furanyl)ketone (1,62 g, 9,98 mmol) and the reaction mixture stirred at 80°C for 16 hours. The reaction mixture was added to 1N. HCl (pH 2) and extracted with methylene chloride (3×50 ml). The combined organic phases are dried, filtered and evaporated, obtaining the crude product. Purification of column chromatography using methylene chloride, gives the ethyl ester of 3,3-bis-(2-furanyl)acrylic acid with the release of 1.31 g (57%).

1H NMR (CDCl3, 400 MHz) δ; to 1.19 (t, 3H), 4,21 (square, 2H), 6,13 (s, 1H), to 6.57 (m, 2H), 7,14 (d, 1H), 7,30-7,40 (m, 2H), 7,58 (s, 1H).

Stage B:

To a solution of ethyl ester of 3,3-bis-(2-furanyl)acrylic acid (1.31 g, to 5.66 mmol) in THF (15 ml) add a solution of DIBAL-H (1M in toluene, of 25.5 ml, 25.5 mmol) at -10°C. the Reaction mixture is stirred for an additional 2 hours. Add a solution of ammoniaand (2 ml), then methylene chloride (250 ml) and dekalim. The mixture is filtered and the filter washed with additional amount of methylene chloride (500 ml) and ethanol (100 ml). The combined organic phase is evaporated, obtaining the crude 3,3-bis-(2-furanyl)prop-2-EN-1-ol with access 953 mg (88%) output.

1H NMR (CDCl3, 400 MHz) δ; 1,98 (s, 1H), 4,59 (d, 2H), 6,24 (s, 1H), 6,60 (t, 1H), 6.73 x (d, 1H), 6,97 (d, 1H), was 7.08 (d, 1H), 7,28 (m, 1H), 7.62mm (s, 1H).

Stage C:

To a solution of 3,3-bis-(2-furanyl)prop-2-EN-1-ol (104 mg,0.55 mmol) and triphenylphosphine (275 mg, of 1.09 mmol) in THF (10 ml) at room temperature under nitrogen atmosphere add DEAD (190 mg, of 1.09 mmol). The reaction mixture is stirred for 5 minutes, then for 15 min add ethyl ester (2-trifluoromethyl-4-mercaptobenzoic)acetic acid (230 mg, 0.82 mmol). The reaction mixture was stirred at 0°C for 2 hours, then for 18 hours at room temperature and 3 hours at 50°C. the Reaction mixture is evaporated and the crude residue purified through column chromatography using ethyl acetate as eluent. The desired ethyl ester {4-[3,3-bis-(2-furanyl)arylsulfonyl]-2-triptoreline}acetic acid allocate exit 11 mg.

1H NMR (CDCl3, 400 MHz) δ; of 1.28 (t, 3H), a 4.03 (s, 2H), 4,27 (square, 2H), 4,69 (s, 2H), 6,56 (m, 2H), 6,80-of 7.60 (m, 8H).

General methods C:

Stage A:

A solution of ethyl ester {4-[3,3-bis-(2-furanyl)arylsulfonyl]-2-triptoreline}acetic acid (35 mg, 0,077 mmol) in 1H. NaOH (0.1 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours. The reaction mixture is evaporated and the residue is dissolved in 1N. HCl (0.15 ml). The aqueous phase is extracted with methylene chloride (3×25 ml), dried (MgSO4) and evaporated, getting mentioned in the title compound with a yield of 30 mg (92%) output.

1H NMR (CDCl3, 400 MHz) δ; a 4.03 (s, 2H), 4,74 (s, 2H), 6,55 (and OSS, 4H), 6.75 in (d, 1H), 6,83 (d, 1H), to 6.88 (d, 1H), 7,15-to 7.32 (m, 2H),7,47 (s, 1H), EUR 7.57 (s, 1H).

Example 38(General procedure (A))

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid

Stage C:

3,3-bis-(4-itfinal)prop-2-EN-1-ol (206 mg, 0.44 mmol, example 5, step B) and tributylphosphine (226 mg, 1.1 mmol) dissolved in dry THF (10 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (281 mg, 1.1 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 min) methyl ester of (4-mercapto-2-methoxyphenoxy)acetic acid (298 mg, 1.4 mmol; obtained analogously to example 23) and stirring is continued for 1 hour at 0°C. Add water (10 ml) and the mixture is evaporated. The residue is triturated with ether. The ether phase is filtered and evaporated, obtaining the crude product. Chromatographic purification using Horizin (eluent: methylene chloride:heptane (1:1) gradient to pure methylene chloride) gives methyl ester {4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid to yield 298 mg (100%).

1H NMR (CDCl3, 300 MHz); δ 3,47 (d, 2H), 3,76 (C, 6N), 4,69 (s, 2H), 6,14 (t, 1H), to 6.57 (d, 2H), 6,66 (d, 1H), 6,80-of 6.90 (m, 4H), EUR 7.57 (d, 2H), to 7.64 (d, 2H).

General methods C:

Stage A:

Methyl ester {4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid (290 mg, 0.43 mmol) was dissolved in heat is ω ethanol (30 ml). At room temperature add 1H. NaOH (2 ml) and the reaction mixture is stirred for 2 hours, then the mixture is evaporated. The residue is treated with 1H. HCl (2.4 ml) and extracted with dichloromethane (3×25 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield 275 mg (97%).

1H NMR (CDCl3, 300 MHz) δ of 3.48 (d, 2H), and 3.72 (s, 3H), br4.61 (s, 2H), 6,13 (t, 1H), only 6.64 (d, 2H), 6,68-of 6.90 (m, 5H), 7,56 (d, 2H), to 7.64 (d, 2H), 8,3-8,6 (USS, 1H).

Example 39(General procedure (A))

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid

Stage C:

3,3-bis-(4-chlorophenyl)prop-2-EN-1-ol (230 mg, 0.82 mmol, example 11 stage B) and tributylphosphine (416 mg, of 2.06 mmol) dissolved in dry THF (10 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (519 mg, of 2.06 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 min) methyl ester of (4-mercapto-2-methoxyphenoxy)acetic acid (240 mg, 1.05 mmol; obtained analogously to example 23) and stirring is continued for 1 hour at 0°C. Add water (10 ml) and the mixture is evaporated. The residue is triturated with ether. The ether phase is filtered and evaporated, obtaining the crude product. Chromatographic purification using Horizin (eluent: methylene chloride: heptane (1:1) gradient docstogo of methylene chloride) gives methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid to yield 288 mg (71%).

1H NMR (CDCl3, 300 MHz); δ 4,48 (d, 2H), of 3.77 (s, 6N), and 4.68 (s, 2H), 6,13 (t, 1H), to 6.67 (d, 1H), 6,76-of 6.90 (m, 4H), 7,05 (d, 2H), 7,22 (d, 2H), 7,27 (d, 2H).

General methods C:

Stage A:

Methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid (280 mg, or 0.57 mmol) was dissolved in warm ethanol (10 ml). At room temperature add 1H. NaOH (1 ml), the reaction mixture is stirred for 2 hours and then the mixture is evaporated. The residue is treated with 1H. HCl (1.2 ml) and extracted with dichloromethane (3×25 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield 245 mg (90%).

1H NMR (CDCl3, 300 MHz) δ of 3.46 (d, 2H), 3,54 (s, 3H), of 4.45 (s, 2H), 6,11 (t, 1H), 6,62 (d, 1H), of 6.68 (s, 1H), 6,76-of 6.90 (m, 3H),? 7.04 baby mortality (d, 2H), 7,19 (d, 2H), 7,27 (m, 2H).

Example 40(General procedure (A))

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid

Stage C:

3,3-bis-(4-chlorophenyl)prop-2-EN-1-ol (200 mg, to 0.72 mmol, example 11 stage B) and tributylphosphine (362 mg, to 1.79 mmol) dissolved in dry THF (10 ml) and cooled to 0°C in nitrogen atmosphere. Add 1,1'-(azodicarbon)dipiperidino (ADDP) (452 mg, to 1.79 mmol) and the reaction mixture is stirred for 5 minutes added Slowly (5 min) ethyl ester (4-mercaptobenzoic)acetic acid (182 mg, 0.86 mmol) and stirring is continued for 2 h the s at 0° C. Add water (10 ml) and the mixture is extracted with methylene chloride (3×25 ml). Methylene phases are dried and evaporated. The residue is triturated with ether. The ether phase is filtered and evaporated, obtaining the crude product. Purification of column chromatography (eluent: methylene chloride) gives ethyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid to yield 130 mg (38%).

1H NMR (CDCl3, 400 MHz); δ of 1.28 (t, 3H), 3.46 in (d, 2H), 4,25 (square, 2H), 4,60 (s, 2H), 6,11 (t, 1H), PC 6.82 (m, 4H), 7,05 (d, 2H), 7,16-7,30 (m, 6N).

General methods C:

Stage A:

Ethyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid (130 mg, 0.27 mmol) was dissolved in warm ethanol (10 ml). At room temperature add 1H. NaOH (1 ml), the reaction mixture is stirred for 18 h and then the mixture is evaporated. The residue is treated with 1H. HCl (1.2 ml) and extracted with ethyl acetate (3×25 ml). The combined organic phases are dried and evaporated, getting mentioned in the title compound with a yield 48 mg (38%).

1H NMR (CDCl3, 300 MHz) δ 3,47 (d, 2H)and 4.65 (s, 2H), 6,11 (t, 1H), 6.75 in-6,86 (m, 3H), 7,05 (d, 2H), 7,15-7,32 (m, 6N).

Example 41(General procedure (A))

(E/Z)-[4-[3-(5-bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid

Potassium carbonate (12.0 g, 0,087 mol) and then 2-bromo-1-(thiophene-2-yl)alanon (7.0 g, 0,034 the ol; obtained by the method J.Med.Chem. 30, 1497 (1987)) is added to a mixed solution of 5-bromosalicylaldehyde (6,9 g 0,034 mol) in acetone (150 ml). First, the mixture is stirred at room temperature for 30 min and then refluxed for 1 hour. The hard part is filtered off, washed with hot acetone (2×50 ml) and the filtrate is evaporated in vacuum. The residue (11.3 g) crystallized from ethanol (15 ml)to give (5-bromo-benzo[b]furan-2-yl)-(thiophene-2-yl)methanon. Yield: 8.0 g (77%). TPL 84-86°C.

RF(SiO2, hexane/ethyl acetate 3:1) 0,70.

Stage A:

In nitrogen atmosphere 2M solution sitedisability in a mixture of tetrahydrofuran/heptane/ethylbenzene (33 ml, 66,0 mmol) are added dropwise to a cooled with ice to a solution of triethylphosphate (12 ml, 60,0 mmol) in tetrahydrofuran (180 ml). The mixture is stirred at room temperature for 30 minutes, added dropwise to the solution obtained above methanone (9,2 g, 30.0 mmol) in tetrahydrofuran (92 ml) and the whole mixture was stirred at room temperature for 39 hours. The mixture is diluted with dichloromethane (150 ml), washed with water (150 ml) and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers washed with water (200 ml), saturated salt solution (200 ml), dried over anhydrous magnesium sulfate and evaporated in vacuum. Purification of the obtained residue column items is matography (silica gel Fluka 60, hexane/ethyl acetate 9:1) gives the ethyl ester of (E/Z)-3-(5-bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)acrylic acid in the form of a yellow oil. Yield: 8.0 g (71%).

RF(SiO2, hexane/ethyl acetate 9:1) 0,30.

Stage B:

Under nitrogen atmosphere a solution of anhydrous aluminofluoride (1,03 g, 7,71 mmol) in dry ether (39 ml) is added dropwise to a suspension of sociallyengaged (0.88 g, with 23.1 mmol) in dry ether (74 ml) at -15°C. the Mixture is stirred for 30 minutes, allowing the temperature of the reaction mixture to reach 0°C. the Suspension is again cooled to -15°C, are added dropwise to the solution obtained above of ester (2,90 g, 7,71 mmol) in dry ether (39 ml) and the resulting the mixture is stirred for 1 hour while cooling. To the cooled mixture is added dropwise water (0.6 ml), 10% aqueous sodium hydroxide solution (0.6 ml) and water (1.8 ml); the precipitation is filtered off and washed with ether (70 ml). The combined ether layers washed with water (2×50 ml), saturated salt solution (2×50 ml), dried over anhydrous magnesium sulfate and evaporated in vacuum. The crude product was then purified column chromatography (silica gel Fluka 60, hexane/ethyl acetate 4:1)to give (E/Z)-3-(5-bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)prop-2-EN-1-ol as a white crystalline substance. Output: 1,61 g (62%). RF(SiO2, hexane/ethyl acetate 4:1) 0,30.

1H NMR spectrum of the primary from the EPA: (250 MHz, CDCl3): 7,71 (DD, J=1.8 and 0.7 Hz, 1H); the 7.43 (DD, J=8.8 and 1.9 Hz, 1H); 7,37 (DM, J=8,8 Hz, 1H); 7.29 trend (DD, J=5.1 and 1.2 Hz, 1H); 7,10 (m, 1H); 7.03 is (m, 1H); 6,76 (s, 1H); 6,35 (t, J=6,6 Hz, 1H); 4,60 (d, J=6.6 Hz, 2H).

General methods B:

Stage A-B:

In nitrogen atmosphere, tetrabromomethane (1.48 g, of 4.46 mmol) is added to ice the solution obtained above hydroxy (1,00 g, 2,98 mmol) and triphenylphosphine (1.25 g, 4.77 mmol) in dry methylene chloride (40 ml). The reaction mixture is stirred for 2 hours at room temperature, quickly filtered through a small layer of silica gel and the filtrate is evaporated in vacuum. To the residue under nitrogen atmosphere add tetrahydrofuran (38 ml), N,N-diisopropylethylamine (0,94 ml, 5.40 mmol) and a solution of ethyl(4-mercapto-2-methylphenoxy)acetate (1.27 g, 5,61 mmol) in tetrahydrofuran (2 ml). The reaction mixture was stirred over night, filtered, precipitated precipitate is washed with tetrahydrofuran (10 ml) and the combined organic solutions are evaporated in vacuum. The residue is purified column chromatography (silica gel Merck 60, hexane/ethyl acetate 15:1)to give ethyl ester of (E/Z)-[4-[3-(5-bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid. Yield: 1.4 g (87%). RF(SiO2, hexane/ethyl acetate 4:1) 0,50.

1H NMR (250 MHz, CDCl3): 7,60-6,27 (m, ˜N); 6.73 x and to 6.22 (t, J=8,3 Hz, 1H); 6,59 and 6,46 (d, J=8,3 Hz, 1H); 4,60 and a 4.53 (s, 2H); 4,24 and 4.12 (sq, J=7.2 Hz, 2H); 3,86 and 3,62 (d, J8,3 Hz, 2H); 2.21 and of 2.08 (s, 3H); and 1,27 1,28 (t, J=7.2 Hz, 3H).

General methods C:

Stage A:

To the cooled mixture of ice-water to the solution obtained above of ester (206 mg, 0,370 mmol) in a mixture of tetrahydrofuran/methanol/water (5:1:1, 7 ml) is added monohydrate of lithium hydroxide (23 mg, 0,548 mmol). The resulting solution was stirred for 45 minutes under cooling and consistently add a dilute solution of tartaric acid (5 ml), then add ether (20 ml). The layers separated, the aqueous layer was extracted with ether (10 ml), the combined ether layers washed with water (3×10 ml) and saturated salt solution (2×10 ml) and dried over anhydrous sodium sulfate. Obtained after evaporation of the organic solution of the oil is purified column chromatography (silica gel Fluka 60, chloroform/methanol 98:2-95:5)to give (E/Z)-[4-[3-(5-bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid. Yield: 94 mg (48%) (foam). RF(SiO2, methylene chloride/methanol 85:15) of 0.25.

To the solution obtained above acid (94 mg, of 0.182 mmol) in a minimal amount of methylene chloride (about 0.4 ml) and dry methanol (5 ml) is added L-lysine (25 mg, 0,171 mmol). The mixture is stirred for 90 min, evaporated in vacuo and the residue triturated twice with anhydrous ether, receiving L-lisinac indicated in the title acid. Yield: 110 mg (91%). TPL 138-163°C (amorphous).

1H NMR (250 MHz, DMSO-d6): 7,68-to 6.22 (m, ˜11N); 4,19 and to 4.15 (s, ˜2H); 3,83 and 3,66 (l, ˜2H); 3,20 (m, 1H); 2.71 to (m, 2H); 2,09 and of 1.93 (s, 3H); 1,71-of 1.33 (m, 6N).

METHODS PHARMACOLOGICAL STUDIES

In vitro activity activation PPAR, PPAR and PPAR

Analyses of PPAR transient TRANS-activation based on transient transfection in HEK293 human cells with two plasmids encoding chimeric test protein and a reporter protein, respectively. Chimeric test protein is a hybrid DNA binding domain (DBD) of the transcription factor GAL4 yeast and the ligand-binding domain (LBD) of PPAR human proteins. PPAR-LBD fragment, in addition to the ligand-binding pocket also contains native activation domain (activation function 2=AF2), which provides the possibility of a hybrid protein to function as a PPAR ligand-dependent transcription factor. GAL4 DBD makes chimeric protein to communicate only with Gal4 enhancers (none of which is present in HEK293 cells). Reporter plasmid contains Gal4 enhancer that controls the expression of the protein of Firefly luciferase. After transfection HEK293 cells Express a GAL4-DBD-PPAR-LBD hybrid protein. A hybrid protein, in turn, binds to the Gal4 enhancer that controls the expression of luciferase and does not exhibit activity in the absence of ligand. After addition to the cells PPAR ligand protein is seperate is produced in quantities appropriate activation of PPAR protein. The amount of protein measured by luciferase light emission after addition of suitable substrate.

CELL CULTURE AND TRANSFECTION

HEK293 cells grown in DMEM+10% FCS (fetal calf serum). Cells were seeded in 96-well tablets the day before transfection in order to achieve the degree of confluence of the order of 50-80% by transfection. Only 0.8 μg DNA containing of 0.64 μg pM1α/γLBD, 0.1 µg pCMVβGal, of 0.08 μg pGL2 (Gal4)5and 0.02 µg pADVANTAGE transferout on the cell, using the reagent FuGene for transfection according to the manufacturer's instructions (Roche). Cells leave for the expression of protein for 48 hours, then add the connection.

Plasmids: Human PPAR α, γ and δ receive as a result of PCR amplification using cDNA synthesized by reverse transcription of mRNA from the liver, adipose tissue and human placenta, respectively. Amplificatoare cDNA clone in pCR2.1 and is sequenced. Domain (LBD), a ligand-binding of each PPAR isoform, create using PCR (PPARα: AK 167-C-end; PPARγ: AK 165-C-end; PPARδ: AK 128-C-end) and hybridized with the DNA binding domain (DBD) transcription factor of yeast GAL4, subcloned fragments on the frame are read into the vector pM1 (Sadowski et al. (1992), Gene 118, 137), generating plasmid pM1αLBD, pMiγLBD and pM1δ. These hybrids check Sequeira what W. The reporter construct, embedded oligonucleotide that encodes five repeats of GAL4 recognition sequence (5× CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988), Nucleic Acids Res. 16, 8192) in the vector pGL2 promoter (Promega), generating plasmid pGL2(GAL4)5. pCMVβGal obtained from Clontech and pADVANTAGE obtained from Promega.

IN VITRO ANALYSIS of DEVELOPMENT

Connections: All connections are dissolved in DMSO and diluted 1:1000 adding to cells. Compounds are tested in four repetitions at concentrations in the range of from 0.001 to 300 μm. Cells treated with compound for 24 h, followed by analysis of luciferase. Each of the compounds tested in at least two separate experiments.

Analysis of luciferase: the Medium containing the test compound, is sucked off and each well was added 100 μl of PBS, 1 mm Mg++ and Ca++. Analysis of luciferase carried out using the LucLite kit according to the manufacturer's instructions (Packard Instruments). Light emission is quantitatively measured by the counter Packard LumiCounter. For measuring the activity β-galactosidase 25 μl of supernatant from each transfection lysate is transferred to a new microplate. Analysis β-galactosidase is carried out in a microwell tablets, using a set of Promega and reading the values using the reader Labsystems Multiscan Ascent. The results obtained for β-galactosidases is, used for normalization (the efficiency of transfection, cell growth, and so on) of the results obtained for luciferase.

STATISTICAL METHODS

The activity of the compounds is calculated as the ratio of induction compared with untreated sample. For each connection efficiency (maximum activity) is given as relative activity compared with Wy14,643 for PPARα, rosiglitazone (Rosiglitazone) for PPARγ and carbacyclin (Carbacyclin) for PPARδ. The value of EC50represents the concentration providing 50% from the maximum observed activity. Value EC50calculated by the method of nonlinear regression using GraphPad PRISM 3.02 (GraphPad Software, San Diego, Ca). The results are expressed as the mean ±SD (standard deviation).

1. The compound of General formula (I)

where X1represents phenyl, 9-membered bicyclic heteroaryl containing S or O as the heteroatom, or a 5-membered heteroaryl containing S or About as heteroatoms, each of which is optionally substituted by one or more substituents selected from the

halogen; or

With1-6of alkyl, which is optionally substituted by one or more halogen; and

X2represents phenyl which is optionally substituted by one or bol is e substituents, selected from halogen,

or 5-membered heteroaryl containing S or O as the heteroatom; and

Ar is phenylene, which is optionally substituted by one or more substituents selected from the

halogen; or

With1-6of alkyl, phenyl, C1-6alkoxy, each of which is optionally substituted by one or more halogen; and

Y1represents O or S; and

Y2is About; and

Z represents -(CH2)n-where n is 1, 2 or 3; and

R1represents hydrogen or C1-6alkoxy; and

R2represents hydrogen, C1-6alkyl; or

its pharmaceutically acceptable salt, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture.

2. The compound according to claim 1, where X1represents phenyl, furyl, thienyl, benzothiazyl or benzofuranyl, optionally substituted by one or more substituents selected from the

halogen; or

With1-6the alkyl, optionally substituted by one or more Halogens.

3. The compound according to claim 2, where X1represents phenyl, thienyl, benzothiazyl or benzofuranyl, optionally substituted by one or more substituents selected from the

halogen; or

C1-6the alkyl, optionally substituted by one who does more Halogens.

4. The compound according to claim 3, where X1represents phenyl, optionally substituted by one or more substituents selected from halogen, C1-6the alkyl or perhalogenated.

5. The compound according to claim 4, where X1represents phenyl, optionally substituted by one or more Halogens.

6. The compound according to claim 2, where X1is thienyl, optionally substituted by one or more substituents selected from halogen or1-6the alkyl.

7. The compound according to claim 2, where X1represents furyl, optionally substituted by one or more substituents selected from halogen or C1-6the alkyl.

8. The compound according to claim 2, where X1is sensational, optionally substituted by one or more substituents selected from halogen or C1-6the alkyl.

9. The compound according to claim 2, where X1is benzofuranyl, optionally substituted by one or more substituents selected from halogen or1-6the alkyl.

10. The compound according to any one of the preceding paragraphs, where X2represents phenyl, optionally substituted by one or more halogen, furyl or thienyl.

11. The connection of claim 10, where X2represents phenyl, optionally substituted by one or more Halogens.

12. The connection of claim 10, where X2is thienyl.

13. The connection of claim 10, where X2present is employed, furyl.

14. The connection of claim 10, where X1is sensational, optionally substituted by one or more substituents selected from halogen or1-6the alkyl.

15. The connection of claim 10, where X1is benzofuranyl, optionally substituted by one or more substituents selected from halogen or1-6the alkyl.

16. The compound according to claim 1, where Ar is phenylene, optionally substituted by one or more substituents selected from halogen, C1-6of alkyl, C1-6alkoxy, phenyl or perhalogenated.

17. The compound according to claim 1, where Y1represents O.

18. The compound according to claim 1, where Yi represents S.

19. The compound according to claim 1, where n=1.

20. The compound according to claim 1, where R1represents hydrogen.

21. The compound according to claim 1, where R2represents hydrogen.

22. The compound according to claim 1, where R2represents methyl or ethyl.

23. The compound according to claim 1, which is a

methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

ethyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2,6-diphenylmethoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)allyloxy]-2,6-diphenylmethoxy}acetic acid, or

their pharmaceutically acceptable salts, any tautomeric fo what we stereoisomers, mixture of stereoisomers including a racemic mixture.

24. The compound according to claim 1, which is a

methyl ester {4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid,

4-[3,3-bis-(4-bromophenyl)allyloxy]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-methylphenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(3-triptoreline)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-ethylenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

methyl ester {4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)-2-ethoxyethylene]-2-methylphenoxy}acetic acid

or their pharmaceutically acceptable salts, any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture.

25. The compound according to claim 1, which is a

(E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(4-bromophenyl)-3-(5-methylthiophene-2-yl)arylsulfonyl]-2-methylphenoxy] acetic acid,

(E/Z)-[4-[3-(furan-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(5-methylthiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]uksosn the Yu acid,

(E/Z)-[4-[3-(benzo[b]thiophene-3-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

(E/Z)-[4-[3-(benzo[b]thiophene-2-yl)-3-(4-triptoreline)arylsulfonyl]-2-methylphenoxy]acetic acid,

{4-[3,3-bis-(4-chlorophenyl)allyloxy]phenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-triptoreline}acetic acid,

{4-[3,3-bis-(3-methylthiophene-2-yl)arylsulfonyl]-2-triptoreline}acetic acid,

[4-(3,3-difuran-2-intellisurvey)-2-triptoreline]acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methoxyphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

(E/Z)-[4-[3-(5-bromobenzo[b]furan-2-yl)-3-(thiophene-2-yl)arylsulfonyl]-2-methylphenoxy]acetic acid, or

their pharmaceutically acceptable salts, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture.

26. The compound according to claim 1, which is:

{4-[3-(2-forfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-FeNi is arylsulfonyl]phenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]phenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-methylphenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-generallyrally the Anil]-2-chlorophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-2-chlorophenoxy }acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-chlorophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-bromophenoxy}acetic acid,/p>

{4-[3-(2-were)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-bromophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-the 2nd is phenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-three is timeteller)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-2-iodinate}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-methylphenoxy}vinegar is th acid,

{4-[3-(3-were)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-methylphenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylal sulfanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic to the slot,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-chlorophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-bromophenoxy}acetic acid is,

{4-[3-(3-were)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-bromophenoxy}acetic acid,

{4-[3-(2-forfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-forfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-forfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-chlorophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-chlorophenyl)-3-phenylalanyl]-3-yo is phenoxy}acetic acid,

{4-[3-(4-chlorophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-bromophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-bromophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-bromophenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-itfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-itfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-itfinal)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-were)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-were)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-were)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-ethylphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-ethylphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-ethylphenyl)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(2-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

4-[3-(2-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(3-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3-(4-triptoreline)-3-phenylalanyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]phenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-harfe the Il)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3_bis-(2-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)allels hanil]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-2-joden the XI}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-2-iodinate }acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-2-iodinate}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-methylpheni is si}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-3-methylphenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-3-chlorophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-3-chlorophenoxy }acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-3-is lovenox}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-3-bromophenoxy}acetic acid,

{4-[3,3-bis-(2-forfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-forfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-forfinal)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-chlorophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-chlorophenyl)arylsulfonyl]-3-codfedex the}acetic acid,

{4-[3,3-bis-(4-chlorophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-bromophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-bromophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-bromophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(2-iodophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(3-iodophenyl)arylsulfonyl]-3-iodinate}acetic acid,

{4-[3,3-bis-(4-iodophenyl)arylsulfonyl]-3-iodinate}acetic acid,

or their pharmaceutically acceptable salts, or any tautomeric forms, stereoisomers, mixture of stereoisomers including a racemic mixture.

27. The compound according to claim 1, where X1represents phenyl, optionally substituted by one or more halogen, X2represents phenyl, optionally substituted by one or more halogen, Ar is phenylene, optionally substituted by one or more substituents selected from halogen, C1-6of alkyl, C1-6alkoxy, phenyl or perhalogenated, and R1represents hydrogen.

28. The compound according to claim 1, where X1represents phenyl, optionally substituted by one or more halogen, X2represents phenyl, optionally substituted by one or more halogen, Ar is phenylene, neoba is consequently substituted by one or more substituents, selected from halogen, C1-6of alkyl, C1-6alkoxy, phenyl or perhalogenated, R1represents hydrogen, Y1represents O.

29. The compound according to claim 1, where X1represents phenyl, optionally substituted by one or more halogen, X2represents phenyl, optionally substituted by one or more halogen, Ar is phenylene, optionally substituted by one or more substituents selected from halogen, C1-6of alkyl, C1-6alkoxy, phenyl or perhalogenated, R1represents hydrogen, Y1is S.

30. The compound according to claim 1, which is an agonist of PPARδ.

31. Connection item 30, which is a selective agonist of PPARδ.

32. The use of compounds according to any one of the preceding paragraphs comprising the pharmaceutical composition having activity against receptor-activated proliferation PPAR peroxisomeδ subtype.

33. Pharmaceutical composition having activity against receptor-activated proliferation PPAR peroxisomeδ subtype containing as active ingredient an effective amount of at least one compound according to any one of claims 1 to 31 with one or more pharmaceutically acceptable carriers or excipients.

34. The pharmaceutical composition according p unit in the Noah dosage form, containing from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg and especially preferred from about 0.5 mg to about 200 mg per day of a compound according to any one of claims 1 to 31.

35. The pharmaceutical composition according to any one of p-34 for oral, nasal, transdermal, pulmonal or parenteral administration.

36. The use of compounds according to any one of claims 1 to 31 for obtaining a pharmaceutical composition having activity against receptor-activated proliferation peroxisome PPAR5 subtype.



 

Same patents:

Kinase inhibitors // 2348635

FIELD: chemistry; pharmacy.

SUBSTANCE: invention concerns new compounds of formula I: , where W is , X is N or C-R1; R is C1-C7alkyl, C3-C7cycloalkyl, (C1-C7alkylene)-(C3-C7cycloalkyl), -SO2-(C1-C7alkyl) or -SO2-NR5R6; R1 is hydrogen, amino, methyl or -N=CH(NMe)2; R is phenyl optionally substituted by one or more substitutes selected independently out of halogen; R3 is hydrogen, C1-C7alkyl, C3-C7cycloalkyl or phenyl optionally substituted by one or more substitutes selected independently out of halogen and trifluoromethyl; R4 is hydrogen or C1-C7alkyl; R5 and R6 are independently selected out of group including C1-C7alkyl; and its pharmaceutically acceptable salts. Also invention concerns pharmaceutical composition and application.

EFFECT: obtaining new bioactive compounds with inhibition effect on kinase p-38.

10 cl, 114 ex

FIELD: chemistry; pharmacy.

SUBSTANCE: invention claims new imidazopyridine derivative of formula I , method of its obtainment, intermediary compounds, pharmaceutical drug for inhibition of gastric acid secretion stimulated in exogenous or endogenous way, thus applicable for prevention and treatment of diseases related to gastric acidity, or inflammatory diseases of gastrointestinal tract.

EFFECT: obtaining compound for prevention and treatment of diseases related to gastric acidity, or inflammatory diseases of gastrointestinal tract.

8 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compound of formula (I) where Ry is , or its pharmaceutically acceptable salts. These compounds have phosphodiesterase (PDE) inhibition effect, particularly for PDE-4. Additionally invention claims application of compound of the formula (I) or its pharmaceutically acceptable salt in manufacturing of medicine for treatment and/or prevention of cognitive ability depression or disorder of humans, e.g. of chronic neurological disorder, such as Alzheimer's disease.

EFFECT: enhanced efficiency of composition and treatment method.

17 cl, 21 tbl, 191 ex

FIELD: chemistry; pharmacy.

SUBSTANCE: invention concerns novel compounds of formula I , where X1 is O; Ar1 is aryl optionally substituted by one or more halogen atoms; R1 is alkoxyalkyl, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, tetrahydropyranyl or piperidinyl optionally substituted by -S(O)2 alkyl group; and R2 is hydroxyalkyl or oxoalkyl. Also invention concerns composition for kinase p38 induced disease control or prevention.

EFFECT: obtaining novel bioactive compounds for kinase p38 induced disease control or prevention.

4 cl, 10 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of pyridazin-3(2H)-one of formula (I), where R1, R2 and R4 are organic radicals described in the claim 1, R3 is cyclic group described in the claim, and R5 is phenyl or heteroaryl group described in the claim. Compounds of formula (I) inhibit phosphodiesterase 4 (PDE-4) and can be applied in treatment of various diseases or pathological states alleviated by PDE-4 inhibition, and in medicine production for treatment of aforesaid diseases. Also invention claims method of obtaining these compounds and intermediate compounds for their obtainment.

EFFECT: obtaining compounds which can be used in treatment of various diseases or pathological states and in medicine production for treatment of aforesaid diseases.

25 cl, 28 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: description is given of a lactam-containing compound-derivative of tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide with formula I , its pharmaceutical salt and pharmaceutical compositions, their content, and their use as Xa factor inhibitors. The given compound can be used for treating thromboembolic diseases.

EFFECT: obtaining a lactam-containing compound, which can be used for treating thromobembolic diseases.

42 cl, 9 tbl, 140 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel azaheterocycles of general formula 1.1-13 and 2, as well as their pharmaceutically acceptable salts, which possess anti-carcinogenic activity, pharmaceutical composition with their application and combinatorial and focused libraries including novel azaheterocycles. In general formulae 1.1-1.3 and 2.

.

For compounds 1.1-1.3 each of R1a R2a independently on each other represent possibly substituted C1-C6alkyl; each of R1d, R2d, R3d, R4d, R5d, R6d and R7d independently on each other represent substitutes of cyclic system, preferably hydrogen atom, or for compounds 1.1 and 1.3 independently R1d and R2d, R3d and R4d, R5d and R6d together with atoms with which they are bound can form through R1d and R2d, R3d and R4d, R5d and R6d respectively, possibly substituted aromatic cycle, such as benzole, 5-6-member heterocycle which includes, at least, one of heteroatoms, selected from S; or for compounds 1.2 independently R1d and R2d, R3d and R4d, R4d and R5d, R6d and R7d together with atoms with which they are bound can form through R1d and R2d, R3d and R4d, R4d and R5d, R6d and R7d respectively, possibly substituted aromatic cycle, such as benzole, 5-6-member heterocycle which includes, at least, one of heteroatoms, selected from S; for compound 2 R1a represents amino group substitute, excluding hydrogen atom, such as possibly substituted C1-C6alkyl, possibly substituted phenyl; R2a represents possibly substituted C1-C6alkyl; R3a represents amino group substitute, such as hydrogen atom, possibly substituted C1-C6alkyl; Rnd represents one or two substitutes of cyclic system, preferably hydrogen atom, solid line with accompanying it dotted line represent single or double bond.

EFFECT: obtaining novel azaheterocycles and their pharmaceutically acceptable salts, which possess anti-carcinogenic activity.

9 cl, 4 dwg, 3 tbl, 7 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 ex

Dpp-iv inhibitors // 2345067

FIELD: chemistry, pharmaceutics.

SUBSTANCE: claimed invention relates to novel compounds of general formula (I) Z-C(R1R2)-C(R3NH2)-C(R4R5)-X-N(R6R7) (I), or its pharmaceutically acceptable salt which is different because Z represents phenyl; where Z can be substituted with one or more R8, where R8 represents halogen; R1, R4 represent H; R2, R5 represent H; R3 represents H; X is selected from group consisting of S(O)2 and C(O); R6, R7 are independently selected from group consisting of H, (C(R29R30))m-X1-Z1 and (C(R31R32))n-X2-X3-Z2 and C1-4alkyl, which carries substitution with one or more R29a, where R29a is independently selected from group consisting of R29b and Z1, on condition that R6 and R7 are selected in such way that R6 and R7 were not simultaneously independently selected from group consisting of H, CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2; R29 R29b, R30, R31, R32 are independently selected from group consisting of H, C1-6alkyl and N(R32a)-C1-6alkyl; R32a represents C1-6alkyl; m is 0, 1 or 2; n is 2; X1 is independently selected from group consisting of covalent bond, -C1-6alkyl and -C1-6alkyl-N(R33)-; X2 represents -N(R35)-; X3 represents -C(O)-; R33 represents C1-6alkyl; R35 represents H; Z1, Z2 are independently selected from group consisting of Z3 and -C(R37a)Z3aZ3b; R37a represents H; Z3, Z3a, Z3b are independently selected from group consisting of T1, T2, C1-6alkyl, C1-6alkyl-T1 and C1-6alkyl-T2; T1 represents phenyl; where T1 is optionally substituted with one or more R38; R38 being independently selected from group consisting of halogen, CN, R39, C(O)NH2, S(O)2NH2, OT3, C(O)N(R40)T3 and T3, T2 is selected from group consisting of C3-7cycloalkyl, indanyl, tetralinyl, heterocycle and heterobicycle, T2 optionally carries substitution with one or more R41, where R41 is independently selected from group consisting of halogen, R42, OH and T3; R39 is selected from group consisting of C1-6alkyl, O-C1-6alkyl, S-C1-6alkyl, C(O)N(R44)-C1-6alkyl, S(O)-C1-6alkyl and S(O)2-C1-6alkyl, where each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F, N(R46R47) and T3; R42 represents C1-6alkyl, each C1-6alkyl optionally carries substitution with one or more R45, where R45 is independently selected from group consisting of F; R40, R46, R47 are independently selected from group consisting of H and C1-6alkyl; R44 represents H; T3 is selected from group consisting of T4 and T5; T4 represents phenyl, where T4 optionally carries substitution with one or more R51, where R51 is independently selected from group consisting of halogen, OR52, S(O)2N(R52R53), C1-6alkyl; R52, R53 are independently selected from group consisting of H and C1-6alkyl; T5 is selected from group consisting of heretocycle C3-7cycloalkyl, where T5 optionally carries substitution with one or more R54, where R54 represents C1-6alkyl; where heterocycle represents ring of cyclobutane, cyclopentane, cyclohexane, which can contain double bonds in number up to maximal, or aromatic or non-aromatic ring which is fully or partially saturated or unsaturated, and in which at least one carbon atom, maximally up to four carbon atoms, are substituted with heteroatom, selected from group including oxygen and nitrogen, and where ring is bound with remaining part of molecule through carbon or nitrogen atom; where heterobicycle represents heterocycle as stated above, which is condensed with phenyl or other heterocycle with formation of bicyclic ring system, on condition that the following compound is excluded from claim:3-amino-N-cyclohexyl-4-phenylbutyramide. Invention also relates to pharmaceutical composition based on compound of general formula (I) and to their application for manufacturing medication for treatment and/or prevention of conditions during which it is desirable to inhibit DPP-IV.

EFFECT: obtaining novel group of compounds possessing useful biological properties.

26 cl, 8 tbl, 193 ex

FIELD: chemistry.

SUBSTANCE: in arylpiperazinyl compounds of general formula , where R1 is unsubstituted alkyl or cycloalkyl; R2 and R3 independently hydrogen; lower alkyl; cycloalkyl; or -NR4R5, where R4 and R5 independently represent H, O, R6 or COR6, where R6 can represent lower alkyl or sulfonamidoalkyl; on condition that R2 and R3 both are not hydrogen; -atoms designated as bound with dotted line, taken together with atoms, to which they are joined, can form six-member ring; - Z represents N or C; - m equals 0, 1 or 2; - n equals 1, 2, 3, 4, 5 or 6; - p equals 0, 1, 2, 3 or 4. Compounds can be used for treatment of diseases, mediated directly or indirectly by 5-HT receptors. Such diseases are disorders of central nervous system.

EFFECT: increase of composition and method of treatment efficiency.

50 cl, 12 dwg, 2 tbl, 41 ex

FIELD: organic chemistry, biochemistry, enzymes.

SUBSTANCE: invention relates to compounds represented by the formula: wherein values of substitutes are given in the invention description. Also, invention relates to pharmaceutically acceptable salts of the compound that can be used in treatment and/or prophylaxis of cathepsin-dependent states or diseases of mammals. Proposed compound are useful in treatment of diseases wherein bone resorption inhibition is desired, such as osteoporosis, increased mineral density of bone and reducing risk of fractures. Proposed claimed compounds are designated for preparing a drug possessing the inhibitory activity with respect to cathepsin.

EFFECT: valuable medicinal and biochemical properties of compounds.

24 cl, 13 sch, 4 tbl, 15 ex

.FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their physiologically acceptable salts also possessing properties for decrease the blood sugar content. In compound of the formula (I) A means phenyl wherein phenyl residue can be substituted up to three times with fluorine (F), chlorine (Cl) and bromine (Br) atoms; R1 and R2 mean hydrogen atom (H); R3, R4, R5 and R6 mean independently of one another H, F, Cl, Br, -NO2, -O-(C1-C6)-alkyl, (C1-C6)-alkyl, -COOH; R7 means H, (C1-C6)-alkyl wherein alkyl can be substituted up to three times with -OH, -CF3, -CN, COOH, -COO-(C1-C6)-alkyl, -CO-NH2, -NH2, -NH-(C1-C6)-alkyl, -N-[(C1-C6)-alkyl]2, -NHCO-(C1-C6)-alkyl, -NHCOO-(C1-C6)-alkyl or -NHCOO-(C1-C4)-alkylenephenyl; in (CH2)m m can mean 0-6 and aryl means phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, pyridyl, indolyl, piperidinyl, tetrahydronapthyl, 2,3-dihydrobenzo[1,4]dioxynyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl wherein aryl residue can be substituted mono- or multiple with R9 wherein R9 means F, Cl, Br, -OH, -NO2, -CF3, -OCF3, (C1-C6)-alkyl, (C1-C6)-alkyl-OH, -O-(C1-C6)-alkyl, -COOH, -COO-(C1-C6)-alkyl. Also, invention relates to a pharmaceutical composition and a method for preparing a medicinal agent.

EFFECT: valuable medicinal properties of derivatives and pharmaceutical composition.

7 cl, 2 sch, 1 tbl, 293 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I) as separate stereoisomers and their mixtures, or their physiologically acceptable salts possessing with inhibitory effect on VIIa factor. In the general formula of compounds of the formula (I) m = 0, 1, 2, 3 or 4; n = 0, 1, 2 or 3; A represents halogen atom; X represents oxygen atom; R1 is chosen from hydrogen atom, (C1-C6)-alkoxycarbonyl and (C6-C14)-aryloxycarbonyl wherein all aryl groups are free or substituted with (C1-C6)-alkoxy-group; R2is chosen from hydrogen atom, (C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, R20 -(C1-C6)-alkyl, R20-(C6-C14)-aryl and R20-(C6-C14)-(C1-C4)-alkyl wherein R20 is chosen from hydroxycarbonyl, aminocarbonyl; R3 is chosen from hydrogen atom, cyano-, hydroxy-group and (C1-C6)-alkyl; R4 is chosen from (C1-C6)-alkyl, (C-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, Het and Het-(C1-C4)-alkyl wherin alkyl, atryl and Het groups are free or substituted with one or some similar or different substitutes R10; R5 is chosen from hydrogen atom, (C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl wherein alkyl and aryl groups are free or substituted with one or some similar or different substituted R10; or R4 and R5 in common with carbon atom with that they are bound form saturated or unsaturated 5-6-membered ring that represents carbocyclic ring or heterocyclic ring comprising 1 or 2 similar ring heteroatoms chosen from nitrogen and oxygen atoms and possibly condensed with one or two saturated or unsaturated carbocyclic ring system comprising from 5 to 10 ring atoms wherein the final R4(R5)C-group is free or substituted with one or some similar or different substitutes R10; R6 is chosen from hydrogen atom and hydroxy-group. Also, invention relates to a method for synthesis of compound of the formula (I) and pharmaceutical composition based on thereof. Compounds of the formula (I) can be used in preparing medicinal agents useful for inhibition or decreasing blood coagulation or inflammatory response or for using in treatment of cardiovascular disorders, thrombo-embolic diseases or restenosis.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 1 sch, 71 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

EFFECT: improved preparing method, valuable medicinal properties of compounds and composition.

18 cl, 3 tbl, 23 ex

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to a method of production of new chemical compounds, diamine consisting of aromatic and cycloaliphatic fragments, specifically disodium salt of N,N-bis-(4-amino-2-sulfophenyl)piperazine, which can be used as a monomer in producing high-strength heat-resistant cation-exchange materials

The invention relates to new Amida aminocarbonyl acids of the General formula:

< / BR>
where R1, R2, R3, R4, R5and "n" and "m" have the following meanings:

R1, R2denote hydrogen, linear or branched (C1-C8)-alkyl;

(C3-C8-cycloalkyl as cyclohexyl; phenyl, which can be single or twofold substituted linear (C1-C4)-alkyl, (C1-C2-alkoxyl, halogen, cyano group, nitro group, trifluoromethyl or acylamino group; phenylalkyl, where the alkyl chain may contain 1-3 C-atoms and a phenyl ring, which may be single or twofold substituted stands, methoxy group, halogen, nitro group, cyano group or acylamino-group;

< / BR>
denotes a morpholine or piperidine which may be substituted by one or twice (C1-C2)-alkyl group or a group

< / BR>
where R6may denote H, NHCО2CH2CH3;

R3does

< / BR>
represents piperidine or morpholine

n = 1-5;

m = 2-4;

their physiologically acceptable salts joining acids, method of production thereof, and to pharmaceutical compositions and their use as pharmaceuticals, in particular for the treatment of cardiac arrhythmias

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of substituted N-phenyl-2-hydroxy-2-methyl-3,3,3-trifluoropropaneamide of the formula (I): wherein R represents methyl or mesyl, or its salt. Also, invention describes methods for synthesis of these compounds, pharmaceutical compositions containing thereof and their using for increasing activity of PDH in warm-blooded animal. Proposed compounds are useful in treatment of diabetes mellitus in warm-blooded animals.

EFFECT: valuable medicinal properties of compounds, improved methods for synthesis.

10 cl, 4 ex

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