MXPA00006035A - Arylthiazolidinedione derivatives - Google Patents

Abstract

Substituted 5-aryl-2,4-thiazolidinediones are potent agonists of PPAR, and are therefore useful in the treatment, control or prevention of diabetes, hyperglycemia, hyperlipidemia (including hypercholesterolemia and hypertriglyceridemia), atherosclerosis, obesity, vascular restenosis, and other PPAR a, d and/or g mediated diseases, disorders and conditions.

Description

ARILTIAZOLIDINODIONA DERIVATIVES FIELD OF THE INVENTION The present invention relates to aryl thiazolidinediones and pharmaceutically acceptable salts thereof, which are useful as therapeutic compounds. Thus, it is an object of the invention to describe said compounds, methods for their preparation, methods for using said compounds, and compositions containing said compounds. Other objects will be evident from the reading of the following description.

BACKGROUND OF THE INVENTION Diabetes refers to a disease procedure derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia. Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk of microvascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, embolism and heart disease. Therefore, the control of glucose homeostasis is a very important approach for the treatment of diabetes. There are two generally recognized forms of diabetes. In the Type I diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates the use of glucose. In type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are equal or even elevated compared to non-diabetic humans; however, these patients have developed a resistance to the stimulatory effect of insulin on the metabolism of glucose and lipid in the main insulin sensitive tissues, muscle, liver and adipose tissue and plasma insulin levels are insufficient to counteract the pronounced insulin resistance. Insulin resistance is not primarily due to a reduced number of insulin receptors, but to a post-insulin receptor binding defect that is still not understood. This resistance to insulin response results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. Common treatments for NIDDM, which have not changed substantially in many years, have limitations. Although physical exercise and reductions in calorie intake will dramatically improve the diabetic condition, compliance with this treatment is very poor due to well-established sedentary lifestyles and over-consumption of foods, especially high-containing foods. amounts of fat. Increasing the level of insulin in the plasma by administration of sulfonylureas (eg, tolbutamide, glipizide) that stimulate pancreatic β-cells to secrete more insulin or by insulin injection after the response to sulfonylureas fails will result in concentrations of insulin high enough to stimulate tissues that are very resistant to insulin. However, dangerously low levels of plasma glucose can result from these two treatments and the increase in insulin resistance can also occur due to even higher plasma insulin levels. Biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenformin, and metformin, can induce lactic acidosis and nausea / diarrhea, respectively. Glitazones (ie, 5-benzylthiazolidino-2,4-diones) are a class of recently described compounds with potential for a novel mode of action to improve many NIDDM symptoms. These agents substantially increase insulin sensitivity in the muscle, liver and adipose tissue in several animal models of NIDDM resulting in a complete correction of elevated levels of plasma glucose, triglycerides and non-esterified fatty acids without hypoglycemia occurring. . Hyperlipidemia is a condition characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in the plasma, but they bind to proteins and transport themselves as macromolecular complexes called lipoproteins. See Merck Manual, 16th Ed. 1992 (see for example pages 1039-1040) and "Structure and Metabolism of Plasma Lipoproteins" in Metabolic Basis of Inherited Disease, 6th Ed. 1989, p. 1 129-1 138. One form of hyperlipidemia is hypercholesterolemia, characterized by the existence of elevated LDL cholesterol levels. The initial treatment for hypercholesterolemia is often to modify the diet to a low in fat and cholesterol, along with appropriate physical exercise, followed by drug therapy when the objectives of lowering LDL are not satisfied only with exercise and diet. LDL is commonly known as the "bad" cholesterol, while HDL is the "good" cholesterol. Although it is desirable to decrease high levels of LDL cholesterol, it is also desirable to increase HDL cholesterol levels. In general, it has been found that increased levels of HDL are associated with a lower risk of coronary heart disease (CHD). See, for example, Gordon, et al., Am. J. Med., 62, 707-714 (1977); Stampfer, et al., N. England J. Med., 325, 373-381 (1991); and Kannel, et al., Ann. Intemal Med., 90, 85-91 (1979). An example of an HDL-enhancing agent is nicotinic acid, but the amounts needed to achieve the HDL increase are associated with undesirable effects, such as redness. Peroxisome proliferators are a group structurally Several compounds that when administered to rodents produce dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the ability of peroxisomes to metabolize fatty acids through the increased expression of the enzymes of the beta-cycle. oxidation. Compounds of this group include but are not limited to the fibrous class of hyperlipidemic drugs, herbicides and phthalate plasticizers. The proliferation of peroxisomes is also triggered by nutritional or physiological factors such as a diet high in fat and cold acclimatization. Three subtypes of peroxisome proliferator activated receptor (PPAR) have been discovered and described; These are peroxisome proliferator activated receptor alpha (PPARa), peroxisome proliferator activated receptor range (PPAR?) and peroxisome proliferator activated receptor delta (PPARd). The identification of PPARa, a member of the nuclear hormone receptor superfamily activated by peroxisome proliferators, has facilitated the analysis of the mechanism by which peroxisome proliferators exert their pleiotropic effects. PPARa is activated by a number of long and medium chain fatty acids, and is involved in the stimulation of ß-oxidation of fatty acids. PPARa is also involved in the activity of fibrous materials and fatty acids in rodents and humans. Fibric acid derivatives such as clofibrate, fenofibrate, bezafibrate, ciporfibrate, beclofibrate and etofibrate, as well as gemfibrozil, produce a substantial reduction in plasma triglycerides along with moderate reduction in LDL cholesterol, and are used particularly for the treatment of hypertriglyceridemia. The PPAR receptor subtypes? they are involved in the activation of the adipocyte differentiation program and are not involved in the stimulation of peroxisome proliferation in the liver. There are two isoforms of PPAR ?: PPAR? L and PPAR? 2, which differ only because PPAR? 2 contains 28 additional amino acids present in the amino terminus. DNA sequences for isotypes are described in Elbrecht, et al., BBRC 224; 431-437 (1996). In mice, PPARγ2 is expressed specifically in fat cells. Tontonoz ef ai, Cell 79: 1147-1 156 (1994) provides evidence to show that a physiological role of PPAR? 2 is to induce adipocyte differentiation. Like other members of the superfamily of nuclear hormone receptors, PPAR? 2 regulates gene expression through interaction with other proteins and binding to hormone response elements for example in the flanking regions of 5 'response genes. An example of a PPAR? 2 response gene is the tissue-specific adipocyte P2 gene. Although some peroxisome proliferators, including fibrous materials and fatty acids, activate the transcriptional activity of PPARs, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR? Subtype, which also binds to thiazolidinedione antidiabetic agents with high affinity The human nuclear receptor gene PPARd (hPPARd) has been cloned from a human osteosarcoma cell cDNA library and is he writes extensively in A. Schimidt et al., Molecular Endocrinology, 6: 1634-1641 (1992), incorporated herein by reference. It should be noted that PPARd is also known in the literature as PPARβ and as NUC1, and each of these names refers to the same receptor; in Schmidt et al., the receptor is referred to as NUC1. In WO96 / 01430, a human PPAR subtype, hNUCI B, is described. The amino acid sequence of hNUCI B differs from human PPARd (referred to herein as hNUC1) by an amino acid, ie, alanine at position 292. In in vivo experiments described there, the authors suggest that the hNUCI B protein represses the activity of hPPARa and thyroid hormone receptor protein. It has been described in WO97 / 28149 that PPARd agonists are useful for increasing HDL levels in plasma. WO97 / 27857, 97/281 15, 97/28137 and 97/27847 describe compounds that are useful as antidiabetic, anti-obesity, anti-atherosclerosis and antihyperlipidemic agents, and that can exert their effect through the activation of PPARs. It has been suggested that glitazones exert their effects by binding to the peroxisome proliferator activated receptor (PPAR) receptor family, controlling certain transcription elements that have to do with the biological entities listed above. See Hulin et al., Current Pharm. Design (1996) 2, 85-102. It has been found that glitazones bind exclusively to the PPAR? Subtype.

All glitazones that have progressed to clinical trials in humans, and almost all glitazones that have been reported in the literature have the molecular motif of an aryl group attached to the 5-position of thiazolidinedione via a carbon spacer. Although several compounds having a 4- (oxy) phenyl group directly attached to the 5-position of thiazolidinedione have been prepared and tested as potential antidiabetic agents, they have been shown to lack hypoglycemic activity. Therefore, the compound 5- [4- [2- (2-benzoxazolylmethylamino) ethoxy] phenyl] -2,4-thiazolidinedione (1) did not show antihyperglycemic activity in ob / ob mice, and subsequent studies showed that this compound requires relatively high amounts for the activation of PPAR ?. (Cantello et al., J. Med. Chem. 1994, 37: 3977-3985 and Willson et al., J. Med. Chem. 1996, 39: 665-668). 1 The compound 5- [4- (phenylethoxy) phenyl] -2,4-thiazolidinedione (2) showed no antihyperglycemic effect in the diabetic mouse model, although it may have aldose reductase inhibitory activity. (Sohda et al, Chem. Pharm. Bull., 1982, 30: 3580-3600, and Sohda et al, Chem. Pharm. Bull., 1982, 30: 3601-3616). Examples of other phenylthiazolidinedione aldose reductase inhibitors include 5- [4- (4-chlorophenoxy) phenyl] -2,4-thiazolidinedione, 5- [4- (4-chlorobenzyloxy) phenyl] -2,4-thiazolidinedione, 5- [4- (2-pyridylethoxy) phenyl ] -2,4-thiazolidinedione, 5- [4- (6-methyl-2-pyridylethoxy) phenyl] -2,4-thiazolidinedione and 5- [4- (2-thienylethoxy) phenyl] -2, 4-thiazolidinedione. (Sohda et al, Chem. Pharm. Bull., 1982, : 3601-3616).

The published PCT application WO97 / 22600 discloses antihyperglycemic 5- [3- (carboxamido) phenyl] -2,4-thiazolidinediones of the formula The present inventors have found that certain 5-aryl-2,4-thiazolidinediones are potent PPAR agonists, in particular subtypes a, d and / or α, and especially the subtype? including dual agonists of the subtypes a / ?. These compounds are therefore useful in the treatment, control or prevention of diabetes, hyperglycemia, hyperlipidemia (including hypercholesterolemia and hypertriglyceridemia), atherosclerosis, obesity, vascular restenosis and other diseases, disorders and mediated conditions for PPAR a, d and / or? DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds having the formula I: wherein, Ar 1 is (1) arylene or (2) heteroarylene, wherein the arylene or heteroarylene is optionally substituted with about 1 to 4 groups selected from Ra; Ar2 is (1) ortho-substituted aryl or ortho-substituted heteroaryl (2), wherein said ortho substituent is selected from R; and the aryl or heteroaryl is optionally substituted with about 1 to 4 groups independently selected from Ra; X and Y are independently O, S, N-Rb, or CH2; Z is O or S; n is 0 to 3; R is (1) C3 -? Alkyl or optionally substituted with 1-4 groups selected from halo or C3-6 cycloalkyl, (2) C3-? 0 alkenyl, or (3) C3-8 cycloalkyl; Ra is (1) alkanoyl of C? .i5, (2) alkyl of C-MS, (3) alkenyl of C2-? 5, (4) alkynyl of C2-15, (5) halo, (6) ORb, (7) aryl, or (8) heteroaryl, wherein said alkyl, alkenyl, alkynyl and alkanoyl are optionally substituted with 1-5 groups selected from Rc, and said aryl and heteroaryl are optionally substituted with 1 to 5 groups selected from Rd; Rb is (1) hydrogen, (2) alkyl of C-MO, (3) alkenyl of C2-0, (4) alkynyl of C2 -? Or, (5) aryl, (6) heteroaryl, (7) aryl -alkyl C-MS, (8) heteroaryl-C-MS alkyl, (9) C-MS alkanoyl, (10) C3-β cycloalkyl, wherein alkyl, alkenyl, alkynyl are optionally substituted with one to four substituents independently selected from Rc, and cycloalkyl, aryl and heteroaryl are optionally substituted with each other four substituents selected from Rd; or R c is (1) halo, (2) aryl, (3) heteroaryl, (4) CN, (5) NO 2, (6) OR f; (7) S (O) mRf, m = 0, 1 or 2, with the proviso that Rf is not H when m is or 2; 8) NRfR f, 9) NRfCOR f, 10) NRfCO2Rf, 1 1) NRfCON (Rf) 2, 12) NRfSO2Rf, with the proviso that Rf is not H, 13) COR, 14) CO2Rf, 15) CON (Rf) 2, 16) SO2N (Rf) 2, (17) OCON (Rf) 2, or (18) C3-8 cycloalkyl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 halo or alkyl groups of d-β; Rd is (1) a group selected from Rc, (2) C1-10 alkyl, (3) C2-10 alkenyl, (4) C2-? 0 alkynyl, (5) aryl-C? -10 alkyl , or (6) heteroaryl-CMO alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with an independently selected group of Re Re is (1) halogen, (2) amino, (3) carboxy, (4) C- alkyl, (5) C- (C) alkoxy, (6) hydroxy, (7) aryl, (8) aryl-alkyl of C1-4, or (9) aryloxy, Rf is (1) hydrogen, (2) C-O alkyl, (3) C2-? 0 alkenyl, (4) C2-? Or (5) aryl alkynyl, (6) heteroaryl, (7) aryl-CMS alkyl, (8) ) heteroaryl-C de _? alkyl, (9) C-15-15 alca alkanoyl, (10) C 3-8 cycloalkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with each other four selected groups of Re; or a pharmaceutically acceptable salt thereof. In a subset of compounds of formula I, Z is sulfur. In another subset of compounds of formula I, Ar1 is arylene optionally substituted with 1-4 groups selected from Ra. The preferred Ar1 is phenylene optionally substituted with 1-2 groups selected from halogen and C1- alkyl. Most preferably Ar1 is phenylene. In another subset of compounds of formula I, X and Y are each CH2, O or S. Preferably X and Y are each O. In another subset of compounds of formula I, Ar2 is wherein R is C3-4 alkyl optionally substituted with one to four groups selected from halogen and C3-6 cycloalkyl, and Ra 'is selected from Ra, or 2 Ra' groups on adjacent carbon atoms taken together complete a ring 5 or 6 member aromatic containing 0-2 heteroatoms selected from N, O and S (O) m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra. In a preferred subset, Ra 'is selected from ORb, aryl optionally substituted with 1 to 5 independently selected groups from Rd, and C?--Alkyl optionally substituted with 1 to 5 groups independently selected from Rc. In another preferred subset, 2 Ra 'groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 1-2 heteroatoms selected from N, O and S (O) m (m is 0-2) , said ring being optionally substituted with 1-2 groups selected from Ra. In a more preferred subset, Ra 'is selected from O-phenyl wherein phenyl is optionally substituted with 1 to 4 groups selected from Rd, phenyl optionally substituted with 1 to 2 halogens, and C ?5 alkyl optionally substituted with 1 to 5. independently selected from halogen, phenyl, and cycloalkyl of C3-s. In another more preferred subset, 2 Ra 'groups on adjacent carbon atoms taken together complete a 5 or 6 membered aromatic ring selected from isoxazole, thiophene (S-oxide and S-dioxide), furan each of which is optionally substituted with 1 to 2 groups selected from Ra. In another subset of compounds of formula I, n is 1 or 2. A preferred embodiment of formula I are compounds of formula la: wherein Ra 'is selected from Ra, or 2 Ra' groups on adjacent carbon atoms taken together complete a 5 or 6 membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra; X, Y, Z, n, R and Ra are as defined in formula I. In a subset of compounds of formula are the compounds of formula la (!): the I) In another subset of compounds of formula are the compounds of formula la (i): the (ii) A more preferred embodiment are compounds of formula la, wherein Z is S. Another more preferred embodiment are compounds of formula la, wherein Y is S or O, and X is O. Another more preferred embodiment are compounds of formula la, wherein R is C3-4 alkyl. Another more preferred embodiment are compounds of formula la, wherein n is 1 or 2.

Another more preferred embodiment are compounds of formula la, wherein Ra 'is O-aryl optionally substituted with 1-3 groups independently selected from Rd, aryl optionally substituted with 1-3 groups selected from Rd, or C-? Optionally substituted with 1-5 groups selected from Rc, or 2 Ra 'groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra. A still more preferred embodiment are the compounds of formula la, wherein Z is S; X is O; And it is (1) O or (2) S; R is C3-4 alkyl; Ra is (1) halogen or (2) C? -5 alkyl; Ra 'is (1) O-aryl optionally substituted with 1 to 3 independently selected groups of Rd, (2) aryl optionally substituted with 1 to 3 groups selected from Rd, (3) C? -5 alkyl optionally substituted with 1 to 5 groups selected from Rc, or 2 Ra 'groups on adjacent carbon atoms taken together complete a 5 or 6 membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) m (m is 0-2) , said ring being optionally substituted with 1-2 groups selected from Ra. Representative compounds of the present invention include those shown in tables 1-3: TABLE 1 * Y-L-X A / B Ra 4 O (CH 2) 3 O O / CH Ph 4 O (CH 2) 3 O O / CH CH 2 C (CH 3) 3 3 O (CH 2) 4 O O / CH CH 2 C (CH 3) 3 3 O (CH 2) 4 O O / CH (CH 2) 2Ph 4 O (CH 2) 3 O O / N Ph 4 O (CH 2) 3 O O / N CH 2 C (CH 3) 3 4 O (CH2) 3O O / N CF3 4 O (CH2) 3O O / N (CH2) 2Ph 4 O (CH2) 3O O / N (CH2) 4Ph 4 O (CH2) 3O O / N CH2-c-Hex ** 4 O (CH2) 3O O / N CH2C (CH3) 2Ph 3 O (CH2) 4O O / N CF3 4 O (CH2) 3O S / CH (CH2) 2Ph 3 O (CH2) OS / CH (CH2) 2Ph 3 O (CH2) O SO / CH (CH2) 2Ph 4 O (CH2) 3O SO / CH (CH2) 2Ph 4 O (CH2) 3O SO2 / CH Ph3O (CH2) 4O SO2 / CH (CH2) 2Ph4O (CH2) 3O SO2 / CH (CH2) 2Ph * point of attachment of Y to the phenyl ring. ** c-Hex is cyclohexyl.

Or I heard O0 C0 0) C? C (/) C0 C0 C () C0) O O C / C0 C0 C0 C0 (/) C0 C0 C C /) N N > ro in Ül o CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO CO C CO CO CO C CO CO CO CO C C CO N O x x x x x x x x x x x x x X X X X X X X X X X 70 • o co ^ ^? or ? ? ^ ^? ? ? ? ^ ^ íi? ? ^? ? w ív w? ? O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O N O) X X X X X X X X X X X X X X X X X X X o o o o X r X o ro M r X X X X? yes ro? ? O O O O O O O O O O O O O O O O O O O O or? -O "O" O "O" O • a -o O? ? ? 7 or 3? o o o o O o o o o o o O •? or T 33 -s "O -a •? o 3 3 O 3" O • a 3 • o 3 T 33 - T3 3 3 • a 3? 3 3 s or 3 73 X or 3. ik ^ 4 ^ j-? ? üi ^ j. ^ ik ^ k ^ 4? ^ 4-ji- i- -l ^ -P "-i ^ i-l > * point of attachment of Y to the phenyl ring. ** point of attachment of the phenoxy group to the phenyl ring. t c-pr is cyclopropyl.

TABLE 3 * n Ra (1) Ra (2) 4 3 4-F-Ph H 3 3 2-naphthyloxy H 3 3 2-dibenzofuranyl H 3 3 phenoxy propyl 4 3 3-isoxazolyl H 3 4 3-isoxazolyl H 4 3 pyrazinyloxy H * point of attachment of O to the phenyl ring. "Alkyl", as well as other groups having the prefix "alk", such as alkoxy, alkanoyl, refers to carbon chains which may be straight or branched or combinations thereof.

Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and fer-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. "Alkenyl" means carbon chains that contain at least less a carbon-carbon double bond, and which may be straight or branched or combinations thereof. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. "Alkynyl" means carbon chains containing at least one carbon-carbon triple bond, and which may be straight or branched or combinations thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. "Cycloalkyl" means saturated mono- or b-cyclic carbocyclic rings, each having from about 3 to about 10 carbon atoms. The term also includes monocyclic ring fused to an aryl group wherein the point of attachment is on the non-aromatic portion. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. "Aryl" (and "arylene") means mono- or bicyclic aromatic rings, which only contain carbon atoms in the ring. The term also includes aryl group fused to a monocyclic heterocyclyl or monocyclic cycloalkyl group wherein the point (s) of attachment is on the aromatic portion. "Heterocyclyl" means a total or partially saturated ring containing at least one heteroatom selected from N, S and O, each of said rings having from 3 to 10 atoms. Examples of aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like. "Heteroaryl" (and heteroarylene) means a mono-, bi- or tricyclic aromatic ring containing at least one heteroatom selected from N, O and S (including SO and SO2), with each ring comprising from about 5 to 6 carbon atoms. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazole, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo (2,3-b) pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like. "Halogen" includes fluorine, chlorine, bromine and iodine. The term "ortho-substituted" means that the substituent is attached to a ring atom that is adjacent to the point of attachment to the base structure of the molecule. The term "composition", as in pharmaceutical composition, attempts to comprise a product that contains the active ingredient (s), and the inert ingredient (s) that form the vehicle, as well as any other product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more ingredients, or of the dissociation of one or more of the ingredients, or of other types of reactions or interactions of one or more of the ingredients. Also, the pharmaceutical compositions of the present invention comprise any composition made by mixing a compound of the present invention and a vehicle pharmaceutically acceptable.

Optical isomers - Diastereomers - Geometric isomers Tautomers Compounds of Formula I may contain one or more asymmetric centers and thus may occur as racemates and racemic mixtures, individual enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is intended to comprise all of these isomeric forms of the compounds of Formula I. Some of the compounds described herein contain olefinic double bonds, and unless otherwise specified, are intended to include both geometric isomers E and Z. Some of the compounds described herein may exist with different hydrogen bonding sites, termed as tautomers. An example may be a ketone and its enol form known as keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed by compounds of formula I. Compounds of formula I can be separated into diastereomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture of them. The pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional means, for example, by the use of an optically active acid as a resolution agent. Alternatively, any enantiomer of a compound of the general formula I or can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

Salts The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous salts, manganous, potassium, sodium, zinc and the like. Particularly preferred salts are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic exchange resins, such as arginine, betaine, caffeine, choline , N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, Theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids, including organic or inorganic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like. Particular preference is given to citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. It will be understood that, as used herein, references to the compounds of formula I are also intended to include pharmaceutically acceptable salts.

Uses The compounds of the present invention are potent agonists of various subtypes of peroxisome proliferator activating receptor, particularly PPARa, PPAR? and / or PPARd. The compounds of the present invention can be selective agonists of a receptor subtype, for example PPARα agonists, or they can be agonists of one or more subtypes of receptors, for example, dual PPARa /? Agonists. The compounds of the present invention are useful in the treatment, control or prevention of diseases, disorders or conditions mediated by the activation of subtypes of individual PPARs (a,? or d), or a combination of PPAR subtypes (eg, a /?). Thus, an aspect of the present invention provides a method for the treatment, control or prevention of said diseases, disorders or conditions in a mammal consisting of administering to said mammal a therapeutically effective amount of a compound of formula I. , disorders or conditions that the compounds of the invention can treat, control or prevent include, but are not limited to, (1) diabetes mellitus, (2) hyperglycemia, (3) obesity, (4) hyperlipidemia, (5) hypertriglyceridemia, (6) hypercholesterolemia (including increased HDL levels), (7) atherosclerosis, (8) vascular restenosis, (9) irritable bowel syndrome, (10) pancreatitis, (1 1) abdominal obesity, (12) cell tumors adipose, (13) adipose cell carcinomas such as liposarcoma, and (14) other disorders in which insulin resistance is a component, including Syndrome X and ovarian hyperandrogenism (polycystic ovary syndrome). co). Another aspect of the invention provides a method for the treatment, control or prevention of hypercholesterolemia comprising administering to a mammal in need of such treatment a therapeutically effective amount of an agonist of both PPARa and PPAR? (dual agonist PPARa /?). Preferably the dual agonist is administered with a cholesterol biosynthesis inhibitor, particularly an inhibitor of HMG-CoA reductase such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin.

Administration and dose scales Any suitable route of administration can be employed to provide an effective dose of a compound of the present invention to a mammal, especially a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like can be employed. Dosage forms include tablets, pills, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably the compounds of formula I are administered orally. The effective dose of active ingredient employed may vary depending on the particular compound used, the mode of administration, the condition to be treated and the severity of the condition to be treated. Said dose can be easily established by one skilled in the art.

When diabetes mellitus and / or hyperglycemia or hypertriglyceridemia or other diseases for which the compounds of formula I are indicated are treated or prevented, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dose of about 0.1. milligrams to approximately 100 milligrams per kilogram of animal body weight, preferably supplied as a single daily dose or in divided doses two to six times a day, or in the form of prolonged release. For most mammals, the total daily dose is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about 50 milligrams In the case of a 70 kg adult human, the total daily dose will generally be around 7 milligrams to about 350 milligrams. This dose regimen can be adjusted to provide the optimal therapeutic response.

Pharmaceutical Compositions Another aspect of the invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical compositions of the present invention comprise a compound of formula I as an active ingredient or a pharmaceutically acceptable sai thereof, and may also comprise a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in a particular case it will depend on the nature and severity of the conditions that are being treated and the nature of the active ingredient. They can be conveniently presented in unit dose form and prepared by any of the methods known in the field of pharmaceutical. In practical use, the compounds of formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional techniques for the formation of pharmaceutical compounds. The vehicle can have a variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral (including intravenous). In preparing the compositions for unit dosage form, it is possible to use any of the common pharmaceutical media, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations. , such as, for example, suspensions, elixirs and solutions; or vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, soft and hard capsules and tablets, with oral solid preparations being more preferred than liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous unit dose form in which case solid pharmaceutical carriers are obviously employed. If desired, the tablets can be coated by standard aqueous or non-aqueous techniques. Said compositions and preparations should comprise at least 0.1 percent active compound. The percentage of compound Active in these compositions can, of course, vary and conveniently be between 2 percent and about 60 percent by weight of the unit. The amount of active compound in said therapeutically useful compositions is such that an adequate dose will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or aspersion. Tablets, pills, capsules and the like may also comprise a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When the unit dose form is a capsule, it may comprise, in addition to the materials of the type mentioned above, a liquid carrier such as a fatty oil. Many other materials can be presented as coatings or to modify the physical form of the unit dose. For example, the tablets may be coated with sugar, shellac or both. A syrup or elixir may comprise, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. The compounds of formula I can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water mixed properly with an agent surfactant such as hydroxypropylcellulose. The dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations comprise a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid to the extent that there is easy injection capacity. It must be stable under manufacturing and storage conditions and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Combination therapy The compounds of formula I can be used in combination with other drugs which may also be useful in the treatment, prevention, suppression or amelioration of diseases or conditions for which the compounds of formula I are useful. Said other drugs can be administered, by a route in a commonly used amount thereof, at the same time or sequentially with a compound of formula I. When a compound of formula I is used at the same time with one or more drugs, a pharmaceutical composition in unit dosage form containing said other drugs and the compound of formula I is also preferred. It is also contemplated that when used in combination With one or more active ingredients, the compound of the present invention and the other active ingredients can be used in lower doses than when used individually. Also, the pharmaceutical compositions of the present invention include those that contain one or more active ingredients, in addition to a compound of formula I. Examples of other active ingredients that can be combined with a compound of formula I, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: a) insulin sensitizers including (i) PPAR agonists? such as glitazones (for example, troglitazone, pioglitazone, englitazone, MCC-555, BRL49653 and the like), and compounds described in WO97 / 27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin; b) insulin or insulin mimetics; c) sulfonylureas such as tolbutamide and glipizide, or related materials; d) α-glucosidase inhibitors (such as acarbose), e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, and pravastatin, fluvastatin, atorvastatin, rivastatin and other statins), (ii) sequestrants (cholestyramine, colestipol and a dialkylaminoalkyl derivative of an interlaced dextran), (iii) nicotinic alcohol, nicotinic acid or a salt thereof, (iv) PPARa agonists such as derivatives of fenofibric acid (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) cholesterol absorption inhibitors for example beta-sitosterol e (acyl CoA: cholesterol acyltransferase) inhibitors for example melinamide and (vi) probucol; f) PPARd agonists such as those described in WO97 / 97/28149; g) antiobesity compounds such as fenfluramine, dexfenfluramine, fentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors and β3 andrenergic receptor agonist; h) loyal bile acid transporter inhibitor.

Biological tests A. White Adipose Tissue In Vitro Test This test measures the efficacy of the compounds herein to improve insulin activation of 14 C-glucose incorporation into glycogen in white adipose tissue (WAT) in a fully in vitro 5-hr system . All procedures are performed on 199 media containing 1% bovine serum albumin, 5 mM HEPES, and antibiotics (100 units / ml penicillin, 100 μg / ml sulfate streptomycin, 0.25 μg / ml amphotericin B), hereinafter called culture medium. Epididymal fat pads were shredded with scissors into small fragments, approximately 1 mm in diameter. The minced fragments of WAT (100 mg) are incubated in a total volume of 0.9 ml of culture medium containing 1 mU / ml of insulin and the test compound in tissue culture incubator at 37 ° C with 5% CO 2. Orbital shaking for 3 hours. The labeled 14C glucose is added and the incubation continues for 2 hours. The tubes are centrifuged at low speed, the infranatant is removed and 1 M NaOH is added. Incubation of WAT treated with alkali for 10 minutes at 60 ° C solubilizes the tissue. The resulting tissue hydrolyzed material is applied to Whatman filter paper strips which are then rinsed in 66% ethanol followed by 100% acetone which removes unincorporated 14C-glucose from 14C-linked glycogen. The dried paper is incubated in amyloglucosidase solution to cut giicogen into glucose. The scintillating fluid is added and the samples are counted for 14C activity. The test compounds that resulted in 14C activity substantially over the incubations with insulin alone are considered active insulin-increasing agents. The active compounds were titrated to determine the concentration of compound that resulted in 50% maximum increase in insulin activation and were termed EC5Q values.

B. Transactivation tests of Gal-4 hPPAR a) Plasmids Chimeric receptor expression constructs, pcDNA3-hPPAR? / GAL4, pcDNA3-hPPARd / GAL4, pcDNA3-hPPARa / GAL4 were prepared by inserting the yeast transcription factor DBD GAL4 adjacent to the ligand binding domains (LBDs ) of hPPAR ?, hPPARd, hPPARa, respectively. The reporter builder, pUAS (5X) -tk-Iuc was generated by inserting 5 copies of the GAL4 response element upstream of the minimal herpes virus thymidine kinase promoter and the luciferase reporter gene. pCMV-lacZ contains the Z-galactosidase gene under the regulation of the cytomegalovirus promoter. b) Cell culture and transactivation tests COS-1 cells were seeded at 12 X 103 cell / well in 96-well cell culture plates in Dulbecco's high glucose modified Eagle's medium (DMEM) containing 10% serum of fetal veal purified with carbon (Gemini Bio-Products, Calabasas, CA), non-essential amino acids, 100 units / ml of Penicillin G and 100 mg / ml of streptomycin sulfate at 37 ° C in a humid atmosphere of 10% CO2 . After 24 hours, transfections with Lipofectamine (GIBCO BRL, Gaithersburg, MD) were performed according to the manufacturer's instructions. Briefly, the transfection mixtures for each cavity contained 0.48 μl of Lipofectamine, 0.00075 μg of pcDNA3-PPAR / GAL4 expression vector, 0.045 μg of pUAS (5X) -tk-luc reporter vector and 0.0002 μg of pCMV-lacZ as an internal control for transactivation efficiency. The cells were incubated in the transfection mixture for 5 hours at 37 ° C in a 10% CO2 atmosphere. The cells were incubated for -48 h in fresh high glucose DMEM containing 5% fetal calf serum purified with carbon, non-essential amino acids, 100 units / ml Penicillin G and 100 mg / ml streptomycin sulfate + increased concentrations of the test compound. Because the compounds were solubilized in DMSO, the control cells were incubated with equivalent concentrations of DMSO; the final concentrations of DMSO were < 0.1%, a concentration that showed that it did not perform transactivation activity. The cell lysates were produced using reporter lysis buffer (Promega, Madison, Wl) according to the manufacturer's instructions. Luciferase activity in cell extracts was determined using luciferase assay regulator (Promega, Madison, Wl) in an ML3000 luminometer (Dinatech Laboratories, Chantilly, VA). The β-galactosidase activity was determined using β-D-galactopyranoside (Calbiochem, San Diego, CA).

C. In vivo studies Male db / db mice (10-1 1 week old C57BI / KFJ, Jackson Labs, Bar Harbor, ME) were housed in 5 cages and allowed ad lib access. a food for rodents Purina and water. The animals, and their food, weighed every 2 days and dosed daily by single feed with vehicle (0.5% carboxymethylcellulose) ± test compound at the indicated dose. The suspensions of the drug were prepared daily. The concentrations of glucose in the plasma, and triglycerides were determined from blood obtained by tail bleeding at intervals of 3-5 days during the study period. Glucose and triglyceride determinations were performed on a Boehringer Mannheim Hitachi 91 1 automated analyzer (Boehringer Mannheim, Indianapolis, IN) using heparinized plasma diluted 1: 6 (v / v) with normal saline. The lean animals were heterozygous mice of similar ages maintained in the same way. The compounds of formula I can be prepared according to the methods presented in the schemes. The various variables in the schemes, unless otherwise specified, have the same meanings as those described above under formula I.

SCHEME 1 H3COOC-CH2-Ar1- Y- CH2 - (CH2) n - CH2- X- Ar2 I1) to. LiHMDS, THF, THSCI, NBS b. when Z = S, thiourea, methoxyethane HCl, reflux Alpha-bromination of an aryl acetate ester intermediate A1 with a halogenating agent (eg, N-bromosuccinimide) in the presence of a base produces a ring-closed halo intermediate using thiourea (Z = S) in the presence of strong aqueous acid or sodium acetate in an alcohol solvent such as 2-methoxyethanol a) high eratures to give the title aryl-thiazolidinediones (I; Z = S).

SCHEME 2 HX- Ar2. { Bl} H3COOC- CH2- Ar1- YH + L-H2C- (CH2) n- CH2 - X - Ar2 i IC1) H3COOC- CH2- Ar1-Y-CH2- (CH2) n-CH2-L + HX-Ar2 C2) Ib) H3COOC- CH2- Ar1- YH (B2) L and L 'are the same or different residual groups Scheme 2 shows the synthesis of intermediate Al, which contains a portion Ar1 and a portion Ar2 connected by a union of > 4 atoms The intermediate A1 can be prepared by convergent synthesis by first fixing the junction T having two residual terminal groups to Ar1 or Ar2; in T, L and L 'independently represent a conventional residual group such as halide (preferably bromide) and sulfonyloxy (for example, mesylate or tosylate). The treatment of the bound molecule C1 or C2 with the other aryl portion B2 or B1, respectively in the presence of an inorganic base (for example, Cs2CO3) in DMF solution provides the intermediate A1 of attached arylacetate ester. The starting material T, B. and B2 are commercially available or can be prepared using known organic synthesis methods. The compounds of formula B2 can be prepared according to the methods described in published PCT applications 97/27857, 97/281 15 and 97/28137.

SCHEME 3 OH H3COOC- CH- Ar1 - YH LH2C- (CH2) n- CH2- X - Ar ^ ÍB3) ÍC1) OH HgCOOC- CH- Ar1- ^ - CH ^ (CH ^ CH2- X - Ar2 ÍA2) or idina, toluene hate, ethanol, In scheme 3 an appropriately substituted mandelic acid ester B3 is reacted with the derivative Ar2 having a residual group L, Cl, in the presence of an inorganic base such as cesium carbonate. The resulting product A2 is cyclized with urea in the presence of a base such as sodium methoxide to form the desired product (I; Z = O).

Alternatively, the hydroxy group of A2 can be converted to the corresponding chloride using thionyl chloride, and the resulting compound is closed with ring as previously described in scheme 1 to provide compounds of formula I wherein Z = S. The starting materials for the synthesis illustrated in Scheme 3 are commercially available or can be prepared using known organic synthesis methodology.

SCHEME 4 1) (Tf) 20, Pyridine HX-Ar? ~ HY-CH- (-C = C-Ar2 (X = O) 2) HYnCH2 (CH2) r ^ C = CH (? = O) QC? 2) n (Y = 0) Pd (PPh3) 4, piperidine 1) H2, Pd / C, Ethanol 2) (Ms) 20, Pi r, CH2Cl2 H3COOC-CH2- Art-Y-CH2- (CH2) n-CH2-X-Ar2 A1 HX-Ar2 (X = 0) B2 Cs2C03, DMF H2) L is a residual group (Tf) 2O = trifluoromethanesulfonic anhydride, (Ms) 2O = methanesulfonic anhydride Scheme 4 shows the synthesis of intermediate Al, which contains an Ar1 portion and an Ar2 portion connected by a > 4 atoms where X or Y is oxygen. The catalysed addition of palladium of an alkyne to either an aryl bromide (E _) or a triflate (E2) gives D_l or D2, respectively. The hydrogenation of the alkyne (D_l or D2) at atmospheric pressure produced the fully saturated material, C_l or C2, which was coupled to Bl or B2 in the presence of an inorganic base (for example, Cs2CO3) in dimethylformamide solution to provide the intermediate of AL-linked arylacetate ester The starting materials for the synthesis illustrated in scheme 4 are commercially available or can be prepared using known organic synthesis methodology. The following examples are provided only to illustrate the invention and are not to be construed as limiting the invention in any respect.

EXAMPLE 1 5-r4- (3- (2-propyl-4-phenoxy-phenoxypropoxy) phenyl-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3-bromopropoxy) phenylacetate A solution of methyl 4-hydroxyphenylacetate (20.0 g, 0.12 moles), 1-3-dibromopropane (97.2 g, 0.48 moles) and cesium carbonate (43.1 g) , 0.13 mol) in dry DMF (250 mL) was stirred at room temperature overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with methylene chloride / hexane (2: 1) to obtain the title compound. 1 H NMR (400 MHz, CDCl 3): d 7.17 (d, 2 H, J = 8.7 Hz), 6.84 (d, 2 H, J = 8.7 Hz), 4.07 (t, 2 H, J = 5.8 Hz), 3.66 (s, 3 H) ), 3.58 (t, 2H, J = 6.5Hz), 3.55 (s, 2H), 2.31 (quint, 2H, J = 6.3Hz).

Step B: Preparation of Methyl 4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxophenylacetate A solution of the product from Step A (1.0 g, 38.58 mmol), 4- phenoxy-2-propylphenol (PCT application WO97 / 28115; 8.0 g, 35.07 mmol) and cesium carbonate (12.0 g, 36.82 mmol) in DMF (80 mL) was stirred at 40 ° C overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound. 1 H NMR (400MHz, CDCl 3): d 7.30-7.18 (m, 4H), 7.02-6.70 (m, 8H), 4.17 (t, 2H, J = 6.3Hz), 4.11 (t, 2H, J = 6.0Hz) , 2.53 (t, 2H, 7.4Hz), 2.26 (quint, 2H, J = 6.3Hz), 1.55 (hex, 2H, 5.6Hz), 0.89 (t, 3H, J = 7.3Hz).

Step C Preparation of 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) phenyl-1,2-thiazolidinedione A solution of lithium bis (trimethylsilyl) amide (27.36 mL, 27.36 mmol) in THF Dry (80 mL) was treated with trimethylsilyl chloride (5.94 mL, 46.76 mmol) at -78 ° C. To this mixture was added dropwise a solution of the product of Step B (10.80 g, 24.87 mmol) in THF (15 mL). The reaction mixture was stirred at -78 ° C for 2 hours. N-bromosuccinimide (4.65 g, 26.12 mmol) was added, and the mixture was allowed to warm to room temperature overnight. THF was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed once with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to provide a-bromo-4- (3- (2-propyl-4-phenoxy) phenoxy) methyl propoxy) phenylacetate as an oil. The residual oil was dissolved in methoxyethanol (100 mL); Thiourea (2.84 g, 37.31 mmol) and sodium acetate (2.14 g, 26.12 mmol) were added. The mixture was heated at 1 15 ° C for 5 hours. Hydrochloric acid (19.43 mL, 6N) was added, and the mixture was heated at 15 ° C for 5 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, dried over sodium sulfate, filtered and evaporated to an oil, which was chromatographed on silica gel 1% methanol in methylene chloride to give the title compound. 1 H NMR (400MHz, CDCl 3): d 8.01 (brs, 1 H), 7.32-7.24 (m, 4H), 7.02-6.79 (m, 8H), 5.32 (s, 3H), 4.17 (t, 2H, J = 6.3Hz), 4.1 1 (t, 2H, J = 6.0Hz), 2.53 (t, 2H, 7.4Hz), 2.26 (quint, 2H, J = 6.3Hz), 1.55 (hex, 2H, 5.6Hz), 0.89 (t, 3H, J = 7.3Hz).

EXAMPLE 2 5-r4- (3- (7-propyl-3-phenyl-6-benzr4.51isoxazolyloxy) propoxy) phene-2,4-thiazoidinedione Step Preparation of methyl 4- (3- (7-propyl-3-phenyl-6-benz [4,51-isoxazolyl] oxy) propoxy) phenylacetate The title compound was prepared according to the method described in Example 1, Step B , using 7-propyl-3-phenyl-6-hydroxy-benz [4,5] isoxazole (PCT application WO97 / 28137) as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.92 (dd, 2H, J = 7.9, 2.6 Hz), 7.64 (d, 1 H, J = 8.7 Hz), 7.52 (m, 3H), 7.18 (d, 2H, J = 8.6Hz), 7.01 (d, 2H, J = 8.8Hz), 6.86 (dd, 2H, J = 8.7, 2.1 Hz), 4.26 (t, 2H, J = 6.1 Hz), 4.18 (t, 2H, J = 6.0Hz), 3.67 (s, 3H), 3.55 (s, 2H), 2.90 (t, 2H, J = 7.3Hz), 2.31 (quint, 2H, J = 6.3Hz), 1.71 (hex, 2H, 5.7 Hz), 0.92 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5- [4- (3- (7-propyl-3-phenyl-6-benz | "4,51-oxazolylloxy) propoxy) phenyl-1,2,4-thiazolidinedione The title compound is prepared according to the method described in Example 1, step C, using methyl 4- (3- (7-propyl-3-phenyl-6-benz [4,5] isoxazolyloxy) propoxy) phenylacetate as the starting material 1 H NMR (400MHz, CDCl 3): d 8.23 (brs, 1 H), 7.92 (dd, 2H, J = 7.9, 2. 6 Hz), 7.64 (d, 1 H, J = 8.7 Hz), 7.52 (m, 3H), 7.31 (d, 2H, J = 8.6Hz), 6.98 (d, 2H, J = 8.8Hz), 6.92 ( dd, 2H, J = 8.7, 2.1 Hz), 4.26 (t, 2H, J = 6.1 Hz), 4.20 (t, 2H, J = 6.0Hz), 3.67 (s, 3H), 3.55 (s, 2H), 2.90 (t, 2H, J = 7.3Hz), 2.31 (quint, 2H, J = 6.3Hz), 1.71 (hex, 2H, 5.7Hz), 0.92 (t, 3H, J = 7.3Hz). Cl-MS: m / e = 503 (M + 1) EXAMPLE 3 5-r4- (3- (7-propyl-3-neopentyl-6-benzr4,51-isoxazolyloxy) propoxy) phenin-2,4- Step A: Preparation of methyl 4- (3- (7-propyl-3-neopentyl-6-benzyl-4,5-isoxazolyloxy) propoxy) phenylacetate The title compound was prepared according to the method described in Example 1, Step B, using 7-propyl-3-neopentyl-6-hydroxy-benz [4,5] isoxazole (PCT application WO97 / 28137) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 7.34 (d, 1 H, J = 8.7 Hz), 7.17 (dd, 2 H, J = 8.7, 2.1 Hz), 6.90 (d, 1 H, J = 8.7 Hz), 6.86 (dd, 2H, J = 8.7, 2.1 Hz), 4.23 (t, 2H, J = 6.0Hz), 4.18 (t, 2H, J = 6.0Hz), 3.67 (s, 3H), 3.54 (s, 2H), 2.85 (t, 2H, J = 7.2Hz), 2.78 (s, 2H), 2.28 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 1. 02 (s, 9H), 0.92 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5-γ4- (3- (7-propyl-3-neopentyl-6-benzr4,51-oxazoxyloxy) propoxyphenopyr-2,4-thiazolidinedione The title compound was prepared in accordance with method described in example 1, step C, using 4- (3- (7-propyl-3-neopentyl-6- methyl benz [4,5] isoxazolyloxy) propoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.10 (brs, 1 H), 7.34-7.30 (m, 3 H), 6.88-6.93 (m, 3 H), 5.32 (s, 1 H), 4.24-4.17 (m, 4 H) ), 2.82 (t, 2H, J = 7.2Hz), 2.78 (s, 2H), 2.28 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 1.02 (s, 9H) ), 0.92 (t, 3H, J = 7.3Hz).

EXAMPLE 4 5- [4- (3- (7-propyl-3-trifluoromethyl-6-benzr4151 isoxazolyloxy) propoxy) phenylene-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (7-propyl-3-trifluoromethyl-6-benzr4,51-oxazolyloxy) propoxy) phenylacetate The title compound was prepared according to the method described in example 1, step B, using 7-propyl-3-trifluoromethyl-6-hydroxy-benz [4,5] isoxazole (PCT application WO97 / 28137) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 7.53 (d, 1 H, J = 8.2 Hz), 7.18 (d, 2 H, J = 8.7, 2.1 Hz), 7.05 (d, 1 H, J = 8.8 Hz), 6.86 (dd, 2H, J = 8.7, 2.1 Hz), 4.27 (t, 2H, J = 6.0Hz), 4.18 (t, 2H, J = 6.0Hz), 3.65 (s, 3H), 3.54 (s, 2H), 2.88 (t, 2H, J = 7.2Hz), 2.30 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5- [4- (3- (7-propyl-3-trifluoromethyl-6-benzr4,51-oxazolyloxy) propoxy) phenyl-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (7-propyl-3-trifluoromethyl-6-benz [4,5] isoxazolyloxy) propoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.05 (brs, 1 H), 7.53 (d, 1 H, J = 8.8Hz), 7.32 (dd, 2H, J = 8.7, 2.1 Hz), 7.06 (d, 1 H, J = 8.6Hz), 6.92 (dd, 2H, J = 8.7, 2.1), 5.32 (s, 1 H), 4.27 (t, 2H, J = 6.1 Hz), 4.18 (t, 2H, J = 6.1 Hz), 2.85 (t, 2H, J = 7.5Hz), 2.28 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz). CI-MS: m / e = 512.3 (M + NH4) EXAMPLE 5 5-r4- (3- (7-propyl-3-phenethyl-6-benzr4,51-isoxazole-oxoxy) -propoxy) -phenin-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (7-propyl-3-phenethyl-6-benz [4,51-isoxazolyl] oxy) propoxy) phenylacetate The title compound was prepared according to the method described in example 1, Step B, using 7-propyl-3-phenethyl-6-hydroxy-benz [4,5] isoxazole (PCT application WO97 / 28137) as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.28-7.16 (m, 8H), 6.88-6.84 (m, 3H), 4.21 (t, 2H, J = 6.0Hz), 4.16 (t, 2H, J = 6.0Hz), 3.67 (s, 3H), 3.54 (s, 2H), 3.22-3.12 (m, 4H), 2.85 (t, 2H, J = 7.2Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5-r4- (3- (7-propyl-3-phenethyl-6-benzyl-4,51-oxazolyloxy) propoxy) -phenin-2,4-thiazolidinedione The title compound was prepared in accordance with method described in example 1, step C, using 4- (3- (7-propyl-3-phenethyl-6- methyl benz [4,5] isoxazolyloxy) propoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.10 (brs, 1 H), 7.32-7.19 (m, 8H), 6.93-6.86 (m, 3H), 4.23-4.17 (m, 4H), 3.22-3.10 (m, 4H), 2.85 (t, 2H, J = 7.2Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz) . CI-MS: m / e = 531.5 (M + 1) EXAMPLE 6 5-4- (3- (7-propyl-3-phenylbutyl-6-benzr4,51-oxazoxy-loxy) propoxy) -phenyl-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (7-propyl-3-phenylbutyl-6-benzr4,51-isoxazole) oxime-methyl-phenolacetate The title compound was prepared according to the method described in example 1, step B, using 7-propyl-3-phenybutyl-6-hydroxy-benz [4,5] isoxazole as the starting material: 1 H NMR (400MHz, CDCl 3): d 7.31 (d, 1 H, J = 8.6 Hz) , 7.26-7.13 (m, 8H), 6.88-6.84 (m, 2H), 4.21 (t, 2H, J = 6.0Hz), 4.16 (t, 2H, J = 6.0Hz), 3.67 (s, 3H), 3.54 (s, 2H), 2.91 (t, 2H, J = 7.4Hz), 2.82 (t, 2H, J = 7.5Hz), 2.66 (t, 2H, J = 7.2Hz), 2.29 (quint, 2H, J = 6.3Hz) , 1.90-1.70 (m, 4H), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5-r4- (3- (7-propyl-3-phenylbutyl-6-benzr4.51isoxazolyloxy) propoxy) phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in the example 1, step C, using methyl 4- (3- (7-propyl-3-phenylbutyl-6-benz [4,5] isoxazolyloxy) propoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.10 (brs, 1 H), 7.32-7.29 (m, 3H), 7. 26-7.20 (m, 2H), 7.17-7.11 (m, 3H), 6.93-6.87 (m, 3H), 4.23-4.16 (m, 4H), 2. 91 (t, 2H, J = 7.4), 2.82 (t, 2H, J = 7.5Hz), 2.66 (t, 2H, J = 7.2Hz), 2.29 (quint, 2H, J = 6.3Hz), 1 .90 -1.70 (m, 4H), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz). CI-MS: m / e = 559.7 (M + 1) EXAMPLE 7 5-r4- 3- (7-propyl-3-phenylbenzofuran-6-yl) oxy) propoxy) phenin-2,4-thiazolidinedione Step A: Preparation of Methyl 4- (3- (7-propyl-3-phenylbenzofuran-6-D-propoxyphenylacetate) The title compound was prepared according to the method described in Example 1, step B, using 6-hydroxycarboxylic acid. 7-propyl-3-phenylbenzofuran (PCT application WO97 / 27857) as the starting material: 1 H NMR (400MHz, CDCl 3): d 7.69 (s, 1 H), 7.68-7.59 (m, 2H), 7.54 (d , 1 H, J = 8.5Hz), 7.45-7.131 (m, 3H), 7.18-7.15 (m, 2H), 6.92 (d, 1 H, J = 8.5Hz), 6.90-6.85 (m, 2H), 4.21-4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.88 (t, 2H, J = 7.4Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.66 (hex , 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5- [4- (3- (7-propyl-3-phenylbenzofuran-6-iDpropoxy) -phenip-2,4-thiazolidinodone The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (7-propyl-3-phenylbenzofuran-6-yl) propoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.18 (brs, 1 H), 7.69 (s, 1 H), 7.63-7.59 (m, 2 H), 7.55 (d, 1 H, J = 8.5 Hz), 7.45-7.40 (m, 2H), 7.36-7.27 (m, 3H), 6.90-6.55 (m, 3H), 5.31 (s, 1 H), 4.21-4.16 (m, 4H), 3.67 (s, 2H), 3.54 ( s, 2H), 2.88 (t, 2H, J = 7.4Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.66 (hex, 2H, J = 5.9Hz), 0.92 (t, 3H, J = 7.3 Hz). CI-MS: m / e = 502.4 (M + 1) EXAMPLE 8 5-r4- (3- (7-propyl-3-phenylbenzothiophen-1,1-dioxido-6-yl) oxy) propoxy) phenin-2,4-thiazoiidinedione Step A: Preparation of Methyl 4- (3- (7-propyl-3-phenylbenzothiophen-1, 1-d, oxido-6-yl) propoxy) phenylacetate The title compound was prepared according to the method described in Example 1, step B, using 6-hydroxy-7-propyl-3-phenylbenzothiophen-1,1-dioxide as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.50-7.42 (m, 4H), 7.31 (d, 2H, J = 8.8Hz), 7.19-7.16 (d, 2H, J = 8.3Hz), 6.92-6.83 (m, 3H), 6.46 (s, 1 H), 4.21-4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.95 (t, 2H, J = 7.4Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.71 (hex, 2H, J = 5.9Hz), 1.01 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5-r4- (3- (7-propyl-3-phenylbenzothiophen-1,1-dioxido-6-yl) propoxy) phene-2,4-thiazolidinedione The title compound was prepared in accordance with method described in example 1, step C, using methyl 4- (3- (7-propyl-3-phenylbenzothiophen-1, 1-dioxido-6-yl) propoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.05 (brs, 1 H), 7.50-7.42 (m, 4 H), 7.31 (d, 2 H, J = 8.8 Hz), 7.19-7.16 (d, 2 H, J = 8.3 Hz ), 6.92-6.83 (m, 3H), 6.46 (s, 1 H), 5.32 (s, 1 H), 4.21-4.16 (m, 4H), 2.95 (t, 2H, J = 7.4Hz), 2.29 ( quint, 2H, J = 6.3Hz), 1.71 (hex, 2H, J = 5.9Hz), 1.01 (t, 3H, J = 7.3Hz). CI-MS: m / e = 567.3 (M + NH4) EXAMPLE 9 5-r4- (3- (7-propyl-3-cyclohexylmetyl-6-benzyl-4,41-isoxazolyl) propoxy) -phenin-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (7-propyl-3-cyclohexylmethyl-6-benzr4,51-isoxazolyl-oxy) -propoxy) phenylacetate The title compound was prepared according to the method described in Example 1, Step B , using (3-cyclohexylmethyl-6-hydroxy-7-propyl) benz [4,5] -isoxazole as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.36 (d, 1 H, J = 8.6 Hz), 7.32 (dd, 2H, J = 6.7, 1.9Hz), 6.93-6.88 (m, 3H), 4.23-4.17 (m , 4H), 3.84 (s, 3H), 3.72 (s, 2H), 2.84 (t, 2H, J = 6.3Hz), 2.77 (d, 2H, J = 7.0Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.85-1.00 (m, 13H), 0.89 (t, 3H, J = 7.3Hz).

Step B: Preparation of 5-r4- (3- (7-propyl-3-cyclohexylmethyl-6-benzr4,5-isoxazolyloxy) propoxy!) Phenyl1-2,4-thiazolidinodone The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (7-propyl-3-cyclohexylmethyl-6-benz [4,5] isoxazoyloxy) propoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.25 (s, 1 H), 7.36 (d, 1 H, J = 8.6Hz), 7.32 (dd, 2H, J = 6.7, 1.9Hz), 6.93-6.88 (m, 3H), 5.32 (s, 1 H), 4.23-4.17 (m, 4H), 2.84 (t, 2H, J = 6.3Hz), 2.77 (d, 2H, J = 7.0Hz), 2.29 (quint, 2H, J = 6.3Hz), 1.85-1.00 (m, 13H), 0.89 (t, 3H, J = 7.3Hz).

EXAMPLE 10 5-f4- (3- 2-propyl-4- (4'-fluorobiphenyloxy) propoxy) phenin-2,4-thiazolidinodone Step A: Preparation of methyl 4- (3- (2-propyl- (4'-fluorobiphenyloxy) propoxy) phenylacetate The title compound was prepared according to the method described in example 1, step B, using 2 -propyl-4- (4-fluorophenyl) -phenol as the starting material: 1 H NMR (400MHz, CDCl 3): d 7.32-7.24 (m, 2H), 7.02-6.79 (m, 7H), 4.20-4.16 (m , 4H), 3.80 (s, 3H), 3.70 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.26 (quint, 2H, J = 6.3Hz), 1.55 (hex, 2H, 5.6Hz ), 0.89 (t, 3H, J = 7.3 Hz).

Step B: Preparation of 5-r4- (3- (2-propyl- (4'-fluorobiphenyloxy) propoxyphenyl1-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C , using methyl 4- (3- (2-propyl- (4'-fluorobiphenyloxy) propoxy) phenylacetate as the starting material: 1 H NMR (400MHz, CDCl 3): d 8.01 (brs, 1 H), 7.32-7.24 ( m, 4H), 7. 02-6.79 (m, 7H), 5.32 (s, 3H), 4.20-4.16 (m, 4H), 2.53 (t, 2H, 7.4Hz), 2.26 (quint, 2H, J = 6.3Hz), 1.55 (hex , 2H, 5.6Hz), 0.89 (t, 3H, J = 7.3Hz).

EXAMPLE 11 5-r4- (3- (2-propyl-4-phenoxyphenoxypropoxy) -3-chlorophenin-2,4-thiazolidinedione Step A: Preparation of 4- (3-bromopropoxy) -3-propylphenyl phenyl ether A solution of 4-phenoxy-2-propylphenol (12.0 g, 52.60 mmole), 1-3-dibromopropane (31.86 g, 157.81 mmole) and carbonate of cesium (18.0 g, 55.23 mmol) in dry DMF (110 mL) was stirred at room temperature overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with methylene chloride / hexane (1: 1) to obtain the title compound.

Step B: Preparation of Methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) 3-chlorophenylacetate A solution of the product of Step A (2.5 g, 7.18 mmol), 3-chloro-4- Methyl hydroxyphenylacetate (1.42 g, 7.1 1 mmol) and cesium carbonate (2.43 g, 7.45 mmol) in DMF (20 mL) was stirred at 40 ° C overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound. 1 H NMR (400MHz, CDCl 3): d 7.24-7.29 (m, 3H), 7.10 (dd, 1 H, J = 8.4, 2.1 Hz), 7.00 (t, 1 H, J = 7.3 Hz), 6.92-6.80 ( m, 6H), 4.22 (t, 2H, J = 6.1 Hz), 4.16 (t, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.30 (quint, 2H, J = 6.3 Hz), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxQ-3-chlorophenyl1-2.4-thiazolidinedione The title compound was prepared according to the method described in example 1, step C, using methyl 4- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -3-chlorophenoacetate as the starting material: 1 H NMR (400MHz, CDCl 3): d 8.46 (brs, 1 H), 7.42 (d, 1 H, J = 2.3 Hz), 7.29-7.23 (m, 3H), 7.02-6.80 (m, 7H), 5.27 (s, 1 H), 4.24 (t, 2H, J = 6.1 Hz), 4.15 (t , 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.30 (quint, 2H, J = 6.3 Hz), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

EXAMPLE 12 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-fluorophenin-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) 3-fluorophenylacetate The title compound was prepared according to the method described in Example 1 1, Step B, using 3- Fluoro-4-hydroxyphenyl-methyl acetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.23-7.28 (m, 3H), 7.1 1 (dd, 1 H, J = 8.4 Hz), 7.03 (t, 1 H, J = 7.3 Hz), 6.92-6.82 (m , 6H), 4.24 (t, 2H, J = 6.1 Hz), 4.14 (t, 2H, J = 6.0 Hz), 3.66 (s, 3H), 3.52 (s, 2H), 2.51 (t, 2H, J = 7.4 Hz), 2.31 (quint, 2H, J = 6.3 Hz), 1.54 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

Step B: Preparation of 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-fluorophenopyr-2,4-thiazolidinodone The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-fluorophenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.98 (brs, 1 H), 7.42 (d, 1 H, J = 2.3 Hz), 7.29-7.23 (m, 3H), 7.02-6.80 (m, 7H), 5.27 ( s, 1 H), 4.24 (t, 2H, J = 6.1 Hz), 4.15 (t, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.30 (quint, 2H, J = 6.3 Hz), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

EXAMPLE 13 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-propylphenin-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxQ3-propylphenylacetate The title compound was prepared according to the method described in example 11, step B, using 4-hydroxy-3 methyl-methyl acetate as the starting material: 1 H NMR (400 MHz, CDCl 3): d 7.31-7.25 (m, 2 H), 7.07-6.80 (m, 9H), 4.18-4.13 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.58-2.53 (m, 4H), 2.29 (quint, 2H, J = 6.3 Hz), 1.61-1.55 (m, 4H), 0.96-0.86 (m, 6H).

Step B: Preparation of 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-propylphenyl1-2,4-thiazolidinodone The title compound was prepared according to the method described in the example 1, step C, using methyl 4- (3- (2-propyl-4-phenoxyphenoxy)) propoxy) -3-propylphenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.04 (brs, 1 H), 7.28-7.24 (m, 2H), 7.18 (dd, 1 H, J = 8.4, 2.3 Hz), 7.12 (d, 1 H, J = 2.5 Hz), 7.00 (t, 1 H, J = 7.4 Hz), 6.92-6.79 (m, 6H), 5.30 (s, 1 H), 4.18-4.13 (m, 4H), 2.58-2.53 (m, 4H) ), 2.29 (quint, 2H, J = 6.3 Hz), 1.61-1.55 (m, 4H), 0.96-0.86 (m, 6H).

EXAMPLE 14 5-F4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) -3-chlorophenin-2,4-thiazolidinedione Step A: Preparation of methyl 3-chloro-4- (3-bromopropylthio) phenylacetate To a solution of methyl 3-chloro-4-dimethylcarbamoylthiophenylacetate (8.5 g, 0.0295 mol) in methanol (30 mL) was added 25% NaOMe in methanol (7 mL, 0.034 mol). The reaction was heated to reflux for 2 hours. TLC analysis showed residual starting carbamate. Additional NaOMe / MeOH (1.0 mL) was added and the mixture was stirred for an additional 30 minutes at reflux. After cooling to room temperature, the theolate solution was added dropwise to a solution of 1-3-dibromopropane (12 mL, 0.12 mol) in methanol (30 mL). The resulting solution was refluxed for 3 hours and then cooled to room temperature. After standing overnight, the reaction was quenched by pouring it into ice water. After adjusting to pH 1 with concentrated HCl, the aqueous solution was extracted with EtOAc (0.2 L then 2 x 0.1 L). The combined organic layers were washed with water, brine, dried over anhydrous MgSO 4, filtered and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound. 1 H NMR (CDCl 3): d 7.25-7.32 (m, 2H), 7.15 (dd, 1 H, J = 8.1, 1.8 Hz), 3.71 (s, 3H), 3.57 (s, 2H), 3.55 (t, 2H) , J = 7.7 Hz), 3.10 (t, 2H, J = 7.7 Hz), 2.18 (m, 2H).

Step B: Preparation of methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) 3-chlorophenylacetate A solution of 4- (3-bromopropoxy) -3-propylphenyl phenyl ether (2.5 g, 7.18 mmol) ), Methyl 3-chloro-4-hydroxyphenylacetate (1.42 g, 7.1 1 mmol) and cesium carbonate (2.43 g, 7.45 mmol) in DMF (20 mL) was stirred at 40 ° C overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound. 1 H NMR (400MHz, CDCl 3): d 7.24-7.29 (m, 3H), 7.10 (dd, 1 H, J = 8.4, 2.1 Hz), 7.00 (t, 1 H, J = 7.3 Hz), 6.92-6.80 ( m, 6H), 4.22 (t, 2H, J = 6.1 Hz), 4.16 (t, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.30 (quint, 2H, J = 6.3 Hz), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5-l4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) -3-chlorophenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) -3-chlorophenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.60 (brs, 1 H), 7.42 (d, 1 H, J = 2.3 Hz), 7.29-7.23 (m, 3H), 7.02-6.80 (m, 7H), 5.27 ( s, 1 H), 4.24 (t, 2H, J = 6.1 Hz), 4. 15 (t, 2H, J = 6.0 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.30 (quint, 2H, J = 6.3 Hz), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

EXAMPLE 15 5-r4- 3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-chlorophenin-2,4-thiazolidinedione Step A: Preparation of 4- (3-bromobutoxy) -3-propylphenyl phenyl ether A solution of 4-phenoxy-2-propylphenol (25.0 g, 0.11 mol), 1-4-dibromobutane (70.99 g, 0.33 mol) and carbonate of cesium (39.28 g, 0.12 moles) in dry DMF (250 mL) was stirred at room temperature overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with methylene chloride / hexane (1: 1) to obtain the title compound.

Step B: Preparation of Methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) 3-chlorophenylacetate A solution of 4- (4-bromobutoxy) -3-propylphenyl phenyl ether (5.7 g, 15.75 mmole), methyl 3-chloro-4-hydroxyphenylacetate (3.0 g, 15.00 mmole) and cesium carbonate (5.38 g, 16.50 mmole) in DMF (50 mL) was stirred at 40 ° C overnight. The reaction mixture was separated between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with 10% ethyl acetate in hexane to obtain the title compound. 1 H NMR (400MHz, CDCl 3): d 7.28-7.24 (m, 3H), 7.10 (dd, 1 H, J = 8.4, 2.2 Hz), 7.02-6.98 (m, 1 H), 6.92-6.76 (m, 6H ), 4.09 (t, 2H, J = 5.7 Hz), 4.01 (t, 2H, J = 5.8 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz ), 2.02 (m, 4H), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5-f4- (3- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenopyr-2,4-thiazolidinodone The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.12 (brs, 1 H), 7.42 (d, 1 H, J = 2.4 Hz), 7.28-7.23 (m, 3H), 7.02-6.75 (m, 7H), 5.28 (s, 1 H), 4.09 (t, 2H, J = 5.7 Hz), 4.03 (t, 2H, J = 5.8 Hz), 3.67 (s, 3H), 3.52 (s, 2H), 2.53 (t, 2H, J = 7.4 Hz), 2.02 (m, 4H), 1.55 (hex, 2H, 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz).

EXAMPLE 16 5-r4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenin-2,4-thiazolidinodone Step A: Preparation of Methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) 3-propylphenylacetate The title compound was prepared according to the method described in Example 15, Step A, using Methyl 3-propyl-4-hydroxy-phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.31-7.25 (m, 2H), 7.07-6.80 (m, 9H), 4.02-4.00 (m, 4H), 3.67 (s, 3H), 3.55 (s, 2H), 2.61-2.53 (m, 4H), 2.03-1.98 (m, 4H), 1.68-1.55 (m, 4H), 0.98-0.90 (m, 6H).

Step B: Preparation of 5- [4- (4- (2-propyl-4-phenoxyphenoxy) butox0-3-propylphenp-2,4-thiazolidinedione The title compound was prepared according to the method described in the example 1, step C, using 4- (4- (2-propyl-4- methyl phenoxyphenoxy) butoxy) -3-propylphenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.14 (brs, 1 H), 7.29-7.24 (m, 2H), 7.19-6.12 (m, 2H), 7.02-6.90 (m, 1 H), 6.84-6.75 (m , 6H), 5.30 (s, 1 H), 4.02-4.00 (m, 4H), 3.67 (s, 3H), 3.55 (s, 2H), 2.61-2.53 (m, 4H), 2.03-1.98 (m, 4H), 1.68-1.55 (m, 4H), 0.98-0.90 (m, 6H).

EXAMPLE 17 5-r4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) pheny1-2.4-thiazolidinedione Step A: Preparation of methyl 4- (4- (2-propyl-4-phenoxyphenoxy) -butoxy-phenylacetate The title compound was prepared according to the method described in example 15, step A, using methyl 4-hydroxyphenylacetate as the starting material. 1H NMR (400MHz, CDCI3): d 7.32-7.23 (m, 5H), 7.02-6.76 (m, 7H), 4.02-4.00 (m, 4H), 2.54 (t, 2H, J = 6.4 Hz), 2.01-1.94 (m, 4H), 1.56 (hex, 2H, J = 6.7 Hz), 0.90 (t, 3H, J = 7.4 Hz).

Step B Preparation of 5-r4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenylH-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.01 (brs, 1 H), 7.32-7.23 (m, 5H), 7.02-6.76 (m, 7H), 5.32 (s, 1 H), 4.02-4.00 (m, 4H ), 2.54 (t, 2H, J = 6.4 Hz), 2.01-1.94 (m, 4H), 1.56 (hex, 2H, J = 6.7 Hz), 0.90 (t, 3H, J = 7.4 Hz).

EXAMPLE 18 5-r 3 - (3- (2-propyl-4-phenoxyphenoxy) butoxy) phenyl-2,4-thiazolidinedione Step Preparation of methyl 3- (3- (2-propyl-4-phenoxyphenoxpropropoxyphenylacetate) The title compound was prepared according to the method described in example 11, step B, using methyl 3-hydroxyphenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.29-7.19 (m, 3H), 7.01-6.72 (m, 9H), 4.16 (t, 2H, J = 6.2 Hz), 4.11 (t, 2H, J = 6.1 Hz) , 3.67 (s, 3H), 3.57 (s, 2H), 2. 55 (t, 2H, J = 6.2 Hz), 2.27 (quint, 2H, J = 6.3 Hz), 1.56 (hex, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.3 Hz).

Step B: Preparation of 5-r3- (3- (2-propy! -4-phenoxyphenoxy) propoxyphenyl] -2,4-thiazolidinedione The title compound was prepared according to the method described in example 1, step C, using methyl 3- (3- (2-propyl-4-phenoxyphenoxy) propoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.48 (brs, 1 H), 7.32-7.24 (m , 3H), 7.02-6.79 (m, 9H), 5.30 (s, 1 H), 4.16 (t, 2H, J = 6.2 Hz), 4.1 1 (t, 2H, J = 6.1 Hz), 3.67 (s, 3H), 3.57 (s, 2H), 2.55 (t, 2H, J = 6.2 Hz), 2.27 (quint, 2H, J = 6.3 Hz), 1.56 (hex, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.3 Hz).

EXAMPLE 19 5-r 3 - (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenin-2,4-thiazolidinodone Step A: Preparation of methyl 3- (4- (2-propyl-4-phenoxyphenoxybutoxy) phenylacetate The title compound was prepared according to the method described in example 15, step A, using methyl 3-hydroxyphenylacetate as the material of 1 H NMR (400MHz, CDCl 3): d 7.31-7.22 (m, 5H), 7.01-6.76 (m, 7H), 4.01-4.00 (m, 4H), 2.54 (t, 2H, J = 6.4 Hz), 2.00-1.94 (m, 4H), 1.55 (hex, 2H, J = 6.7 Hz), 0.91 (t, 3H, J = 7.4 Hz).

Step B: Preparation of 5-33- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenyl1-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1 , step C, using methyl 3- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.93 (brs, 1 H), 7.31-7.22 (m, 5H), 7.00-6.75 (m, 7H), 5.31 (s, 1 H), 4.02-4.00 (m, 4H ), 2.53 (t, 2H, J = 6.4 Hz), 2.01-1.93 (m, 4H), 1.55 (hex, 2H, J = 6.7 Hz), 0.91 (t, 3H, J = 7.4 Hz).

EXAMPLE 20 5-r 3 - (3- (2-propyl-4-phenoxyphenoxy) propoxy) phenin-2,4-tlazolidinedione Step A: Preparation of 3- (3- (2-propyl-4-phenoxyfenoxy) propoxymethyl methacrylate A solution of methyl 3-hydroxymandelate (253 mg, 1.39 mmol), ether 4- (3-bromopropoxy) -3 phenylpropylphenyl (500 mg, 1.44 mmol) and cesium carbonate (475 mg, 1.46 mmol) in dry DMF (5 mL) was stirred at room temperature overnight.The reaction mixture was separated between ethyl acetate and 0.2N. HCl The organic layer was washed twice with water, and then dried over sodium sulfate The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with methylene chloride / hexane (1: 1). ) to obtain the title compound.1H NMR (400MHz, CDCl3): d 7.29-7.24 (m, 3H), 7.03-6.79 (m, 9H), 5.12 (d, 1 H, J = 5.7 Hz), 4.18 ( t, 2H, J = 6.2 Hz), 4.13 (t, 2H, J = 6.1 Hz), 3.40 (d, 1 H, J = 5.7 Hz), 2.55 (t, 2H, J = 6.2 Hz), 2.27 (quint , 2H, J = 6.3 Hz), 1.56 (hex, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.3 Hz).

Step B Preparation of 5- [3- (3- (2-propyl-4-phenoxyphenoxy) propoxyphenyl] -1- 2,4-oxazo! Idinodione A solution of 3- (3- (2-propyl-4-phenoxyphenoxy) methyl propoxy) mandelate (194 mg), urea (39 mg) and sodium methoxide (0.90 mL, 0.5 M) were refluxed overnight.The reaction mixture was divided between ethyl acetate and water. it was washed twice with water, dried over sodium sulfate, filtered and evaporated to an oil which was subjected to chromatography on silica gel with 3% methanol in methylene chloride to obtain the title compound.1H NMR (400MHz , CDCI3): d 7.34 (t, 1 H, J = 7.6 Hz), 7.30-7.24 (m, 2H), 7.03-6.79 (m, 9H), 5.74 (s, 1 H), 4.18 (t, 2H, J = 6.2 Hz), 4.13 (t, 2H, J = 6.1 Hz), 2.55 (t, 2H, J = 6.2 Hz), 2.27 (quint, 2H, J = 6.3 Hz), 1.56 (hex, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.3 Hz).

EXAMPLE 21 5-r4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) fenip-2,4-oxazolidinedione Step A: Preparation of 4- (3- (2-propyl-4-phenoxyphenoxy) Propoxyl Ethyldemandetate The title compound was prepared according to the method described in Example 20, step A, using ethyl 4-hydroxymandetate as the 1 H NMR (400MHz, CDCl 3): d 7.32-7.24 (m, 5H), 7.01 (t, 1 H, J = 7.4 Hz), 6.92-6.79 (m, 6H), 5.03 (d, 1 H, J = 5.7 Hz), 4.26 (quart, 2H, J = 7.4 Hz), 4.18 (t, 2H, J = 6.2 Hz), 4.13 (t, 2H, J = 6.1 Hz), 3.36 (d, 1 H, J = 5.7 Hz), 2.55 (t, 2H, J = 6.2 Hz), 2.27 (quint, 2H, J = 6.3 Hz), 1.56 (hex, 2H, J = 7.2 Hz), 1.21 (t, 3H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.3 Hz).

Step Bj Preparation of 5-r4- (3- (2-propyl-4-phenoxyphenoxpropoxQfenip-2,4-oxazolidinedione The title compound was prepared according to the method described in Example 20, Step B, using 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) ethyl mandelate as the starting material. 1 H NMR (400MHz, CDCl 3): d 7.32-7.24 (m, 5H), 7.01 (t, 1 H, J = 7.4 Hz), 6.92-6.79 (m, 6H), 5.74 (s, 1 H), 4.18 (t, 2H, J = 6.2 Hz), 4.13 (t, 2H, J = 6.1 Hz), 2.55 (t, 2H) , J = 6.2 Hz), 2.27 (quint, 2H, J = 6.3 Hz), 1.56 (hex, 2H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.3 Hz).

EXAMPLE 22 5-r 4 - (3- (2-propyl-4- (4'-methylsulfonyl) phenoxy-phenoxyproxy) phenyl-2,4-thiazolindinodione Step A: Preparation of 2-propyl-4- (4'-methylsulfonyl) phenoxyphenol A solution of hydroquinone (33.00 g, 0.30 mole) and potassium carbonate (45.6 g, 0.33 mole) in dry DMF (250 mL) was stirred at 40 ° C for 30 minutes. Allyl bromide (5.20 mL, 0.06 mol) was added and the reaction was stirred overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with hexane / ethyl acetate (4: 1) to obtain 4-allyloxyphenol. 1 H NMR (400MHz, CDCl 3): d 6.74 (dd, 4H, J = 9.0 Hz, 12.5 Hz), 6.03 (m, 1 H), 5.37 (dd, 1 H, J = 1.3 Hz, 15.7 Hz), 5.25 ( dd, 1 H, J = 1.3 Hz, 9.0 Hz), 4.64 (s broad, 1 H), 4.46 (d, 2H, J = 5.3 Hz). A solution of 4-allyloxyphenol (4.3 g, 28.70 mmol), 4-fluorophenylmethylsulfone (5.00 g, 28.70 mmol) and potassium carbonate (4.8 g, 34. 45 mmol) in dry N, N-dimethylacetamide (50 mL) was heated to reflux overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with hexane / ethyl acetate (5: 1) to obtain 4- (4'-methylsulfonyl) -phenoxyphenyl allyl ether. 1 H NMR (400 MHz, CDCl 3): d 7.84 (d, 2 H, J = 8.9 Hz), 7.00 (m, 6 H), 6.08 (m, 1 H), 5.44 (dd, 1 H, J = 1.5 Hz, 15.5 Hz ), 5.31 (dd, 1 H, J = 1.4 Hz, 8.8 Hz), 4.45 (d, 2H, J = 5.6 Hz), 3.02 (s, 3H). A solution of 4 - ((4'-methylsulfonyl) -phenoxy) phenyl allyl ether (5.20 g, 0.12 mol), in dry 1,2-dichlorobenzene was heated at 180 ° C overnight. After removing the solvent in vacuo, the residue was chromatographed on silica gel with hexane / ethyl acetate (4: 1) to give 2-allyl-4- (4'-methylsulfonyl) phenoxyphenol. 1 H NMR (400 MHz, CDCl 3): d 7.84 (d, 2 H, J = 8.9 Hz), 7.34 (s, 1 H), 7. 01 (dd, 2H, J = 9.8 Hz, 2.0 Hz), 6.84 (d, 2H, J = 2.2 Hz), 5.97 (m, 1 H), 5.18 (d, 1 H, J = 1.4 Hz), 5.15 ( dd, 1 H, J = 1.5 Hz, 5.8 Hz), 4.93 (s, 1 H), 3.38 (d, 2H, J = 6.5 Hz), 3.02 (s, 3H). A solution of 2-allyl-4- (4'-methylsulfonyl) phenoxyphenol (3.8 g, 12.40 mmol) and 5% palladium on carbon (1.2 g) in ethyl acetate (50 mL) was stirred at room temperature under an hydrogen for 3 hours. The reaction was filtered through celite, passed through a short pad of silica gel and concentrated in vacuo, to an oil obtain 2-propyl-4- (4'-methylsulfonyl) phenoxyphenol which was used without further purification. 1 H NMR (400 MHz, CDCl 3): d 7.86 (d, 2 H, J = 8.9 Hz), 7.02 (d, 2 H, J = 9.9 Hz), 6.84 (s, 1 H), 6.78 (d, 2 H, J = 1.0 Hz), 4.73 (s, 1 H), 3.02 (s, 3H), 2.56 (t, 2H, J = 9.9 Hz), 1.62 (quint, 2H, J = 7.5 Hz), 0.95 (t, 3H, J = 7.5Hz).

Step B: Preparation of Ethyl 4- (3-bromopropoxy) mandelate A solution of ethyl 4-hydroxymandelate (19.6 g, 0.1 mole), 1,3-dibromopropane (60.75 g, 0.3 mole) and cesium carbonate (35.75 g) , 0.1 1 mole) in dry DMF (200 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.1 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel, using a gradient of 100% hexane to methylene chloride / hexane (2: 1) to obtain the title compound. 1 H NMR (400MHz, CDCl 3): d 7.30 (m, 2H); 6.86 (m, 2H); 5.82 (d, 1 H, J = 5.6 Hz); 4.2 (m, 2H); 4.08 (t, 3H, J = 5.6 Hz); 3.58 (t, 2H, J = 0.016 ppm); 3.37 (d, 1 H, J = 5.6 Hz); 2.29 (m, 2H); 1.21 (t, 3H, J = 7.2 Hz).

Step C: Preparation of 4- (3- (2-propyl-4- (4'-methylsulfonyl) phenoxy-phenoxypropoxyl Ethyldemandelate A solution of (2-propyl-4- (4'-methylsulfonyl) phenoxyphenol (19.0 g, 62. 0 mmol) (as prepared in step A), potassium carbonate (9.4 g, 68.2 mmol) and DMF (100 mL) was stirred at 40 ° C for 0.5 hour. Then 4- (3-bromopropoxy) ethyl mandelate (19.5 g, 58.9 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and 0.1 N HCl. The organic layer was washed twice with water, once with brine and then dried over sodium sulfate. The organic layer was filtered and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel, using acetate / hexane / methylene chloride (1: 4: 5) to obtain the title compound. 1 H NMR (400MHz, CDCl 3): d 7.30 (m, 2H); 6.86 (m, 2H); 5.82 (d, 1 H, J = 5.6 Hz); 4.2 (m, 2H); 4.08 (t, 3H, J = 5.6 Hz); 3.58 (t, 2H, J = 6.4 Hz); 3.37 (d, 1 H, J = 5.6 Hz); 2.29 (m, 2H); 1.21 (t, 3H, J = 7.2 Hz).

Step D: Preparation of a-chloro-4- (3- (2-propyl-4- (4'-methylsulfonyOfenoxOfenoxQpropoxOphenylacetate ethyl) To a solution of 4- (3- (2-propyl-4- (4'-methylsulfonyl) phenoxy-phenoxyproxy) ethyl mandelate from step C (16.8 g, 30.18 mmol), pyridine (2.95 mL, 36.51 mmol) and toluene (160 mL) was added thionyl chloride (2.88 mL, 39.54 mmol). it was stirred overnight and then partitioned between ethyl acetate and water.The organic layer was washed twice with water, once with brine, dried over sodium sulfate and filtered.The solvent was removed under vacuum and the oil The resultant was filtered through a silica pad, using acetone / hexane (1: 4) to obtain the compound of the title. 1 H NMR (400MHz, CDCl 3): d 7.86 (m, 2H); 7.35 (m, 2H); 7.03 (m, 2H); 6.92 (m, 2H); 6.87 (bs, 3H); 5.12 (bs, 1 H); 4.2 (m, 6H); 3.05 (s, 3H); 2.59 (t, 2H, J = 7.6 Hz); 2.31 (m, 2H); 1.60 (m, 3H); 1.25 (m, 3H); 0.93 (t, 3H, J = 7.2 Hz).

Step E: Preparation of 5-r4- (3- (2-propyl-4- (4'-methylsulfonyl) phenoxy) phenoxy) propoxy) phenyl-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C (second paragraph), using ethyl a-chloro-4- (3- (2-propyl-4- (4'-methylsulfonylphenoxy) phenoxy) propoxy) phenol acetate as the starting material. H NMR (400MHz, CDCl 3): d 8.18 (broad s, 1 H), 7.84 (d, 2H, J = 8.9 Hz), 7.35 (d, 2H, J = 8.7 Hz), 6.99 (t, 2H, J = 8.7 Hz), 6.92 (d, 2H, J = 9.8 Hz), 6.84 (s, 3H), 5.35 (s, 1 H), 4.12 (t, 2H, J = 6.6 Hz), 4.08 (t, 2H, J = 6.3 Hz), 3. 02 (s, 3H), 2.57 (t, 2H, 7.5 Hz), 2.28 (q, 2H, J = 6.4 Hz), 1.57 (hex, 2H, 5.8) Hz), 0.91 (t, 3H, J = 7.5 Hz).

EXAMPLE 23 5-r 4 - (3- (2-propyl-4- (4'-methylphenoxy) phenoxypropoxy) phenyl-2,4-thiazole dionenedione Step A: Preparation of 2-propyl-4- (4'-methylphenoxy) phenol A solution of 4-methylphenol (4.52 g, 40.29 moles), 4-fluoro-benzaldehyde (5.00 g, 40.29 mmoles) and potassium carbonate (6.70) g, 48.35 mmoles) in dimethylacetamide (40 mL) was refluxed for 12 hours and cooled to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give an oil which was chromatographed on silica gel (15% ethyl acetate / hexane) to obtain 4- (4'-methylphenoxy). benzaldehyde. A solution of 4- (4'-methylphenoxy) benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chlorobenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 hours. hours at room temperature. The reaction was washed with saturated aqueous NaHSO3, saturated aqueous NaHCO3, and water. The organic layer was concentrated and the residual oil was taken up in MeOH (10 mL) containing a few drops of concentrated HCL and stirred for 1 hour at room temperature. The solvent was removed under vacuum and the The resulting oil was chromatographed on silica gel (20% ethyl acetate / hexane) to obtain 4- (4'-methylphenoxy) phenol. A solution of 4- (4'-methylphenoxy) phenol ether (4.75 g, 23.30 mmol), potassium carbonate (4.17 g, 30.30 mmol) and aiyl bromide (2.22 mL, 25.60 mmol) in dry DMF (50 mL) were added. stirred at 60 ° C for 5 hours. After cooling, the reaction mixture was neutralized with 1 N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to give an oil which was chromatographed on silica gel with (15% ethyl acetate / hexane) to give ether 4- (4 ') -methyphenoxy) allylic fenii. 4- (4'-Methylphenoxy) phenyl allyl ether (4.0 g, 16.37 mmol) was taken up in 1,2-dichlorobenzene (50 mL) and refluxed for 20 hours. After cooling, the solvent was removed in vacuo and the resulting crude oil was chromatographed on silica gel (15% ethyl acetate / hexane) to obtain 4- (4'-methylphenoxy) -2-allylphenol. A solution of 4- (4'-methylphenoxy) -2-amino-phenol (2.30 g, 9.42 mmol) and 5% Pd / c (0.90 g) in ethyl acetate (30 mL) was stirred at room temperature under H2 atmosphere for 3 hours. The reaction mixture was filtered through a short pad of silica gel and concentrated in vacuo, to obtain the title of the compound, which was used as such. H NMR (400MHz, CDCl 3): d 7.19 (d, 2H), 6.86 (d, 1 H), 6.83 (dd, 2H), 6.72 (d, 2H), 4.61 (s, 1 H), 2.53 (t, 2H), 2.28 (s, 3H), 1.61 (hex, 2H), 0.96 (t, 3H).

Step Bj Preparation of methyl 4- (3- (2-propyl-4- (4'-methy! Phenoxy) phenoxy) propoxyphenylacetate The title compound was prepared according to the method described in example 1, step B, using 2-propy! -4- (4'-methylphenoxy) phenol (19.5 g, 62.0 mmol) and methyl 4- (3-bromopropoxy) phenylacetate (19.5 g, 58.9 mmol) (example 1, step A) as the materials of 1 H NMR (400MHz, CDCl 3): d 7.18 (d, 2H), 7.07 (d, 2H), 6.85 (m, 5H), 6.76 (d, 1 H), 6.70 (d, 1 H), 5.33 (d. s, 1 H), 4.15 (t, 2H), 4.10 (t, 2H), 3.67 (s, 3H), 3.55 (s, 2H), 2.53 (t, 2H), 2.28 (s, 3H), 2.25 ( quint, 5H), 1.59 (hex, 2H), 0.89 (t, 3H).

Step C: Preparation of 5-r4- (3- (2-propyl-4- (4'-methylphenoxy) -phenoxy) propoxy) phenan-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (2-propyl-4- (4'-methylphenoxy) phenoxy) propoxy) phenylacetate (19.5 g, 58.9 mmol) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.32 (broad s, 1 H), 7.32 (d, 2 H); 7. 09 (d, 2H); 6.94 (d, 2H); 6.85 (d, 2H); 6.83 (d, 1 H), 6.77 (dd, 2H), 5.33 (s, 1 H); 4.05 (t, 2H); 4.00 (t, 2H); 2.55 (t, 2H); 2.31 (s, 3H), 2.00 (quint, 2H), 1.59 (hex, 2H), 0.93 (t, 3H).

EXAMPLE 24 5-r4- (3- (2-propyl-4- (4'-chlorophenoxy) phenoxy) propoxy) phenan-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-chlorophenol instead of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 8.19 (broad s) , 1 H), 7.33 (d, 2H), 7. 22 (d, 2H), 6.93 (d, 2H), 6.85 (d, 1 H), 6.84 (d, 2H), 6.80 (dd, 2H), 5.32 (s, 1 H), 4.18 (t, 2H) , 4.11 (t, 2H), 2.54 (t, 2H), 2.37 (quint, 2H), 1.55 (hex, 2H), 0. 89 (t, 3H).

EXAMPLE 25 5-r4-f3- (2-propyl-4-f4'-phenyl) phenoxy) phenoxy) propoxy) phenyl-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-phenylphenol instead of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 8.01 (broad s) , 1 H), 7.54 (d, 2H), 7. 50 (d, 2H), 7.40 (t, 2H), 7.32 (d, 2H), 7.31 (t, 1 H), 6.98 (d, 2H), 6.91 (d, 2H), 6.98 (d, 1 H) , 6.85 (dd, 1 H), 6.87 (d, 1 H), 5.28 (s, 1 H), 4.05 (t, 2H), 4.00 (t, 2H), 2. 56 (t, 2H), 1.99 (quint, 2H), 1.59 (hex, 2H), 0.92 (t, 3H).

EXAMPLE 26 5-r 3 - (3- (2-propyl-4'-methoxy-phenoxy) propoxy) -phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-methoxyphenol instead of 4-methylphenol as the starting material in step A and methyl 3- (3-bromopropoxy) phenylacetate instead of Methyl 4- (3-bromopropoxy) phenylacetate in step B. 1 H NMR (400MHz, CDCl 3): d 8.09 (broad s, 1 H), 7.31 (t, 1 H), 7.23 (m, 1 H), 7.25 (dd, 1 H), 6.95 (d, 1 H), 6.89 (d, 2H), 6.83 (d, 2H), 6.78 (d, 1 H), 6.75 (d, 1 H), 6.72 (dd, 1 H), 5.31 (s, 1 H), 4.17 (t, 2H), 4.10 (t, 2H), 3.77 (s, 3H), 2.52 (t, 2H), 2.26 (quint, 2H), 1.54 (hex, 2H), 0.88 (t, 3H).

EXAMPLE 27 S-rS ^ S-fS-propiM ^ '- fluorofenoxDfenoxppropoxDfenin ^^ - thiazolidinedione The title compound was prepared according to the method described in Example 26, using 4-fluorophenol instead of 4-methoxyphenol as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.01 (broad s, 1 H), 7.54 (d, 2 H), 7.49 (d, 2 H), 7.40 (t, 1 H), 7.31 (d, 1 H), 7.29 ( d, 1 H), 6.95 (d overlap, 2H), 6.87 (d, 1 H), 6.85 (dd, 1 H), 5.32 (s, 1 H), 4.21 (t, 2H), 4.15 (t, 2H) ), 2.56 (t, 2H), 2. 29 (quint, 2H), 1.57 (hex, 2H), 0.90 (t, 3H).

EXAMPLE 28 5-r4- 4- (2-propyl-4-phenoxyphenoxy) butyl) phen-2,4-thiazolidinedione Step A: Preparation of methyl 4-bromophenylacetate A solution of 4-bromophenylacetic acid (10.0 g, 46.5 mmol), in methanol (125 mL) and sulfuric acid (5 mL) was heated to reflux overnight. The reaction mixture was concentrated and partitioned between ethyl ether and saturated aqueous sodium bicarbonate. The organic layer was washed with water and brine, and then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil to obtain the title compound. H NMR (400MHz, CDCl 3): d 7.42 (d, 2H, J = 8.3 Hz), 7.13 (d, 2H, J = 8.3 Hz), 3.67 (s, 3H), 3.56 (s, 2H).

Step B: Preparation of methyl (4- (4-hydroxyl-1-butyl) phenylacetate A solution of the product from step A (1.45 g, 6.35 mmol), 1- hydroxy-3-butyne (0.89 g, 12.7 mmol), tetrakis (triphenylphosphine) -palladium (0) (0.239 g, 4 mol%), copper bromide (I) (0.109 g, 12 mol%) in triethylamine (12.5 mL) ) was purged with nitrogen and heated to reflux for 1 hour. The reaction mixture was concentrated and partitioned between ethyl ether and saturated aqueous ammonium chloride. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with chloroform / ethyl acetate (10: 1) to give the title compound. 1 H NMR (400MHz, CDCl 3): d 7.34 (d, 2H, J = 8.3 Hz), 7.12 (d, 2H, J = 8.3 Hz), 3.79 (t, 2H, J = 6.2 Hz), 3.67 (s, 2H ), 3.59 (s, 3H), 2.67 (t, 2H, J = 6.2 Hz).

Step C: Preparation of methyl (4- (4-hydroxybutyl) phenylacetate A solution of the product from step B (1.38 g, 6.35 mmol) in ethanol (25 mL) was degassed and purged with nitrogen, palladium on carbon was added (10%), the reaction mixture was degassed and purged with hydrogen The mixture was stirred under hydrogen at room temperature for 2 hours and filtered through celite The filtrate was evaporated to give the title compound. NMR (400MHz, CDCI3): d 7.13-7.18 (m, 4H), 3.62-3.66 (m, 5H), 3.57 (s, 2H), 2.60 (t, 2H, J = 7.2 Hz), 1.59-1.68 (m, 4H), 1.40 (brs, 1 H).

Step D: Preparation of methyl (4- (4- (2-propyl-4-phenoxy-phenoxy-buty-phenylacetate) A solution of the product from step C (0.395 g, 1.80 mmol), methanesulfonic anhydride (0.470 g, 2.70 mmol), 4- (dimethylamino) -pyridine (0.001 g, catalytic amount) and pyridine (0.267 mL, 2.70 mmol) in methylene chloride (2 mL) was stirred at room temperature for 1 hour.The reaction mixture was concentrated, diluted with acetate ethyl acetate and washed twice with water and brine The organic layer was dried over sodium sulfate, filtered and evaporated to an oil.The residual oil was added to a reaction mixture containing 4-phenoxy-2-propylphenol ( 0.483 g, 2.12 mmol), and cesium carbonate (0.749 g, 2.30 mmol) in DMF (2 mL) The resulting mixture was stirred at 60 ° C overnight.The reaction mixture was partitioned between ethyl acetate and 0.45. M citric acid The organic layer was washed once with water, brine and dried over sodium sulfate The organic layer was filtered and evaporated to an oil which was chromatographed on silica gel with toluene / hexane (1: 1) to give the title compound. 1 H NMR (400MHz, CDCl 3): d 7.27-7.18 (m, 7H), 6.92-6.75 (m, 5H), 3.93 (brs, 2H), 3.67 (s, 3H), 3.58 (s, 2H), 2.67 ( brs, 2H), 2.54 (t, 2H, J = 7.3Hz), 1.81 (brs, 4H), 1.56 (m, 2H), 0.90 (t, 3H, J = 7.3Hz).

Step E: Preparation of 5-r4- (4- (2-propyl-4-phenoxy-phenoxy) butyl) phenyl1-2,4-thiazolidinedione The title compound was prepared according to the method described in example 1, step C, using methyl 4- (4- (2-propyl) -4-phenoxy-phenoxy) butyl) phenylacetate as the starting material. 1 H NMR (400MHz, CDCl 3): d 8.24 (brs, 1 H), 7.34-7.22 (m, 6H), 6.92-6.75 (m, 6H), 5.34 (s, 1 H), 3.93 (brs, 2H), 2.69 (brs, 2H), 2.52 (t, 2H, J = 7.4 Hz), 1.82 (brs, 4H), 1.57 (quint, 2H, 7.5 Hz), 0.90 (t, 3H, J = 7.3 Hz).

EXAMPLE 29 5-r 4 - (4- (2-propyl-4- (4'-methoxyphenoxy) phenoxy) butyl) phenylene-2,4-thiazole dinodone The title compound was prepared according to the method described in Example 28, using 2-propyl-4- (4'-methoxyphenoxy) phenol instead of 2-propyl-4-phenoxyphenol as the starting material in step D 1 H NMR (400 MHz, CDCl 3): d 7.98 (brs, 1 H), 7.34 (m, 2 H), 7.24 (m, 3 H), 6.71-6.90 (m, 6 H), 5.34 (s, 1 H), 3.91 (brs, 2H), 3.77 (s, 3H), 2.69 (brs, 2H), 2.52 (t, 2H, J = 7.3 Hz), 1.81 (brs, 4H), 1.57 (m, 2H), 0.89 (t, 3H, J = 7.3 Hz).

CI-MS m / e = 528.3 (M + Na) EXAMPLE 30 5-r 4 - (4- (2-propyl-4- (4'-chlorophenoxy) phenoxy) butyl) phen-2,4-thiazolidinedona The title compound was prepared according to the method described in Example 28, using 2-propyl-4- (4'-chlorophenoxy) phenol in place of 2-propyl-4-phenoxyphenol as starting materials in step D. 1 H NMR (400 MHz, CDCl 3): d 7.98 (brs, 1 H), 7.32 (m, 2 H), 7.19 (m, 3 H), 6.75-6.84 (m, 6 H), 5.35 (s, 1 H), 3.93 (brs, 2H), 2.69 (brs, 2H), 2.54 (t, 2H, J = 7.6 Hz), 1.81 (brs, 4H), 1.55 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz) . CI-MS m / e = 532.2 (M + Na) EXAMPLE 31 5-r 3 - (4- (2-propyl- - (4'-chlorophenoxy) phenoxy) butphenyl-2,4-thiazoiidinodone The title compound was prepared in accordance with the method described in Example 28, using methyl (3-bromo) phenylacetate in place of methyl (4-bromo) phenylacetate as the starting material in step B and 2-propyl. 4- (4'-chlorophenoxyphenol in place of 2-propyl-4-phenoxy phenol as starting material in step D. 1 H NMR (400 MHz, CDCl 3): d 8.20 (brs, 1 H), 7.32-7.20 ( m, 5H), 6.85-6.75 (m, 6H), 5.33 (s, 1 H), 3.93 (brs, 2H), 2.70 (brs, 2H), 2.54 (t, 2H, J = 7.6 Hz), 1.81 ( brs, 4H), 1.55 (m, 2H), 0.90 (t, 3H, J = 7.3 Hz) CI-MS m / e = 532.2 (M + Na) EXAMPLE 32 5-r3- (5- (2-propyl-4-phenoxy-phenoxy) pentyl) phenylH-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 28, using methyl 3-bromophenylacetate instead of methyl 4-bromophenylacetate and 4-pentyin-1-ol instead of 3-butyn-1-ol as starting material in step B. H NMR (400 MHz, CDCl 3): d 8.1 1 (brs, 1 H), 7.32- 7.22 (m, 6H), 7.21-6.7 (m, 6H), 5.33 (s, 1 H), 3.91 (t, 2H, 6.3 Hz), 2.65 (t, 2H, 7.6 Hz), 2.52 (t, 2H), 1.83-1.50 (m, 8H), 0.89 (t, 3H, 7.3 Hz).

CI-MS: m / e = 490.3 (M + 1) EXAMPLE 33 5-r 3 - (5- (2-propyl-4,4'-methoxyphenoxy) phenoxy) pentyl) phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 28, using methyl 3-bromophenylacetate instead of methyl 4-bromophenylacetate and 4-pentyin-1-ol instead of 3-butyn-1-ol as starting materials in step B, and 2-propyl-4- (4'-methoxyphenoxy) -phenol in place of 2-propyl-4-phenoxyphenol as starting material in step D. 1 H NMR (400 MHz, CDCl 3) : d 8.19 (brs, 1 H), 7.34 (m, 1 H), 7.21 (m, 3H), 6.9-6.71 (m, 7H), 5.3 (s, 1 H), 3.91 (t, 2H, J = 6.3 Hz), 3.76 (s, 3H), 2.64 (t, 2H, J = 7.6 Hz), 1.81-1.59 (m, 8H), 0.89 (t, 3H, J = 7.3 Hz). CI-MS: m / e = 519.3 (M +) EXAMPLE 34 5-r3- (5- (2-propyl-4- (4'-fluorophenoxy) phenoxy) pentipfenin-2,4-thiazolidonendone The title compound was prepared according to the method described in Example 28, using methyl 3-bromophenylacetate instead of methyl 4-bromophenylacetate and 4-pentyin-1-ol instead of 3-butyn-1-oi as starting materials in step B and 2-propyl-4- (4'-fluorophenoxy) phenol in place of 2-propyl-4-phenoxyphenol as starting material in step D. 1 H NMR (400 MHz, CDCl 3): d 8.33 (brs, 1 H), 7.34 (m, 1 H), 7.21 (m, 3H), 6.9-6.71 (m, 7H), 5.3 (s, 1 H), 3.90 (t, 2H, 6.3 Hz), 2.64 (t, 2H, 7.6 Hz), 2.51 (t, 2H, 7.6 Hz), 1.82-1.59 (m, 8H), 0.89 (t, 3H, 7.3 Hz). CI-MS: m / e = 507.2 (M +) EXAMPLE 35 5-r 3 - (5- (2-propyl-4- (4'-phenylphenoxy) phenoxy) pentoxyl) -phenin-2,4-thiazolidinedione Step A: Preparation of 5- (2-propyl-4- (4'-phenylphenoxy) phenyl) pentin-1-ol A solution of 4- (4 '- (phenylphenoxy) -2-propy1phenol (1.0 g, 3.30 mmol) Trifluoromethanesulfonic anhydride (0.832 mL, 4.95 mmol) and pyridine (0.400 mL, 4.95 mmol) in methylene chloride were stirred (0 ° C at room temperature) overnight.The reaction mixture was concentrated, diluted with ethyl acetate and it was washed twice with water and once with brine.The organic layer was dried over sodium sulfate, filtered and evaporated to an oil.A solution of residual oil (1.30 g, 3.03 mmol), 4-pentyl 1- ol (0.567ml, 6.1mmol), tetrakis (triphenylphosphine) palladium (0) (0.175g, 0.151mmol), in pyridine (3.0ml) was purged with nitrogen and heated at 80 ° C overnight. The mixture was concentrated and partitioned between ethyl acetate and saturated aqueous ammonia chloride, the organic layer was washed with water and brine, then dried over sodium sulfate. The organic phase was filtered and evaporated to an oil which was chromatographed on silica gel with toluene / ethyl acetate (10: 1) to give the title compound. 1 H NMR (400 MHz, CDCl 3): d 7.55 (m, 5 H), 7.41 (t, 2 H, J = 7.3 Hz), 7.32 (m, 2 H), 7.05 (m, 2 H), 6.78 (m, 1 H) , 3.82 (t, 2H, J = 6.1 Hz), 2.68 (t, 2H, J = 7.6 Hz), 2.55 (t, 2H, J = 6.9 Hz), 1.86 (t, 3H, J = 6.22 Hz), 1.62 (m, 2H), 0.94 (t, 3H, J = 7.3 Hz).

Step B: Preparation of 5- (2-propy! -4- (4'-phenylphenoxyphen!) Pentane! The title compound was prepared according to the method described in example 28, step C, using 5- (2- propyl-4- (4'-phenyphenoxy) -phenyl) pentin-1-ol as starting material: 1 H NMR (400 MHz, CDCl 3): d 7.55 (m, 5H), 7.41 (t, 2H, J = 7.3 Hz), 7.32 (m, 2H), 7.05 (m, 2H), 6.78 (m, 1 H), 3.65 (t, 2H, J = 6.5 Hz), 2.61-2.52 (m, 4H), 1.63-1.44 ( m, 8H), 0.95 (t, 3H, J = 7.3 Hz).

Step C: Preparation of methyl (3- (5- (2-propyl-4- (4'-phenylphenoxy) -phenyl) pentoxy) phenylacetate The title compound was prepared according to the method described in example 28, step D, using 5- (4- (4'-phenylphenoxy) -2-propy1phenyl) -1-pentanol and methyl 3-hydroxyphenylacetate as starting materials: 1 H NMR (400 MHz, CDCl 3): d 7.55 (m, 4H) , 7.42 (t, 2H, J = 7.3 Hz), 7.38 (m, 1 H), 7.02-7.1 1 (m, 4H), 6.79-6.86 (m, 5H), 3.95 (t, 2H, J = 6.4 Hz ), 3.67 (s, 3H), 3.57 (s, 2H), 2.60-2.53 (m 4H), 1.80 (m, 2H), 1.59-1.52 (m, 6H), 0.95 (t, 3H, J = 7.3 Hz ).

Step C: Preparation of 5-33- (5- (2-propyl-4- (4'-phenylphenoxy) -phenyipentoxy) phenyl-2,4-thiazole dinandiione The title compound was prepared in accordance with the method described in example 1, step C, using methyl (3- (5- (2-propyl-4- (4'-phenylphenoxy) phenyl) pentoxy) phenylacetate as starting materials. 1 H NMR (400 MHz, CDCl 3): d 7.55-7.51 (m, 5H), 7.50-7.38 (m, 2H), 7.29-7.24 (m, 1 H), 7.10-7.01 (m, 3H), 6.86-6.81 (m, 6H), 5.25 (s, 1 H), 3.95 (brs, 2H), 2.60-2.52 (m, 4H), 1.80 (m, 2H), 3.57 (s, 2H), 1.60-1.54 (m, 6H), 0.96 (t, 3H, 7.3 Hz). CI-MS m / e = 588.3 (M + Na) EXAMPLE 36 5-r4- (4- (2-propyl-4- (4'-methoxyphenoxy) phenyl) butoxy) phenyl-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 35, using 4- (4'-methoxyphenoxy) -2-propylphenol in place of 4- (4'-phenylphenoxy) -2-propylphenol as the starting material in step A, and 3-butin-1-ol in place of 4-pentin-1-ol as starting material in step A (second paragraph). 1 H NMR (400 MHz, CDCl 3): d 8.51 (brs, 1 H), 7.31 (d, 2 H), 7.24-6.74 (m, 9 H), 5.32 (s, 1 H), 3.96 (t, 2 H, 6.3 Hz), 3.78 (s, 3H), 2.61 (t, 2H), 2.51 (t, 2H), 2.02-1.59 (m, 6H), 0.92 (t, 3H, J = 7.3 Hz). CI-MS m / e = 505.6 (M +) EXAMPLE 37 5-r3- (4- (2-propyl-4- (4'-fioruophenoxy) phenyl) butoxy) phen-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 35, using 4- (4'-fluorophenoxy) -2-propylphenol in place of 4- (4'-phenylphenoxy) -2-propylphenol as starting materials in step A, and 3-butin-1-ol in place of 4-pentyl-1-ol as starting materials in step A (second paragraph). 1 H NMR (400MHz, CDCl 3): d 8.51 (brs, 1 H), 7.27 (t, 2H), 7.08-6.72 (m, 9H), 5.30 (s, 1 H), 3.97 (m, 2H,)), 2.63 (t, 2H), 2.52 (t, 2H), 1.85-1.54 (m, 6H), 0.92 (t, 3H, J = 7.3 Hz). CI-MS m / e = 517.2 (M + Na) EXAMPLE 38 5-r3- (5- (2-propyl-4- (4'-chlorophenoxy) fenippentoxy) phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 35, using 4- (4'-chlorophenoxy) -2-propylphenol in place of 4- (4-phenylphenoxy) -2-propylphenol as the starting material in the step A. 1 H NMR (400MHz, CDCl 3): d 8.07 (brs, 1 H), 7.31-6.71 (m, 1 1 H), 5.31 (s, 1 H), 3.96 (t, 2H), 3.78 (s, 3H), 2.61-2.51 (m, 4H)), 1.83 (m, 2H), 1.62-1.51 (m, 6H), 0.94 (t, 3H, J = 7.3 Hz). CI-MS m / e = 546.2 (M + Na) EXAMPLE 39 5-f3- (3- (2-propyl-4- (3'-methyl-4'-chlorophenoxy) phenoxy) propoxy) phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-chloro-3-methylphenol instead of 4-methylphenol as a starting material. 1 H NMR (400MHz, CDCl 3): d 8.04 (brs, 1 H), 7.35-7.20 (m, 4H), 7.02-6.67 (m, 6H), 5.32 (s, 3H), 4.19 (m, 4H), 2.55 (t, 2H, J = 7.4 Hz), 2.26 (quint, 2H, J = 6.3 Hz), 1.60 (hex, 2H, J = 5.6 Hz), 0.89 (t, 3H, J = 7.3 Hz). CI-MS: m / e = 544 (M + NH4) EXAMPLE 40 5-r4- (3- (2-propyl-4-f4'-isobutylfenoxy) -phenoxy) propoxy) phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-isobutylphenol instead of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 7.89 (brs, 1 H), 7.34 (d, 2H), 7.06 (d, 2H), 7.04-6.78 (m, 7H), 5.35 (s, 1 H) 4.2 (t, 2H) 4.16 (t, 2H), 2.54 (t, 2H, J = 7.4 Hz), 2.41 (d, 2H), 2.25 (t, 2H), 1.81 (m, 1 H) 1.57 (m, 4H), 1.23 (t, 3H, J = 7.3 Hz), 0.90 ( m, 9H). CI-MS: m / e = 533.35 (M +) EXAMPLE 41 5-r3- (3- (2-propyl- - (4'-cyclopentylphenoxy) phenoxy) propoxy) phenan-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-cyclopentyl phenol instead of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 9.79 (brs, 1 H), 7.39 (t, 1 H), 7.18 (d, 2H), 7.16-6.81 (m, 8H), 5.34 (s, 1 H), 4.21 (t, 2H, J = 6.2 Hz), 4.16 (t , 2H, J = 6.0 Hz), 2.95 (quart, 1 H), 2.56 (t, 2H, J = 7.4 Hz), 2.30 (t, 2H, J = 6.0 Hz), 2.07 (brm, 2H), 1.80- 1.54 (m, 8H), 0.90 (m, 3H, 7.3 Hz). CI-MS: m / e = 545.38 (M +) EXAMPLE 42 5-r 3 - (3- (2-propyl-4- (4'-isopropylphenoxy) phenoxy) propoxy) phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 4-isopropylphenol in place of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 8.23 (brs, 1 H), 7.27 (d, 2H), 7.16 (d, 2H), 6.90 (d, 2H), 6.90-6.80 (m, 5H), 5.34 (s, 1 H), 4.21 (t, 2H, J = 6.2 Hz), 4.15 (t, 2H), 1.64 (m, 2H), 1.26 (m, 6H), 0.96 (t, 3H, J = 7.4 Hz). CI-MS: m / e = 521.2 (M + H) EXAMPLE 43 5-r3- (3- (2-propyl-4- (naphthyloxy) phenoxy) propoxy) phen.p-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 2-naphthol in place of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 8.05 (s, 1 H), 7.83 (d, 2H), 7.66 (d, 1 H), 7.46-7.39 (m, 2H), 7.38-7.20 (m, 2H), 6.92-6.78 (m, 3H), 5.35 (s, 1 H), 4.29 (m, 4H), 2.59 (t, 2H, J = 7.4 Hz), 2.35 (t, 2H), 1.69 (quart, 4H), 0.99 (t, 3H). CI-MS: m / e = 528.3 (M + H) EXAMPLE 44 5-r 3 - (3- (2-propyl-4- (dibenzofuran-2-yloxy) phenoxy) propoxyphenn-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 23, using 2-hydroxydibenzofuran instead of 4-methylphenol as the starting material in step A. 1 H NMR (400MHz, CDCl 3): d 7.99 (brs, 1 H), 7.87 (d, 1 H), 7.66-7.46 (m, 4H), 7.38-7.22 (m, 2H), 6.92-6.78 (m, 3H), 5.35 (s, 1 H), 4.22 (t, 2H), 4.17 (t, 2H), 2.59 (t, 2H, J = 7.4 Hz), 2.35 (t, 2H), 1.60 (quart, 2H), 0.99 (t, 3H). CI-MS: m / e = 567.3 (M + NH4) EXAMPLE 45 5-r3- (3- (2,6-b.spropyl-4-phenoxypropoxy) phen.p-2,4-thiazolidinedione Step A: Preparation of 2,6-bispropyl-4-phenoxyphenol To a solution of 4-phenoxy-2-propylphenol (PCT Application) WO97 / 28115) in DMF was added potassium carbonate and allyl bromide. The reaction was stirred for 5 hours at 50 ° C, and after cooling it was neutralized with 1 N HCl and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, filtered and concentrated to an oil which was subjected to chromatography on silica gel (15% ethyl acetate: hexanes) to give 2-propyl-4-phenoxyphenyl ether. allyl The pure 2-propyl-4-phenoxyphenyl allyl ether was used to prepare the title compound according to the method described in example 23, step A, paragraphs 4 and 5. 1 H NMR (400 MHz, CDCl 3): d 7.31- 6.69 (ar, 7H), 4.49 (s, 1 H), 2. 54 (t, 4H, J = 7.47 Hz), 1.59 (m, 4H), 0.96 (t, 6H, J = 7.33 Hz).

Step B: Preparation of 5-r3- (3- (2,6-bispropyl-4-phenoxyproxy) phenin-2,4-thiazolidinedione Using methyl 3- (3-bromopropoxy) mandelate and 2,6-bispropyl-4-phenoxyphenol (as was prepared in step A) as starting materials of example 22, step B: the title compound was prepared according to the methods described in the example 22 steps from B to D. 1 H NMR (400 MHz, CDCl 3): d 7.36-6.69 (ar, 11 H), 5.35 (s, 1 H), 4.26 (t, 2H, J = 6.04 Hz), 3.94 (t, 2H, J = 5.98 Hz) 2.52 (m, 4H), 2.27 ( quint, 2H, J = 6.05 Hz), 1.54 (m, 4H), 0.86 (t, 6H, J = 7.36 Hz).

EXAMPLE 46 5-r4- 3- 7-propyl-3-neofyl-6-benzr4,51-isoxazolyloxy) propoxy) phen.p-2,4-thiazolidinedione Step A: Preparation of methyl 4- (3- (7-propyl-3-neophyl-6-benzr4,51-oxazo! Yloxy) propoxy) phenyl! Acetate The title compound was prepared according to the method described in Example 1, step B, using 7-propyl-3-neophyll-6-hydroxy-benz [4,5] isoxazole (PCT application WO97 / 28137) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 7.38 (d, 2 H, J = 7.32 Hz), 7.30-7.16 (ar, 9 H), 6.85 (d, 2 H, J = 8.67 Hz), 6.67 (d, 1 H, J = 8.75 Hz), 6.50 (d, 1 H, J = 8.71 Hz), 4.15 (m, 4H), 3.66 (s, 3H), 3.55 (s, 2H), 3.18 (s, 2H), 2.81 (t , 2H, J = 7.38 Hz), 2.25 (quint, 2H, J = 6.06 Hz), 1.63 (hex, 2H, J = 7.53 Hz), 1.44 (s, 6H), 0.91 (t, 3H, J = 7.36 Hz ).

Step B: Preparation of 5-r4- (3- (7-propyl-3-neofyl-6-benzr4,51-oxazol-oxy-oxy) propoxy) -phenn-2,4-thiazolidinedione The title compound was prepared in accordance with the method described in example 1, step c, using methyl 4- (3- (7-propyl-3-neofyl-6-benz [4,5] isoxazoyloxy) propoxy) phenol acetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.02 (brs, 1 H), 7.38-7.16 (ar, 9 H), 6.9 (d, 2 H, J = 8.71 Hz), 6.66 (d, 1 H, J = 8.78 Hz ), 5.32 (s, 1 H), 4.15 (m, 4H), 3.17 (s, 2H), 2.79 (t, 2H, J = 7.61 Hz), 2.26 (quint, 2H, J = 6.14 Hz), 1.60 ( hex, 2H, J = 6.14), 1.43 (s, 6H), 0.91 (t, 3H, J = 7.45 Hz).

EXAMPLE 47 5-r3- (4- (7-propyl-3-trifluoromethyl-6-benzr4,51-isoxazolyloxy) butoxy) phenin-2,4-thiazolidinedione Step A: Preparation of Ethyl 3- (4- (7-propyl-3-trifluoromethyl-6-benzyl-4,5,5-oxazoloxy) butoxy) mandelate The title compound was prepared according to the method described in Example 22 , step C, using 7-propyl-3-trifluoromethyl-6-hydroxy-benz [4,5] isoxazole (PCT application WO97 / 28137) and 3- (4-bromobutoxy) mandelate as starting materials. 1 H NMR (400 MHz, CDCl 3): d 7.5 (d, 1 H, J = 8.5 Hz), 7.25-6.83 (ar, 5H), 4.28-4.24 (m, 2H), 4.17-4.031 (m, 4H), 2.89 (t, 2H, J = 7.41 Hz), 1.22 (t, 3H, J = 7.16 Hz), 0.94 (t, 3H, J = 7.41 Hz).

Step B: Preparation of ethyl α-chloro-3- (4- (7-propyl-3-trifluoromethyl-6-benzyl-4,11-isoxazolylloxy) butoxy) phenylacetate The title compound was prepared according to the method described in Example 22, step D, using ethyl 3- (4- (7-propyl-3-trifluoromethyl-6-benz [4,5] isoxazolyloxy) butoxy) mandelate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.18 (brs, 1 H), 7.5 (d, 1 H, J = 8.14 Hz), 7.32-6.88 (ar, 5H), 5.31 (s, 1 H), 4.16 ( t, 2H, 4.28), 2.89 (t, 2H, J = 7.41 Hz), 2.03 (m, 4H), 1.67 (sext, 2H, 7.45), 0.94 (t, 3H, J = 7.36 Hz).

EXAMPLE 48 5-r4- (3- (2-propyl-4- (4'-methoxyphenoxy) phenoxy) propoxy) -3-propylphenn-2,4-thiazolidinedione Step A: Preparation of phenyl 4- (3-bromopropoxy) -3-propy! Phenyl ether The title compound was prepared according to the method described in example 11, step A, using 2-propyl-4- (4 ') -methoxyphenoxy) phenol as starting material.

Step B: Preparation of Methyl 4- (3- (2-propyl-4 (4'-methoxyphenoxy) -phenoxy) -propoxy) -3-propylphenylacetate The title compound was prepared according to the method described in Example 1 1, step B, using methyl 4-hydroxy-3-propylphenylacetate and 4- (3-bromopropoxy) -3-propylphenyl ether phenyl (as prepared in step A) as starting materials. 1 H NMR (400 MHz, CDCl 3): d 7.09-6.74 (ar, 10H), 4.19-4.14 (m, 4H), 3.81 (s, 3H), 3.70 (s, 3H), 3.56 (s, 2H), 2.60 -2.54 (quint, 4H, J = 7.6 Hz), 2.29 (quint, 2H, J = 6 Hz), 1.59 (quint, 4H, J = 7.7), 0.93 (quart, 6H, J = 6.7 Hz).

Step Preparation of 5-r4- (3- (2-propyl-4 (-4'-methoxyphenoxfenoxi) propoxy) -3-propylphenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using methyl 4- (3- (2-propyl-4- (4'-methoxyphenoxy) phenoxy) -propoxy) -3-propylphenol acetate as the starting material. 1 H NMR (400 MHz, CDCl 3 ): d 7.89 (brs, 1 H), 7.29-6.74 (ar, 10H), . 34 (s, 1 H), 4.20 (t, 2H, J = 6.1 Hz), 4.15 (t, 2H, 5.8 Hz), 3.81 (s, 3H), 2.61- 2.53 (m, 4H), 2.3 (quint, 2H, J = 6.1 Hz), 1.57 (m, 4H,), 0.92 (m, 6H).

EXAMPLE 49 5-r4- (4- (2-propyl-4- (4'-methoxyphenoxy) phenoxy) butoxy) phen-214-thiazolidinedione Step A: Preparation of 4- (4- (2-propyl) -4- (4'-methoxyphenoxy-phenoxy) butox-Mandelate The title compound was prepared according to the method described in example 22, step C, using 4- (4'-bromobutoxy) mandelate and 2-propyl-4- (4'-methoxyphenoxy) phenol (as prepared in example 23, step A using 4-methoxyphenol) as starting materials. 1 H NMR (400 MHz, CDCl 3 ): d 7.31-7.29 (m, 2H), 7.02-6.76 (m, 9H), 5.09-5.07 (d, 1 H, J = 5.7 Hz), 4.27-4.04 (m, 2H), 4.02-3.96 (m , 4H), 3.36 (d, 1 H, J = 5.8 Hz), 2.53 (t, 2H, J = 7.41 Hz), 0.90 (t, 3H, J = 7.32 Hz).

Step B: Preparation of ethyl α-chloro-4- (4- (2-propyl-4 (-4'-methoxy-phenoxyphenoxybutoxy) phenylacetate The title compound was prepared according to the method described in example 22, step D, using 4- (4- (2-propyl-4- (4'-methoxy) phenoxy) phenoxy) butoxy) ethyl mandelate (as prepared in step A) as starting material. 1 H NMR (400 MHz, CDCl 3): d 7.40-7.38 (d, 2H, J = 8.78 Hz), 6.91-6.72 (ar, 9H), 5.28 (s, 1 H), 4.23-4.17 (m, 2H), 4.04-3.96 (m, 4H), 2.53 (t, 2H, J = 7.61 Hz), 0.90 (t, 3H, J = 7.36 Hz).

Step Preparation of 5-f4- (4- (2-propyl-4 (-4"methoxyphenoxphenoxy) butoxyQfenip-2,4-thiazolidinedione The title compound was prepared according to the method described in example 22, step E, using ethyl a-chloro-4- (4- (2-propyl-4- (4'-methoxy) phenoxy) phenoxy) butoxy) phenylacetate (as prepared in step B) as the starting material. (400 MHz, CDCI3): d 8.18 (brs, 1 H), 7.40-7.38 (d, 2H, J = 8.78 Hz), 6.91-6.72 (ar, 9H), 5.32 (s, 1 H), 4.04-3.95 (m, 4H), 2.53 (t, 2H, J = 7.61 Hz), 1.95 (m, 4H), 1.56 (sext, 2H, 7.5 Hz), 0.90 (t, 3H, J = 7.36 Hz).

EXAMPLE 50 5-r4-f4- (2-propyl-4- (4'-fluorophenoxy) phenoxy) butoxy) phenin-2,4-thiazolidinedione Step A: Preparation of 4- (4- (2-propyl-4- (4'-fluorophenoxy) phenoxy) ButoxQmandelate The title compound was prepared according to the method described in example 22, step C, using 2- propyl-4- (4'-fluorophenoxy) phenol (as prepared in example 26 using 4-fluorophenol) and ethyl 4- (4-bromobutoxy) -mandelate as starting materials. 1 H NMR (400 MHz, CDCl 3): d 7.31 (d, 2H), 6.98-6.74 (ar, 9H), 5.10 (d, 1 H, J = 5.78 Hz), 4.25-4.1 1 (m, 2H), 4.09-3.97 (m, 4H), 3.36 (d, 1 H, J = 5.77 Hz), 2.54 (t, 2H, J = 7.57 Hz), 0.90 (t, 3H, J = 7.37 Hz).

Step B: Preparation of ethyl α-chloro-4- (4- (2-propyl-4 (-4'-fluorophenoxy)) phenoxophoxy-3-phenylacetate The title compound was prepared according to the method described in example 22, step D, using 4- (4- (2-propyl-4- (4'-fluoro-phenoxy) phenoxy) butoxy) ethyl mandelate (as prepared in step A) as starting material. 1 H NMR (400 MHz, CDCI3): d 7.4 (d, 2H), 6.98-6.75 (ar, 9H), 5.28 (s, 1 H), 4.25-4.15 (m, 2H), 4.05-3.97 (m, 4H), 2.54 (t, 2H, J = 7.33 Hz), 0.90 (t, 3H, J = 7.33 Hz).

Step C: Preparation of 5-í4- (4- (2-propyl-4 (-4'-fluorophenoxy) -phenoxy) -butoxy) -phenin-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 22, step E, using a-chloro-4- (4- (2-propyl-4- (4'-fluorophenoxy) phenoxy) butoxy) ethyl phenylacetate (as prepared in step B) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.08 (broad s, 1 H), 7.32 (s, 1 H), 7.30 (s, 1 H), 6.98-6.74 (ar, 9H), 4.04 (t, 2H, J = 5.82 Hz), 3.98 (t, 2H, J = 7.68 Hz), 2.54 (t, 2H, J = 7.6 Hz), 2.28 (q, 2H, J = 6.4 Hz), 1.55 (hex, 2H, J = 7.4 Hz), 0.90 (t, 3H, J = 7.3 Hz).

EXAMPLE 51 5-r 3 - (4- (2-propyl-4- (4'-methoxy-phenoxy) phenoxy) butoxy) -phenin-2,4-thiazolidinedione Step A: Preparation of 4- (4-bromobutoxy) -3-propyl (4'-methoxyphenyl) -phenyl ether The title compound was prepared according to the method described in example 15, step A, using 2-propyl- 4- (4'-methoxyphenoxy) phenol (as prepared in example 23, step A) using 4-methoxyphenol) as starting material.

Step B: Preparation of methyl 3- (4- (2-propyl-4- (4'-methoxyphenoxy) -phenoxy) butoxhephenylacetate The title compound was prepared according to the method described in example 15, step B, using methyl 3-hydroxyphenyl acetate and 4- (4-bromobutoxy) -3-propylphenyl] 4-methoxyphenyl methyl as starting materials: 1 H NMR (400 MHz, CDCl 3): d 7.24-7.19 (m, 2H), 6.91- 6.73 (ar, 9H), 4.02-3.96 (m, 4H), 3.77 (s, 3H), 3.67 (s, 3H), 3.57 (s, 2H), 2.54 (t, 2H, J = 7.41 Hz), 0.90 (t, 3H, J = 7.33 Hz).

Step Preparation of 5-γ3- (4- (2-propyl-4 (-4'-methoxyphenoxphenoxy) butoxy) phenyn-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1 , step C, using methyl 3- (4- (2-propyl-4- (4'-methoxy) phenoxy) phenoxy) butoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.14 (brs, 1 H), 7.3 (m, 1 H), 6.98-6.69 (m, 10 H), 5.31 (s, 1 H), 4.00 (m, 4 H), 2.53 (t, 2H, J = 7.52 Hz), 2.03 (m, 4H), 1.59 (m, 4H), 1.58 (m, 2H), 0.90 (t, 3H, J = 7.32 Hz).

EXAMPLE 52 5-r3- (4- (2-propyl-4- (4'-chlorophenoxy) phenoxy) butoxy) phen-2,4-thiazolidinedione Step A: Preparation of 4- (4-bromobutoxy) -3-propylphenyl 4-chlorophenyl ether The title compound was prepared according to the method described in Example 15, step A, using 2-propyl-4- (4 ') chlorophenoxy) -phenol (as prepared in example 23, step A) using 4-chlorophenol) as starting material.

Step B: Preparation of methyl 3- (4- (2-propyl-4- (4'-chlorophenoxy) -phenoxy) butoxophenylacetate The title compound was prepared according to the method described in example 15, step B, 4- (4-bromobutoxy) -3-propylpheniyl] 4-chlorophenyl ether and methyl 3-hydroxyphenylacetate as starting materials: 1 H NMR (400 MHz, CDCl 3): d 7.23-7.19 (m, 2H), 6.86-6.78 ( ar 9H), 4.04 (m, 4H), 3.68 (s, 3H), 3.58 (s, 2H), 2.55 (t, 2H, J = 7.33 Hz), 0.90 (t, 3H, J = 7.36 Hz).

Step C: Preparation of 5-r3- (4- (2-propy! -4 (-4'-chlorophenoxy) phenoxy) butoxy) phenan-2,4-thiazolidinedione The title compound was prepared in accordance with method described in example 1, step C, using methyl 3- (4- (2-propyl-4- (4'-chloro-phenoxy) phenoxy) butoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.22 (brs, 1 H), 7.32-7.20 (m, 2 H), 6.99-6.77 (m, 9 H), 5.31 (s, 1 H), 4.00 (m, 4 H) , 2.54 (t, 2H, J = 7.32 Hz), 2.00 (m, 4H), 1.59 (m, 2H), 0.90 (t, 3H, J = 7.33 Hz).

EXAMPLE 53 5-r 3 - (3- (2-propyl-4'-4-methylsulfonylphenoxy) phenoxypropoxy) phenyl-2,4-thiazolidinedione Step A: Preparation of methyl 3- (3- (2-propyl-4- (4'-methylsulfonyl-phenoxyphenoxy-oxalate) The title compound was prepared according to the method described in example 22, step C, using 3 - Methyl (3-bromopropoxy) mandelate as starting material. 1 H NMR (400 MHz, CDCl 3): d 7.81 (m, 2H), 7.00-6.84 (ar, 9H), 5.13 (d, 1 H, J = 5.58 Hz), 4.19-4.13 (m, 4H), 3.74 ( s, 3H), 3.41 (d, 1 H, J = 5.62 Hz), 3.02 (s, 3H), 2.56 (t, 3H, J = 7.52 Hz), 0.90 (t, 3H, J = 7.33 Hz).

Step B: Preparation of methyl a-chloro-3- (3- (2-propyl-4- (4'-methylsulfonylphenoxyphenoxyproxephenylacetate) The title compound was prepared according to the method described in example 22, step D, 3- (3- (2-propyl-4 (4'-methylsulfonylphenoxy) phenoxy) propoxy) methyl mandelate (as prepared in step A) as starting material: 1 H NMR (400 MHz, CDCl 3): d 7.86 (m, 2H), 7.27-6.85 (ar, 9H), 5.30 (s, 1H), 4.20-4.13 (m, 4H), 3.68 (s, 3H), 3.75 (s, 3H), 3.02 (s, 3H), 2.56 (t, 2H) 7.49), 0.90 (t, 3H, J = 7.32 Hz).

Step C: Preparation of 5-r3- (3- (2-propyl-4 (-4'-methylsulfoni! Phenoxy) phenoxy) propoxy) pheyp-2,4-thiazo! Idinodione The title compound was prepared in accordance with Method described in Example 22, step E, using ethyl a-chloro-3- (3- (2-propyl-4- (4'-methylsufonylphenoxy) phenoxyphenylacetate as starting material. 1 H NMR (400 MHz, CDCl 3): d 8.20 (brs, 1 H), 7.84 (m, 2H), 7.30-6.83 (ar, 9H), 5.35 (s, 1 H), 4.16 (t, 2H, J = 6.71 Hz), 4.06 (t, 2H) , J = 6.43 Hz), 3.02 (s, 3H), 2.56 (t, 2H, 6.8 Hz), 2.28 (quint, 2H, J = 6.02 Hz), 1.55 (m, 2H), 0.90 (t, 3H, J = 7.32 Hz).

EXAMPLE 54 5-r3- (4- (2-propyl-4- (4'-methylsulfonylphenoxy) phenoxy) butoxy) phenin-2,4-thiazolidinodone Step A: Preparation of methyl 3- (4- (2-propyl-4- (4'-methylsulfonyl-phenoxy) phenoxy) butoxy) methyl ester The title compound was prepared according to the method described in example 22 , step C, using methyl 3- (4-bromobutoxy) mandelate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 7.82 (m, 2H), 7.26-6.83 (ar, 9H), 5.13 (d, 1 H, J = 5.58 Hz), 4.07-4.02 (m, 4H), 3.74 ( s, 3H), 3.41 (d, 1 H, J = 5.62 Hz), 3.02 (s, 3H), 2.57 (t, 3H, J = 7.24 Hz), 2.0 (m, 4H), 0.90 (t, 3H, J = 7.33 Hz).

Step B: Preparation of methyl a-chloro-3- (3- (2-propyl-4- (4'-methylsulfonylphenoxyphenoxyproxephenylacetate) The title compound was prepared according to the method described in example 22, step D, 3- (4- (2-propyl-4 (4'- methylsulfonylphenoxy) phenoxy) propoxy) methyl mandelate (as prepared in step A) as starting material. 1 H NMR (400 MHz, CDCl 3): d 7.86 (m, 2H), 7.27-6.85 (ar, 9H), 5.30 (s, 1 H), 4.07-4.02 (m, 4H), 3.75 (s, 3H), 3.02 (s, 3H), 3.02 (s, 3H), 2.57 (t, 2H, J = 7.24 Hz), 0.90 (t, 3H, J = 7.32 Hz).

Step Preparation of 5- [3- (4- (2-propyl-4 (-4'-methylsulfonylphenoxy) phenoxy) butoxy) phenan-2,4-thiazolidinodone The title compound was prepared from according to the method described in example 22, step E, using ethyl a-doro-3- (3- (2-propyl-4- (4'-methylsulfonylphenoxy) phenoxy) butoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.20 (brs, 1 H), 7.84 (m, 2H), 7.30-6.83 (ar, 9H), 5.35 (s, 1 H), 4.16 (t, 2H, J = 6.71 Hz), 4.06 (t, 2H, J = 6.43 Hz), 3.02 (s, 3H), 2.56 (t, 2H, 6.8 Hz), 2.28 (quint, 2H, J = 6.02 Hz), 2.0 (m, 4H ), 0.90 (t, 3H, J = 7.32 Hz).

EXAMPLE 55 5-r4- (3- (2-propyl-5-phenoxy) phenoxypropoxy) phenin-2,4-thiazolidinedione Step A: Preparation of 2-propyl-5-phenoxy-phenol A solution of 1-phenoxy- (3-propenyloxy) benzene (29.0 g) in ortho-dichloro (200 ml) was refluxed for 24 hours. The mixture was cooled to room temperature and subjected to chromatography to give two labeled intermediates 1 (3.33 g) and 2 (2.81 g). Compound 1 was hydrogenated over Pd / C catalyst (0.8 g) in methanol. The reaction was filtered through celite and all volatile elements were removed to give the title compound. 1 H NMR (400 MHz, CDCl 3): d 7.16-7.01 (m, 6H); 6.54 (dd, 1 H, J = 8.2 Hz); 6.45 (d, 1 H, J = 2.3 Hz); 4.72 (s, 1 H); 2.56 (t, 2H, J = 7.05 Hz); 1.64 (m, 2H), 0.98 (t, 3H, J = 7.4 Hz).

Step B: Preparation of methyl 3- (3- (2-propyl-5-phenoxyphenoxy) -propoxy) phenylacetate The title compound was prepared according to the method described in example 1, step B, using 2-propyl- 5-phenoxyphenol as starting material. H NMR (400 MHz, CDCl 3): d 7.31-6.82 (m, 10H); 6.55 (d, 1 H, J = 2.3 Hz); 6.52 (dd, 1 H, J = 8.2 Hz and 2.3 Hz); 4.13 (t, 2H, J = 6.2 Hz); 4.05 (t, 2H, J = 6.0 Hz); 3.66 (s, 3H); 3.54 (s, 2H); 2.52 (t, 2H, J = 7.4 Hz); 2.23 (quit, 2H, J = 6.2 Hz); 1.54 (hex, 2H, J = 7.4 Hz); 0.90 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5- [4- (3- (2-propyl-5-phenoxyphenoxy) -phenn-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1 , step C, using methyl 3- (3- (2-propyl-5-phenoxyphenoxy) propoxy) phenylacetate (as prepared in step B) as starting material: 1 H NMR (400 MHz, CDCl 3): d 7.95 ( brs, 1 H), 7.31-6.87 (m, 10H), 6.55 (d, J = 2.3 Hz), 6.52 (dd, 1 H, J = 8.2 Hz and J = 2.3 Hz), 5.32 (s, 1 H); 4.13 (t, 2H, J = 6.2 Hz), 4.05 (t, 2H, J = 6.0 Hz), 2.52 (t, 2H, J = 7.4 Hz), 2.23 (quit, 2H, J = 6.02 Hz), 1.54 (hex, 2H, J = 7.4 Hz),), 0.9 (t, 3H, J = 7.3 Hz).

EXAMPLE 56 5-f4- (3- (2-propyl-3- (phenoxyphenoxy) propoxy) phenin-2,4-thiazole diene Step A: Preparation of 2-propyl-3-phenoxyphenol Intermediate 2 (2.81 g) obtained as described in example 55, step A, was hydrogenated over Pd / C catalyst (0.61 g) in methanol The reaction was filtered through celite and all volatile elements were removed to give the title compound. 1 H NMR (400 MHz, CDCl 3): d 7.34-6.95 (m, 6H); 6.6 (dd, 1 H, J = 8.0 Hz); 6.48 (d, 1 H, J = 8.0 Hz); 4.8 (s, 1 H); 2.65 (t, 2H, J = 7.6 Hz); 1.64 (m, 2H), 0.97 (t, 3H, J = 7.4 Hz).

Step B: Preparation of methyl 3- (3- (2-propyl-3- (phenoxy-phenoxy) propoxy) phenylacetate The title compound was prepared according to the method described in example 1, step B, using 2 -propyl-3-phenoxyphenol as starting material: 1 H NMR (400 MHz, CDCl 3): d 7.29-6.85 (m, 10H), 6.65 (d, 1 H, J = 7.7 Hz), 6.49 (d, 1 H, J = 8.2 Hz), 4.17-4.13 (m, 4H), 3.66 (s, 3H), 3.54 (s, 2H), 2.6 (t, 2H, J = 7.6 Hz), 2.27 (quit, 2H, J = 6.1 Hz), 1.5 (hex, 2H, J = 7.6 Hz), 0.87 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5-í4- (3- (2-propyl-3-phenoxyphenoxy) propoxy) -phenn-2,4-thiazole-dinandione The title compound was prepared according to the method described in the example 1, step C, using methyl 3- (3- (2-propyl-3-phenoxyphenoxy) propoxy) phenylacetate (as prepared in step B) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.05 (brs, 1 H), 7.32-6.88 (m, 10H); 6.64 (d, 1 H, J = 7.4 Hz); 6.49 (d, 1 H, J = 7.3 Hz); 5.32 (s, 1 H); 4.2-4.13 (m, 4H), 2.6 (t, 2H, J = 7.3 Hz); 2.28 (quit, 2H, J = 6.0 Hz); 1.49 (hex, 2H, J = 7.5 Hz); 0.86 (t, 3H, J = 7.3 Hz).

EXAMPLE 57 5-r 3 - (4- (2-propyl-3-phenoxy-phenoxy) butoxy) phenyl-2,4-thiazole-8-noodone The title compound was prepared according to the method described in example 22 (step B-E), using ethyl 3- (4-bromobutoxy) -mandelate 2-propyl-3-phenoxyphenol (example 56, step A). 1 H NMR (400 MHz, CDCl 3): d 7.96 (brs, 1 H); 7.36-6.93 (m, 10H); 6.8 (d, 1 H, J = 8.2 Hz); 6.53 (t, 2H, J = 8.3 Hz); 5.35 (s, 1 H); 4.08 (m, 4H); 2.66 (t, 2H, J = 7.6 Hz); 2.03 (m, 4H); 1.56 (m, 2H); 0.92 (t, 3H, J = 7.4 Hz).

EXAMPLE 58 5-r 3 - (3- (2- (2-propenyl) -4- (phenoxyphenoxy) propoxy) phenin-2,4-thiazolidinedione Step A: Preparation of 2 - (- 2-propenyl) -4-phenoxyphenol A solution of 1-phenoxy- (4-propenyloxy) benzene (11.0 g) in ortho-dichlorobenzene (150 ml) was refluxed for 24 hours. The mixture was cooled to room temperature and subjected to chromatography on silica gel to give the title compound (10.3 g). 1 H NMR (400 MHz, CDCl 3): d 7.4-6.76 (m, 8H); 6.06-5.96 (m, 1 H); 5.21-5.15 (ddt, 2H); 4.86 (s, 1 H); 3.4 (d, 2H, J = 1.4 Hz).

Step B: Preparation of 5- (3- (3- (2- (2-propeniQ-4- (phenoxy-phenoxy) propoxy-phenyl-2,4-tizolidinone) The title compound was prepared according to the method described in example 22, (steps BE), using ethyl 3- (3-bromopropoxy) -mandelate and 2- (2-propenyl) -4-phenoxyphenol. 1 H NMR (400 MHz, CDCl 3): d 8.25 (brs, 1 H), 7.35-6.83 (m, 12H), 5.97-5.88 (m, 1 H), 5.32 (s, 1 H), 5.05-5.0 (m, 4H), 4.17 (dt, 4H) ); 2.28 (m, 2H).

EXAMPLE 59 5-r3- (3- (1'-fluoropropyl-4-phenoxyfenoxy) propoxyphenin-2,4-thiazolidinedione Step A: Preparation of 2- (1'-fluoro-propyl) -4-phenoxy-phenol To a solution of 2- (2-propenyl) -4-phenoxyphenol (5.0 g, example 58-step A) in tetrahydrofuran (THF, 49) ml) a solution of borane-methyl sulfide in THF (1.25 M equiv) was added at 0 ° C. The solution was stirred for 3 hours during which, the temperature was allowed to rise to room temperature. Subsequently, absolute ethanol (10 ml) was added followed by the addition of sodium hydroxide (2.27 g) in water (10 ml). The solution was cooled to 0 ° C and 4.5 ml of 30% hydrogen peroxide was carefully added. The reaction mixture was partitioned between water and ether. The ether extracts were washed with water, brine and dried over sodium sulfate. Concentration under reduced pressure followed by chromatography on silica gel gave the desired intermediate. H NMR (400 MHz, CDCl 3): d 7.33-6.9 (m, 8H); 4.12 (t, 2H, J = . 2 Hz); 3.68 (t, 2H, J = 5.9 Hz); 2.77 (t, 2H, J = 6.8 Hz); 1.89 (hex, 2H J = 5.9 Hz).

This intermediate (2.2 g) was dissolved in tetrahydrofuran (30 ml) and treated with triflorurodiethylaminosulfur (DAST) (4.76 ml) at 0 ° C. The solution was stirred for 4 hours, quenched by the addition of aqueous NaHCO3, washed with water, dried (Na2SO4), concentrated and chromatographed on silica gel to provide 2- (1'-fluoropropyl) -4 -phenoxyphenol. 1 H NMR (400 MHz, CDCl 3): d 7.33-6.75 (m, 8H); 4.69 (s, 1 H); 4.45 (dt, 2H, J = 47.3 Hz and 5.9 Hz); 2.74 (t, 2H, J = 7.3 Hz); 2.05 (m, 2H).

Step B: Preparation of 5-r3- (3- (1 '-fluoropropyP-4- (phenoxyphenoxy) propoxyphenyl-2,4-thiazolidinedione The title compound was prepared according to the method described in example 22 (steps BE), using ethyl 3- (3-bromopropoxy) -mandelate and 2- (1'-fluoropropyl) -4-phenoxyphenol. 1 H NMR (400 MHz, CDCl 3): d 7.94 (brs, 1 H); 7.4-6.8 (m, 12H), 5.35 (s, 1 H), 4.44 (dt, 2H, J = 47.3 Hz and 5.9 Hz), 4.22 (t, 2H, J = 6.1 Hz), 4.17 (t, 2H, J = 6.1 Hz); 2.27 (quit, 2H, J = 6.1 Hz), 2.73 (t, 2H, J = 7.2 Hz), 2.3 (m, 2H), 1.95 (m, 2H).

EXAMPLE 60 5-r 3 - (3- (1'-Fluoropropyl-4-phenoxyphenoxy) propoxyphen-p-2,4-thiazole-dinodone Step A: Preparation of 2- (propyl-4- (4'-ethoxycarbonyl) phenoxyphenol A solution of 4-allyloxyphenol (10.0 g), 4-fluoroethylbenzoate (12.33 g) and sodium hydride (2.93 g, 60 % dispersion in mineral oil) in dimethyl sulfoxide (50 ml) was stirred at 150 ° C for 24 hours.The solution was cooled and the excess carefully destroyed using water.The reaction mixture was extracted with ethyl acetate, washed with water and dried over sodium sulfate The organic layer was filtered and evaporated to an oil which was subjected to chromatography on silica gel to give 4- (4'-ethoxycarbonylphenoxy) phenyl allyl ether. (4'-ethoxycarbonylphenoxy) phenyl-allyl (3.9 g) in 1,2-d-chlorobenzene (50 ml) was heated to reflux for 30 hours.After cooling to room temperature, the mixture was subjected to chromatography on silica gel for give the intermediate (3.46 g) which was hydrogenated over Pd / C (0.3 g) in ethanoi (130 ml). through celite and concentrated in vacuo to give 2-propyl-4- (4'-ethoxycarbonylphenoxy) -phenol. 1 H NMR (400 MHz, CDCl 3): d 7.99 (d, 2 H, J = 9.0 Hz); 6.93 (d, 2H, J = 9.0 Hz); 6.87 (s, 1 H); 6.8 (dd, 2H); 4.36 (q, 2H, J = 7.0 Hz); 2.59 (t, 2H, J = 7.4 Hz); 1.68-1.60 (m, 2H); 0.98 (t, 3H J = 7.2 Hz).

Step B: Preparation of 5-r3- (3- (2-propyl) -4- (4'-ethoxycarbonylphenoxy) -phenoxypropoxy) phenyl1-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 22 (steps BE), using ethyl 3- (3-bromopropoxy) -mandelate and 2-propyl-4- (4'-ethoxycarbonyl) phenoxyphenol. 1 H NMR (400 MHz, CDCl 3): d 8.0 (d and brs, 3H); 7.4-6.8 (m, 9H); 5.35 (s, 1 H); 4.36 (q, 2H, J = 7.0 Hz); 4.22 (t, 2H, J = 6.1 Hz); 4.18 (t, 2H, J = 6.0 Hz); 2.59 (t, 2H, J = 7.3 Hz); 0.93 (t, 3H, J = 7.2 Hz).

EXAMPLE 61 5-f4- (3- (4- (1, 2-benzsoxasol-3-yl) -2-propylfenoxy) propoxy) phenyH-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 22 (step BE), using ethyl 4- (3-bromopropoxy) -mandelate and 4-1,2-benzisoxazol-3-yl) -2-propylphenol (request PCT WO97 / 281 15). 1 H NMR (400 MHz, CDCl 3): d 7.91 (brs, 1 H); 7.9-6.9 (m, 1 1 H); 5.33 (s, 1 H); 4.21 (q, 2H, J = 6.2 Hz); 4.22 (t, 2H, J = 6.1 Hz); 4.22 (t, 2H, J = 6.1 Hz); 2.66 (t, 2H, J = 7.5 Hz); 2.32 (hex, 2H, J = 6.0 Hz); 1.64 (m, 2H); 0.95 (t, 3H, J = 7.3 Hz).

EXAMPLE 62 5-r3- (4 - ((1,2-benzisoxazol-3-yl) 2-propylphenoxy) butoxy) f-nill-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 22, using ethyl 3- (4-bromobutoxy) -mandelate and 4- (1,2-benzisixazol-3-yl) -2-propylphenol (PCT Application WO97 / 28115). H NMR (400 MHz, CDCl 3): d 8.31 (brs, 1 H); 7.9-6.9 (m, 11 H); 5.31 (s, 1 H) 4.12 (t, 2H, J = 5.2 Hz); 4.06 (t, 2H, J = 5.0 Hz); 2.67 (t, 2H, J = 7.7 Hz); 2.0 (m, 4H); 1.66 (m, 2H); 0.96 (t, 3H, J = 7.3 Hz).

EXAMPLE 63 5-r4- (3- (3-phenylethyl) -7-propyl-benzothiophen-6-yl) oxy) -1-propoxyphenyl-2,4-thiazolidinedione Step A: Preparation of 1-Diazo-4-phenyl-2-butanone A solution of hydrazinamoyl chloride (10.0 grams, 100 ml of dry diethyl ether) was carefully added to freshly prepared ether diazomethane (85.6 grams Diazald, 10 ml ether dry ethyl) at 0 ° C. The reaction was maintained at 0 ° C until gas removal was completed (15 minutes), then it was raised to room temperature (15 minutes). Acetic acid (5.0 ml) was added and the reaction was partitioned (pH 4 regulator of phthalate and methyl tert-butyl ether). The organic layer was washed with water, dried over MgSO and filtered to provide, upon evaporation, an oil containing the title compound. The crude product was used without further purification or retardation. 1 H NMR (400 MHz, CDCl 3): d 7.32-7.18 (mult, 5H); 5.19 (vbrs, 1 H); 3.04-2.92 (mult, 4H).

Step B: Preparation of 1-bromo-4-phenyl-2-butanone A solution at 0 ° C of the crude product from step A (12.89 grams, dry dichloromethane, 150 ml) was treated by dripping with 48% HBr (36.0 ml ). When gas removal was stopped, the solution was warmed to room temperature. After 15 minutes, the reaction was partitioned (isopropyl acetate and water), washed 2 times with water and dried (magnesium sulfate). Filtration and evaporation produced the title compound as an oil, which crystallized upon standing. 1 H NMR (400 MHz, CDCl 3): d 7.30-7.16 (mult, 5H); 3.83 (s, 2H); 2.97-2.91 (mult, 4H).

Step C: Preparation of 1- (3-methoxy-phenyl) thio-4-phenyl-2-butanone A solution in DMF (225 ml) of the product from step B (20.212 grams), dried was exposed to di-isopropylethylamine (16.22). ml), subsequently to methoxythiophenol (1 1424 grams). Stirring at room temperature for 6 hours followed by a division (isopropyl acetate and pH4 regulator of phthalate). The organic layer was washed twice with water, dried (magnesium sulfate) and filtered). The isolation of the title compound was completed by concentration and chromatography on silica gel (5: 1 1 H NMR (400 MHz, CDCl 3): d 7.26-7.12 (mult, 6H), 6.83 (dd, 2H, J = 4.7, 2.2 Hz); 6.73 (dd, 1 H, J = 8.3, 2.4 Hz); 3.76 (s, 3H); 3.63 (s, 2H); 2.88 (oct, 4H, J = 5.8 Hz).

Step D: Preparation of 3- (2-phenylethylP6-methoxy-benzothiophene The product of step C (8.45 grams) dissolved in dry CH2Cl2 (85 ml) was added dropwise to a solution of CH2Cl2 (34 ml) at 0 ° C. of methanesulfonic acid (17 ml) The reaction was maintained at 0 ° C for 20 minutes, then briefly warmed to room temperature The reaction was poured rapidly into a cold mixture stirred vigorously with excess 5N NaOH and methyl ether of tert-butyl ether. The organic layer was dried over magnesium sulfate and filtered The concentration and chromatography on silica gel (5: 1 hex / CH 2 Cl 2) gave the title compound as a clear oil.1H NMR (400 MHz, CDCl 3): d 7.66 (d, 1 H, J = 8.8 Hz), 7.37-7.20 (mult, 6H), 7.05 (dd, 1 H, J = 8.8, 2.4 Hz), 6.91 (t, 1 H, J = 0.9 Hz); 3.90 (s, 3H); 3.16-3.02 (mult, 4H).

Step E: preparation of 3- (2-phenylethyl) -6-hydroxy-benzothiophene A stirred solution at -10 ° C of the product from step D (5.483 grams, dry methylene chloride, 60 ml) was treated with a tribromide solution of 1 M boron (methylene chloride, 20.81 ml). After 2 hours, the reaction was momentarily heated to room temperature. It was partitioned between aqueous isopropyl acetate and sodium bicarbonate, washed once with water and dried over magnesium sulfate. Filtration and evaporation produced a semi-solid. Chromatography on silica gel (2.5: 1 hex / ethyl acetate) resulted in isolation of the title compound, a pale yellow solid. 1 H NMR (400 MHz, CDCl 3): d 7.60 (d, 1 H, J = 8.8 Hz); 7.35-7.23 (mult, 6H); 6.94 (dd, 1 H, J = 8.7, 2.3 Hz); 6.88 (s, 1 H); 5.40 (s, 1 H); 3.13-3.02 (mult, 4H).

Step F: Preparation of 3- (2-phenylethyl) -6-allyloxy-benzothiophene A stirred solution of the product from step E (4.651 grams) in dry DMF (40 ml) was exposed to allyl bromide (1.66 ml) followed by carbonate of cesium (6.26 grams). After 2.5 hours at room temperature, the reaction was partitioned between isopropyl acetate and phthalate pH 4 regulator. The organic layer was washed twice with water, dried over magnesium sulfate and filtered. Evaporation gave a residue, which upon chromatography on silica gel (3: 1 hex / CH2Cl2), gave the title compound as a clear oil. 1 H NMR (400 MHz, CDCl 3): d 7.73 (d, 1 H, J = 8.8 Hz); 7.47-7.34 (mult, 6H); 7.19 (dd, 1 H, J = 8.8, 2.3 Hz); 6.99 (s, 1 H); 6.22 (dquints, 1 H, J = 4.3 Hz); 5.62 (dquarts, 1 h, J = 17.3, 1.6 Hz); 5.44 (dquarts, 1 H, J = 10.5, 1.4 Hz); 4.96 (t, 1 H, J = 1.5 Hz); 4.67 (t, 1 H, J = 1.5 Hz); 3.25-3.12 (mult, 4H).

Step Preparation of 3- (2-phenylethyl) -6-hydroxy-7-allyl-benzothiophene The product of step F (4.373 grams), dissolved in 1,2-dichlorobenzene (45 ml) was refluxed under nitrogen for 8.5 hours. The solution was cooled to approximately 50 ° C. High vacuum was applied and the solvent was removed until the residue solidified. The solid was dissolved in CH2 CI2 (100 ml), recovered and re-evaporated, and subjected to chromatography on silica gel (CH2 Cl2). Evaporation of the appropriate fractions gave the title compound as a pale yellow solid. H NMR (400 MHz, CDCl 3): d 7.53 (d, 1 H, J = 8.5 Hz), 7.35-7.20 (mult, 5H); 6.95 (d, 1 H, J = 8.5 Hz); 6.93 (d, 1 H, J = 8.4 Hz); 6.06 (aparent dpent, 1 H, J = 7.1, 3.9 Hz); 5.23 (d, 1 H, J = 15.7, 1.7 Hz); 5.17 (dquart, 1 H, J = 1.5, 1.8 Hz); 5.09 (s, 1 H); 3.67 (dt, 2H, J = 6.3, 1.6 Hz); 3.13-3.01 (mult, 4H); 1.27 (t, 3H, J = 7.2 Hz).

Step H: Preparation of 3- (2-phenylethyl) -6-hydroxy-7-propyl-benzothiophene The product from step G (3.062 grams) was dissolved in tert-butyl methyl ether (60 ml) and placed in a hydrogenation container. The 5% Pd / C catalyst was added and the mixture was hydrogenated for 1 hour using a Parr apparatus (0.4892 kg / cm2). Filtration through celite and evaporation gave the title compound as a yellow oil. Upon standing, it was produced in pale yellow solid, which did not require further purification. 1 H NMR (400 MHz, CDCl 3): d 7.45 (d, 1 H, J = 8.5 Hz); 7.32-7.20 (mult, 6H); 6.89 (d, 1 H, J = 8.4 Hz); 5.28 (s, 1 H); 3.10-3.01 (mult, 4H); 2.84 (dd, 2H, J = 7.7, 1.6 Hz); 1.74 (hex, 2H, J = 6.0 Hz), 1.02 (t, 3H, J = 7.4).

Step I: Preparation of methyl 4-F3- (3- (2-phenylethyl-P-7-propylbenzothiophen-6-yloxy) -1 -propoxy-phenylacetate The title compound was prepared according to the method described in the example 1, step B, using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene as starting material.1H NMR (400 MHz, CDCl3): d 7.50-7.42 (m, 4H), 7.31 (d, 2H, J = 8.8 Hz), 7.19-7.16 (d, 2H, J = 8.3 Hz), 6.92-6.83 (m, 3H), 6.46 (s, 1 H), 4.21-4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.95 (t, 2H, J = 7.4 Hz), 2.29 (quint, 2H, J = 6.3 Hz), 1.71 (hex, 2H, J = 5.9 Hz), 1.01 (t, 3H, J = 7.3 Hz).

Step J: Preparation of 5-β4- (3- (3- (2-phenylethyl) -7-propyl-benzothiophen-6-yloxy) -1-propoxyphenyl-2,4-thiazolidinedione The title compound was prepared in accordance with the method described in example 1, step C, using methyl [4- (3- (2- (7-propyl-3- (2-phenylethyl) benzothiophen-6-yloxy) -1-propoxy)] phenylacetate from step I above as starting material: 1 H NMR (400 MHz, CDCl 3): d 9.46 (brs, 1 H), 7.59 (d, 1 H, J = 8.6 Hz), 7.38-7.24 (m, 4H), 7.09 (d , 1 H, J = 8.8 Hz), 6.98 (d, 2H, J = 8.8 Hz), 6.92-6.83 (m, 3H), 6.46 (s, 1 H), 5.30 (s, 1 H), 4.26 (bdquart , 4H, Jprom = 5.5 Hz), 3.11 (vbdquint, 4H), 2.91 (bdd, 2H, J = 7.4, 1.4 Hz), 2.34 (quint, 2H, J = 6.0 Hz), 1.76 (hex, 2H, J = 7.5 Hz), 1.03 (t, 3H, J = 7.3 Hz).

EXAMPLE 64 5-r 3 - (4- 3- (2-phenylethyl) -7-propyl-benzothiophen-1,1-dioxide-6-yloxy) -1-butoxy) -lphenyl-2,4-thiazolidinedione Step A: Preparation of 3- (2-phenylethyl) 6-hydroxy-7-propyl-benzothiophene-1,1-dioxide The product of example 63, step H (3.515 grams in a solution of CH2Cl2 (40 ml) was stirred carefully (0 ° C) and treated with 75% m-dichloroperbenzoic acid (5,474 grams) in portions.After 15 minutes the reaction was warmed to room temperature and stirring was continued for 1 hour. The aqueous sodium bicarbonate was followed by washing the organic layer once with aqueous sodium bicarbonate, then water, extracting over magnesium sulfate, filtration and evaporation gave a solid which was subjected to chromatography on silica gel (5%). : 1 hex / ethyl acetate) The title compound was achieved as a white solid. 1 H NMR (400 MHz, CDCl 3): d 7.35-7.19 (m, 4H); 7.04 (d, 1 H, J = 8.1 Hz); 6.89 (d, 1 H, J = 8.2 Hz); 6.63 (vbrs, 1 h); 6.29 (t, 1 H, J = 1.5 Hz); 2.97-2.78 (m, 6H); 1.74 (dsex, 2H, J = 7.2, 2.9 Hz); 1.03 (t, 3H, J = 7.4 Hz).

Step B: Preparation of methyl 3- (4- (7-propyl-3- (2-phenylethyl) -benzothiophen-1., 1-dioxy-6-yloxy) -1-butoxy) phenylacetate The title compound was prepared according to the method described in example 1, step B, using 3- (2-phenylethyl-6-hydroxy-7-propylbenzothiophene-1,1-dioxide (step A above) as starting material. 1 H NMR (400 MHz , CDCI3): d 7.50-7.42 (m, 4H), 7.31 (d, 2H, J = 8.8 Hz), 7.19-7.16 (d, 2H, J = 8.3 Hz), 6.92-6.83 (m, 3H), 6.46 (s, 1 H), 4.21-4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.95 (t, 2H, J = 7.4 Hz), 2.29 (quint, 2H, J = 6.3 Hz), 1.71 (hex, 2H, J = 5.9 Hz), 1.01 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5-β3- (4- (3- (2-phenylethyl-V7-propy-benzothiophen-1,1-dioxide-6-loxy) -1-butoxy) -1-phenyl-2,4-thiazolidinedione The title compound is prepared according to the method described in example 1, step C, using 3 - ((4- (7-propyl-3- (2-phenylethyl) -benzothiophen-1,1-dioxide-6-yl) oxy) - Methyl 1-butoxy) phenylacetate as starting material 1 H NMR (400 MHz, CDCl 3): d 8.42 (brs, 1 H), 7.32-7.19 (m, 6H); 7.12 (d, 1 H, J = 8.3 Hz ), 6.98 (d, 1 H, J = 8.1 Hz), 6.91-6.85 (m, 4H), 6.30 (s, 1 HOUR); 5.30 (s, 1 H); 4.04 (brquart, 4H, J = 6.3 Hz); 2.94-2.88 (m, 4H); 2.02-1.98 (m, 4); 1.69 (hex, 2H, J = 5.2 Hz); 0.99 (t, 3H, J = 7.3 Hz).

EXAMPLE 65 5-r 4 - (3- (7-propyl-3- (2-phenylethyl) -benzothiophen-1,1-dioxide-6-yloxy-1-propoxy-1-phenyl-2,4-thiazolidinedione Step A: Preparation of Methyl 4- (3- (7-propyl-3- (2-phenylethyl-D-benzothiophen-1, 1-dioxy-6-yloxy) -1-propoxy-l-phenylacetate of the title was prepared according to the method described in example 1, step B, using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene-1,1-dioxide (example 64, step A) as materials 1H NMR (400 MHz, CDCI3): d 7.50-7.42 (m, 4H), 7.31 (d, 2H, J = 8.8 Hz), 7.19-7.16 (d, 2H, J = 8.3 Hz); 6.83 (m, 3H), 6.46 (s, 1 H), 4.21-4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.95 (t, 2H, J = 7.4 Hz); 2.29 (quint, 2H, J = 6.3 Hz), 1.71 (hex, 2H, J = 5.9 Hz), 1.0 (t, 3H, J = 7.3 Hz).

Step B: Preparation of 5-r4- (3- (3- (2-phenylethyl) -7-propyl-benzothiophen-1,1-dioxido-6-yloxy) -1-propoxy) 1-phenyl-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using 4- (3- (3- (2-phenylethyl) -7-propyl-benzothiophen-1,1-dioxido-6-yloxy) ) 1-propoxy) phenylacetate (step A above) as starting material. 1 H NMR (400 MHz, CDCl 3): d 7.87 (brs, 1 H); 7.32-7.24 (m, 6H); 7.21 (t, 2H, J = 7.1 Hz); 7.12 (d, 1 H, J = 8.1 Hz); 6.90 (d, 2H, J = 8.7 Hz); 6.89 (d, 1 H, J = 8.2 Hz); 6.30 (s 1 H); 5.31 (s, 1 H); 4.16 (quart, 4H, J = 5.9 Hz); 2.95-2.87 (m, 4H); 2.81 (t, 2H, J = 7.7 Hz); 2.29 (quint, 2H, J = 6.0 Hz); 1.67 (hex, 2H, J = 7.7 Hz); 0.98 (t, 3H, J = 7.4 Hz).

EXAMPLE 66 5-r3- (4- (3- (2-phenylethyl) -7-propyl-benzothiophen-1-oxide-6-yloxy) -1-butoxy) lphenyl-2,4-thiazolidine Step A: Preparation of 3- (2-phenylethyl) -6-hydroxy-7-propyl-benzothiophene-1-oxide The product of example 63, step H (2.017 grams) in a solution of CH2Cl2 (40 ml) was stirred ( 0 ° C) and treated with 75% solid m-chloroperbenzoic acid (1,567 grams) in portions. The reaction was warmed to room temperature after 15 minutes and stirred for 1.5 hours. The cleavage of the reaction between isopropyl acetate and aqueous sodium bicarbonate was followed by washing the organic layer with aqueous sodium bicarbonate and subsequently water. Drying over magnesium sulfate, filtration and evaporation gave a solid which was subjected to chromatography on silica gel (2 step gradient, 5: 1 hex / ethyl acetate, 5: 2 hex / ethyl acetate, 5: 2). : 0.35 hex / ethyl acetate / methanol). The title compound was obtained as a white solid. 1 H NMR (400 MHz, CDCl 3): d 8.53 (brs, 1 H); 7.33-7.18 (mult, 5H); 7.01 (d, 1 H, J = 8.2 Hz); 6.88 (d, 1 H, J = 8.2 Hz); 6.50 (s, 1 H); 2.99-2.77 (mult, 4H); 1.67 (hex, 2H, J = 7.6 Hz); 0.95 (t, 3H, J = 6.7 Hz).

Step B: Preparation of Methyl 3- (4- (3- (2-phenylethyl-P-7-propyl-benzothiophen-1-oxide-6-yloxp 1 -butoxy) phenylacetate The title compound was prepared by adhesion to the specified method in Example 1, step B, using 3- (2-phenylethyl) -6-hydroxy-7-propyl-benzothiophene-1-oxide (step A above) as the starting material.

H NMR (400 MHz, CDCl 3): d 7.50-7.42 (m, 4H); 7.31 (d, 2H, J = 8.8 Hz); 7.19-7.16 (d, 2H, J = 8.3 Hz); 6.92-6.83 (m, 3H); 6.46 (s, 1 H); 4.21-4.16 (m 4H); 3.67 (s, 3H); 3.54 (s, 2H); 2.95 (t, 2H, J = 7.4 Hz); 2.29 (quint, 2H, J = 6.3 Hz); 1.71 (hex, 2H, J = 5.9 Hz); 1.01 (t, 3H, J = 7.3 Hz).

Step C: Preparation of 5- [3- (4- (3- (2-Phenylethyl-7-propyl-benzothiophen-1-oxide-6-ylxp-1-butoxy) -1-phiol-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C, using 3- (4- (3- (2-phenylethyl) -7-propyl-benzothiophen-1-oxide-6-yloxy) -1-butoxy) Methyl phenylacetate (step B above) as starting material: 1 H NMR (400 MHz, CDCl 3, diastereomeric pair): d 9.62-9.53 (vbrs, 1 H); 7.32-7.17 (m, 6H); 6.96-6.86 (m , 4H), 3.01-2.84 (m, 6H), 2.05-2.00 (m, 4H), 1.70 (bhex, 2H, J = 8.5 Hz), 0.98 (t, 1.5H, J = 7.4 Hz), 0.95 (t , 1.5H, J = 7.3 Hz).

EXAMPLE 67 5-r4- (3- 3- (2,2-dimethylpropyl) -7-propyl-benzofuran-6-yloxy) -1-propoxyphenyl-2,4-thiazolidinodone Step A: Preparation of 1-diazo-4,4-dimethyl-2-pentanone A solution of urea-butyl acetyl chloride (1.136 grams) in dry ethyl ether (10 ml) was slowly added to a solution of diethyl ether (20 ml) at 0 ° C of freshly generated diazomethane (20 grams of Diazald). After stirring for 30 minutes, the reaction was warmed to room temperature for another 30 minutes. Acetic acid (2 ml) was added and the reaction was partitioned between methyl-fer-butyl ether and water. The organic layer was washed once with water, dried over magnesium sulfate and filtered. The concentration gave an oil containing the title compound, which was immediately used without further purification. 1 H NMR (400 MHz, CDCl 3): d 5.18 (brs, 1 H); 2.15 (brs, 2H); 1.01 (s, 9H).

Step B: Preparation of 1-bromo-4,4-dimethyl-2-pentanone To a stirred -10 ° C solution of the crude product from step A (1.233 grams) in methylene chloride (12 ml) was added 48% HBr dropwise (1.14 ml). After the evolution of gas stopped, the reaction was stirred for 15 minutes at room temperature. The reaction was partitioned between isopropyl acetate and water. The organic layer was washed once with water, dried over magnesium sulfate and filtered. Evaporation gave an oil containing the title compound that was used without further purification. 1 H NMR (400 MHz, CDCl 3): d 3.85 (s, 2H); 2.50 (s, 2H); 1.01 (s, 9H).

Step C: Preparation of 1- (3-methoxyphenoxyp-4,4-dimethyl-2-pentanone) A stirred solution of the product from step B (1626 grams) in dry DMF (18 ml) was combined with 3-methoxyphene (1.256 grams) and carbonate of cesium (3292 grams) The mixture was stirred for 2.5 hours The mixture was partitioned between isopropyl acetate and phthalate pH 4. The organic layer was washed twice with water, dried over magnesium sulfate and filtered The concentration made an oil from which the title compound was isolated by chromatography on silica gel (4: 1 hex / ethyl acetate). 1 H NMR (400 MHz, CDCl 3): d 7.18 (ddd, 1 H, J = 7.7, 6.9, 0.7 Hz), 4.47 (s, 2H), 3.78 (s, 3H), 2.44 (s, 2H), 1.05 (s, 9 Hz).

Step D: Preparation of 3- (2,2-dimethylpropyl) -6-methoxybenzofuran The product from step C (1,408 grams) dissolved in dry methylene chloride (15 ml) was added to phosphorous oxychloride (30 ml). The reaction was stirred 2 hours at 40 ° C. The solution was diluted twice with xylenes (30 ml) and concentrated under high vacuum. The non-volatile elements were divided between isopropyl acetate and aqueous sodium bicarbonate. The organic layer was backwashed with aqueous sodium bicarbonate, dried over magnesium sulfate and filtered. Removal of solvents gave a residue which was subjected to chromatography on silica gel (3: 1 \ rtexJC 2C \ 2), yielding the title compound.

H NMR (400 MHz, CDCl 3): d 7.40 (d, 1 H, J = 8.6 Hz); 7.31 (s, 1 H); 7.00 (d, 1 H, J = 2.2 Hz); 6.88 (dd, 1 H, J = 8.6, 2.4 Hz); 3.85 (s, 3H); 2.52 (s, 2H); 0.98 (s, 9H).

Step Preparation of 3- (2,2-dimethylpropyl-6-hydroxybenzofuran) To a solution at -10 ° C of the product from step D (2379 grams) in dry methylene chloride (35 ml) was added a solution of tribromide 1M boron (CH2Cl2, 3.70 ml), warmed to room temperature and then stirred for 1 hour.The reaction was partitioned between isopropyl acetate and aqueous sodium bicarbonate.The organic layer was washed twice with water and dried over Magnesium sulfate The filtration and removal of volatile materials provided a residue which was subjected to chromatography on silica gel (5: 1 hex / ethyl acetate) to give the title compound.1H NMR (400 MHz, CDCl3): d 7.34 (d, 1 H, J = 8.4 Hz); 7.28 (s, 1 HOUR); 6.93 (d, 1 H, J = 2.2 Hz); 6.76 (dd, 1 H, J = 8.4, 2.2 Hz); 4.98 (s, 1 H); 2.49 (s, 2H); 0.95 (s, 9H).

Step F: Preparation of 3- (2,2-dimethylpropi-6-allyloxybenzofuran) A stirred solution of the product from step E (2880 grams) in Dry DMF was treated with allyl bromide (1282 grams) followed by cesium carbonate (4828 grams). After 2 hours, the mixture was partitioned between isopropyl acetate and phthalate pH4 regulator. The organic layer was washed twice with water, dried over magnesium sulfate and filtered. The concentration gave the title compound in such a purity that no further purification was required. 1 H NMR (400 MHz, CDCl 3 1): d 7.37 (d, 1 H, J = 8.6 Hz); 7.28 (s, 1 H); 6.99 (d, 1 H, J = 2.2 Hz); 6.87 (dd, 1 H, J = 8.6, 2.2 Hz); 6.07 (mult 1 H); 5.43 (dquart, 1 H, J = 17.3, 1.6 Hz); 5.29 (dquart, 1 H, J = 10.5, 1.6 Hz); 4.56 (t, 1 H, J = 1.5. Hz); 4.55 (t, 1 H, J = 1.5 Hz); 2.49 (s, 2H); 0.95 (s, 9H).

Step G: Preparation of 3- (2,2-dimethylpropyl) -6-hydroxy-7-allylbenzofuran A solution prepared from 1,2-dichlorobenzene (65 ml) and the product of step F (3.226 grams) was subjected to reflux for 8 hours. The reaction, cooled to approximately 50 ° C, it was subjected to high vacuum, removing the solvent by distillation. The remaining solid was digested in refluxing cyclohexane, cooled to room temperature and filtered. The mother liquor was evaporated and chromatographed on silica gel (2.5: 1 hex / ethyl acetate), yielding more solid, which was added to the previous one, providing all the available title compound. 1 H NMR (400 MHz, CDCl 3): d 7.32 (s, 1 H); 7.26 (d, 1 H, J = 8.3 Hz); 6.80 (d, 1 H, J = 8.4 Hz); 6.09 (tquart, 1 H, J = 13.3, 1.0 Hz); 5.26 (quart, 1 H J = 1.7 Hz); 5.20 (hex, 1 H, J = 2.5 Hz); 5.16 (quart, 1 H, J = 1.5 Hz); 3.72 (t, 1 H, J = 1.5 Hz); 3.70 (t, 1 H, J = 1.5 Hz); 2.51 (s, 2H); 0.98 (s, 9H).

Step H: Preparation of 3- (2,2-dimethylpropi-6-hydroxy-7-propylbenzofuran) A solution of the product from step G (1912 grams) in methyl-butyl ether (20 ml) was combined with Pd / C catalyst 5% (200 mg) in a hydrogenation container The mixture was hydrogenated using a Parr apparatus at 0.4892 kg / cm2 for 1 hour.The catalyst was removed by filtration through celite and the filtrate was evaporated. used without further purification 1 H NMR (400 MHz, CDCl 3): d 7.28 (s, 1 H), 7.17 (d, 1 H, J = 8.3 Hz), 6.72 (d, 1 H, J = 8.4 Hz); (s, 1 H), 2.83 (t, 2H, J = 7.7 Hz), 2.48 (s, 2H), 1.70 (hex, 2H, J = 9.2 Hz), 0.99 (t, 3H, J = 7.5 Hz); 0.95 (s, 9H).

Step I: Preparation of Methyl 4- (3- (3- (2,2-d.methylpropyl) -7-propiibenzofuran-6-yloxy) -1 -propoxy) phenylacetate The title compound was prepared according to the method described in Example 1, step B, using 3- (2,2-dimethyl-1-propyl) -6-hydroxy-7-propyl benzofuran, (step H above) as starting material. 1 H NMR (400 MHz, CDCl 3): d 7.50-7.42 (m, 4H); 7.31 (d, 2H, J = 8.8 Hz); 7.19-7.16 (d, 2H, J = 8.3 Hz); 6.92-6.83 (m, 3H); 6.46 (s, 1 H) 4.21-4.16 (m, 4H); 3.67 (s, 3H); 3.54 (s, 2H); 2.95 (t, 2H, J = 7.4 Hz); 2.29 (quint, 2H, J = 6.3 Hz); 1.71 (hex, 2H, J = 5.9 Hz); 1.01 (t, 3H, J = 7.3 Hz).

Step J: Preparation of 5- | 4- (3- (3- (2,2-dimethylpropyl) -7-propyl-benzofuran-6-oxo-1-propoxy-1-phenyl-2,4-thiazole; The title compound was prepared according to the method described in example 1, step C, using 4- (3- (3- (2,2-dimethyl-1-propyl) -7-propyl-benzofuran-6 -iIoxi) -1-propoxy) methyl phenylacetate as starting material. 1 H NMR (400 MHz, CDCl 3): d 8.43 (brs, 1 H); 7.32-7.23 (m, 5H); 6.92 (d, 2H, J = 8.8 Hz), 6.84 (d, 1 H, J = 8.6 Hz), 5.32 (s, 1 H), 4.19 (apparent quarter, 4H, Jprom = 6.0 Hz), 2.82 (dd, 2H, J = 7.6, 1.5 Hz), 2.27 (quint, 2H, J = 6.1 Hz), 1.64 (hex, 2H, J = 7.3 Hz), 0.94 (s, 9H), 0.92 (t, 3H, J = 7.4 Hz).

EXAMPLE 68 5-f3- (4- (3- (2,2-D-methylpropyl) -7-propyl-benzofuran-6-yloxy) -1-butoxy) 1-phenyl-2,4-thiazolidinedione Step A: Preparation of methyl 3- (4- (3- (2,2-dimethylpropyl) -7-propyl-benzofuran-6-yloxy) -1-butoxybenzyl acetate The title compound was prepared in accordance with the method described in example 1, step B, using 3- (2,2-dimethyl-1-propyl) -6-hydroxy-7-propyl benzofuran (example 67, step H) as starting material. MHz, CDCl 3): d 7.50-7.42 (m, 4H), 7.31 (d, 2H, J = 8.8 Hz), 7.19-7.16 (d, 2H, J = 8.3 Hz), 6.92-6.83 (m, 3H); 6.46 (s, 1 H), 4.21 -4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.95 (t, 2H, J = 7.4 Hz), 2.29 (quint, 2H, J = 6.3 Hz), 1.71 (hex, 2H, J = 5.9 Hz), 1.01 (t, 3H, J = 7.3 Hz).

Step B: Preparation of 5-f3- (4- (3- (2,2-dimethylpropyl) -7-propyl-benzofuran-6-yloxy) -1-butoxyl-phenyl-2,4-thiazolidinedione Compound title was prepared according to the method described in example 1, step C, using 3- (4- (7-propii-3- (2,2-dimethyl-1-propyl) benzofuran-6-yloxy) -1- butoxy) methyl phenylacetate (step A above) as starting material: 1 H NMR (400 MHz, CDCl 3): d 9.41 (brs, 1 H); 7.31-7.24 (m, 3H); 6.90 (dd, 1 H, J = 8.3, 1.8 Hz), 6.85 (d, 1 H, J = 8.6 Hz), 5.27 (s, 1 H), 4.08-4.04 (m, 4H), 2.87 (dd, 2H, J = 7.5, 1.4 Hz); 2.50 (s, 2H); 2.00 (m, 4H): 1.69 (hex, 2H, J = 7.5 Hz), 0.97 (s, 9H), 0.95 (t, 3H, J = 7.4).

EXAMPLE 69 5-r3- (4- (3- (2-phenyletin-7-propyl-benzofuran-6-ylxp-1-butoxy) lphenyl-2,4-thiazolidinedione Step A: Preparation of 1- (3-methoxyphenoxy) -4-pheny! -2-butanone A solution of dry DMF (80 ml) of the product of example 63, step B (5.519 grams was exposed to 3-methoxyphenol (3.608 grams ) followed by cesium carbonate (9481 grams) After stirring at room temperature for 2 hours, the reaction was divided between isopropium acetate and phthalate pH4 regulator.The organic layer was washed twice with water, dried ( magnesium sulfate) and filtered The concentration and chromatography on silica gel (5: 1 hex (ethyl acetate) completed isolation of the title compound as a yellow solid.1H NMR (400 MHz, CDCl3): d 7.29 -7.14 (mult, 6H), 6.54 (dd, 1 H, J = 8.3, 2.3 Hz), 6.42 (t, 1 H, J = 2.4 Hz), 6.39 (dd, 1 H, J = 8.1, 2.5 Hz); 4.49 (s, 2H), 3.76 (s, 3H), 2.93 (s, 2H, overlapping to one dt, 1 H), 2.70 (dt, 1 H, J = 7.9, 10.5 Hz).

Step B: Preparation of 3- (2-phenyletiQ-6-methoxy-benzofuran) The product from step A (2.368 grams), dissolved in CH2Cl2 (25 ml) was added dropwise to a solution (10 ml) of CH2Cl2. at -10 ° C methanesulfonic acid (5.68 ml) The reaction was warmed to room temperature and stirred for 30 minutes The reaction was poured rapidly into a vigorously stirred cold mixture of excess 5N NaOH and methyl tert-butyl ether. The organic layer was dried over magnesium sulfate and filtered The concentration and chromatography on silica gel (gradient step: 4: 1 hex / CH 2 Cl 2 to 1: 1 hex / CH 2 Cl 2) gave the title compound as a clear oil. H NMR (400 MHz, CDCl 3): d 7.36 (d, 1 H, J = 8.5 Hz), 7.31-7.19 (mult, 6H), 7.00 (d, 1 H, J = 2.2 Hz), 6.87 (dd, 1 H, J = 8.5, 2.2 Hz), 3.84 (s, 3H), 3.02-2.91 (mult, 4H).

Step C: Preparation of 3- (2-phenylethyl) -6-hydroxy-benzofuran A stirred solution at -10 ° C of the product from step B (2066 grams, dry methylene chloride, 20 ml) was treated with a tribromide solution of 1 M boron (methylene chloride, 8.40 ml). After 15 minutes, the reaction was warmed to room temperature and stirred another 15 minutes. It was partitioned between isopropyl acetate and pH 7 phosphate buffer, washed twice with pH 7 regulator and dried over magnesium sulfate. Filtration and evaporation yielded an oil which was chromatographed on silica gel (gradient step CH2Cl2 at 40: 1 CH2Cl2 / ethyl acetate). The title compound was isolated as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3): d 7.32 (d, 1 H, J = 8.4 Hz); 7.30-7.19 (mult, 6H); 6.93 (d, 1 H, J = 2.2 Hz); 6.76 (dd, 1 H, J = 8.4, 2.2 Hz); 4.88 (vbrs, 1 H); 3.01-2.90 (mult, 4H).

Step D: Preparation of 3- (2-phenylethyl) -6-allyloxy-benzofuran A stirred solution of the product from step C (1128 grams) in dry DMF (15 ml) was exposed to allyl bromide (0.43 ml) followed by carbonate of cesium (1,620 grams). After stirring overnight at room temperature, the mixture was partitioned between isopropyl acetate and phthalate pH 4 regulator. The organic layer was washed twice with water, dried over magnesium sulfate and filtered. Evaporation gave the title compound, which did not require further purification. 1 H NMR (400 MHz, CDCl 3): d 7.36 (d, 1 H, J = 8.6 Hz); 7.30-7.18 (multi, 6H); 7.00 (d, 1 H, J = 2.2 Hz); 6.89 (dd, 1 H, J = 8.6, 2.3 Hz); 6.13-6.03 (multi, 1 H); 5.43 (dquarts, 1 H, J = 17.3, 1.6 Hz); 5.30 (dquarts, 1 H, J = 10.5, 1.4 Hz); 4.57 (t, 1 H, J = 1.5 Hz), 4.56 (t, 1 H, J = 1.5 Hz); 3.01-2.91 (multi, 4H).

Step Preparation of 3- (2-phenylethyl) -6-hydroxy-7-allyl-benzofurane The product of step D (1245 grams), dissolved in 1,2-dichlorobenzene (20 ml) was refluxed under nitrogen for 1 hour. 1 hours The solution was cooled to approximately 50 ° C. High vacuum was applied and the solvent was removed until the residue solidified. The solid dissolved in CH2 C (100 ml), was recovered and re-evaporated, and subjected to chromatography on silica gel (5: 1 hex / ethyl acetate). Evaporation of the appropriate fractions gave the title compound as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3): d 7.35-7.19 (mult, 7H) 6.82 (d, 1 H, J = 8.2 Hz); 6.12 (multi, 1 H); 5.25-5.14 (overlapping dquarts, 2H; lower J = 17.2, 1.7 Hz; higher J = 10.1, 1.6 Hz); 3.73 (t, 1 H, J = 1.6 Hz); 3.70 (t, 1 H, J = 1.6 Hz); 3.06-2.92 (multi, 4H).

Step F: Preparation of 3- (2-phenylethyl) -6-hydroxy-7-propyl-benzofuran The product of step E (1.1-16 grams) was dissolved in tert-butyl-methyl ether (12 ml) and placed in a hydrogenation container. The 5% Pd / C catalyst (10 mg) was added and the mixture was hydrogenated for 0.5 hour using a Parr apparatus (0.4892 kg / cm2). Filtration through celite and evaporation gave the title compound as a yellow oil. Upon standing, a pale yellow solid was produced which did not require further purification. 1 H NMR (400 MHz, CDCl 3): d 7.36-7.22 (multi, 7H); 6.78 (d, 1 H, J = 8.3 Hz); 5.17 (s, 1 H); 3.06-2.95 (multi, 4H); 2.91 (t, 2H, J = 7.6Hz); 1.79 (hex, 2H, J = 6.0 Hz); 1.04 (t, 3H, J = 7.3 Hz).

Step G: Preparation of methyl 3- (4- (3- (2-phenylethyl) -7-propyl-benzofuran-6-ylox-1-butoxy) phenylacetate The title compound was prepared according to the method of Example 1, step B. Using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzofuran (step F above) as starting material: 1 H NMR (400 MHz, CDCl 3): d 7.50-7.42 (m, 4H) 7.31 (d, 2H, J = 8.8 Hz), 7.19-7.16 (d, 2H, J = 8.3 Hz), 6.92-6.83 (m, 3H), 6.46 (s, 1 H), 4.21-4.16 (m, 4H), 3.67 (s, 3H), 3.54 (s, 2H), 2.95 (t, 2H, J = 7.4 Hz), 2.29 (quint, 2H, J = 6.3 Hz), 1.71 (hex, 2H, J = 5.6) Hz); 1 .01 (t, 3H, J = 7.3 Hz).

Step H: 5-r3- (5- (2-propyl-4- (4'-phenylphenoxy) -phenyl] pentoxy) phenyl1-2.4-thiazolidinedione The title compound was prepared according to the method described in the example 1, step C, using methyl 3- (4- (3- (2-phenylethyl) -7-propyl-benzofuran-6-yloxy) -1-butoxy) phenylacetate (step G above) as starting material. 1 H NMR (400 MHz, CDCl 3): d 8.67 (brs, 1 H); 7.32-7.18 (m, 4H); 6.90 (dd, 1 H, J = 8.3, 2.5 Hz); 6.85 (d, 1 H, J = 8.5 Hz); 5.29 (s, 1 H); 4.14-4.04 (m, 4H); 2.94 (m, 4H) 2.85 (t, 2H, J = 7.6 Hz); 2.00 (bm, 4H); 1.67 (hex, 2H, J = 5.6 Hz); 0.94 (t, 3H, J = 7.4 Hz).

EXAMPLE 70 5-r3- (4- (3- (2-Phenyletin-7-propyl-benzothiophen-6-yloxn-1-butoxy) 1-phenyl-2,4-thiazo-dinedione Step A: Preparation of methyl 3- (4- (3- (2-phenylethyl) -7-propyl-benzothiophen-6-yloxy-1-butoxyphenylacetate The title compound was obtained using the method described in example 1, step B, using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene (example 63, step H) as starting material. 1 H NMR (400 MHz, CDCl 3): d 7.57 (d, 1 H, J = 8.7 Hz); 7.34 (t, 2H, J = 7.3 Hz); 7.28-7.24 (muiti, 4H); 7.06 (d, 1 H, J = 8.7 Hz); 6.92-6.84 (multi, 4H); 4.14 (brt, 2H, J = 5.2 Hz); 4.08 (brt, 2H, J = 5.5 Hz); 3.71 (s, 3H); 3. 62 (s, 2H) 3.13-3.06 (multi, 4H); 2.91 (dd, 2H, J = 9.2, 7.6 Hz); 2.05 (brpent, 4H, J = 2.7 Hz); 1.77 (hex, 2H, J = 7.5 Hz); 1.04 (t, 3H, J = 7.4 Hz).

Step B: Preparation of 5-33- (4- (3- (2-phenylethi-7-propyl-benzothiophen-6-yloxy) -1-butoxophenyl-2,4-thiazolidinedione The title compound was prepared in accordance with the method described in example 1, step C, using methyl 3- (4- (3- (2-phenylethyl) -7-propylbenzothiophen-6-yloxy) -1-butoxy) phenylacetate (step A above) as starting material: 1 H NMR (400 MHz, CDCl 3): d 9.41 (brs, 1 H), 7.56 (d, 1 H, J = 8.8 Hz), 7.35-7.20 (multi, 6H), 7.05 (d, 1 H, J = 8.8 Hz), 6.99-6.85 (multi, 4H), 5.26 (brs, 1 H) 4.12 (brs, 2H), 4.07 (brs, 2H), 3.08 (brquart, 4H), 2.90 (brt, 2H) , J = 7.5 Hz), 2.04 (brs, 4H), 1.76 (brhex, 2H, J = 7.6 Hz), 1.02 (t, 3H, J = 7.3 Hz).

EXAMPLE 71 5-r4- (3- (3- (2-phenylethyl) -7-propyl-benzothiophen-1-oxide-6-yloxy) -1-propoxyphenyl-2,4-thiazolidinedione The title compound was prepared by the method described in Example 66, Step A, using 5- [3- (4- (3- (2-phenylethyl) -7-propyl-benzothiophen-6-yloxy) -1-butoxy ) phenyl-2,4-thiazolidinedione as the starting material. 1 H NMR (400 MHz, CDCl 3, diastereomeric pair): d 8.83 (brs, 1 H); 7.36-7.32 (multi, 4H); 7.28-7.20 (multi, 4H); 6.99-6.93 (multi, 3H); 6.64 (d, 1 H, J = 1.4 Hz); 5.34 (s, 1 H); 4.21 (brt, 4H, J = 5.9 Hz); 3.07-2.92 (multi, 4H); 2.87 (brt, 2H, J = 7.6 Hz); 2.33 (pent, 2H, J = 5.8 Hz); 1.70 (brhex, 2H, J = 7.8 Hz); 1.01 (dt, 3H, J = 7.3, 1.7 Hz).

EXAMPLE 72 d- -p-tea ^ ropiM - ^ '- fluorofenoxOfenoxOpropoxOfenip-S ^ - thiazolidinedione Step Preparation of 5-r4- (3- (2-propyl-4- (4'-fluorophenoxy) phenoxy) -propoxy) phenin-2,4-thiazolidinedione This compound was prepared using the procedure described in example 22, step C , using 2-propyl-4- (4'-fluorophenoxy) -phenol (as prepared in example 23, step A using 4-fluorophenol); followed by the procedure described in Example 23, step D. 1 H NMR (400 MHz, CDCl 3): d 7.98 (broad s, 1 H); 7.32 (d, 2H, J = 8.66 Hz); 6.9 (m, 6H); 6.76 (m, 3H); 5.37 (s, 1 H); 4.17 (t, 2H, J = 4.14 Hz); 4. 09 (t, 2H, J = 5.94 Hz); 2.52 (q, 2H, 7.5 Hz); 2.26 (t, 2H, J = 6.02 Hz); 1.54 (m, 2H, 7.5 Hz); 0.88 (t, 3H, J = 7.32 Hz).

EXAMPLE 73 5-r4- (3- (2-propyl-4'-tolylsulfonamidophenoxy) phenoxy) -propoxy) phenin-2,4-thiazolidinedione Step A: Preparation of 2-propyl-4- (4'-tolylsulfonamidophenoxy) phenol A solution of 4-allyloxyphenol (as prepared in example 22, step A, first paragraph) (5.0 g, 33.3 mmole), 4-fluoro-1-nitrobenzene (5.17 g, 36.6 mmol), potassium carbonate (6.9 g, 49.9 mmol) and dimethylacetamide (20 ml) was heated to reflux overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated. Subsequently, the residue was chromatographed on silica gel using methylene chloride and hexane (20% to 50%) to give the desired product as a yellow oil (7.3 g). The yellow oil (7.3 g) was taken in dichlorobenzene (30 ml) and refluxed overnight. The reaction solution was concentrated to a Black oil and chromatographed on silica gel using 10% acetone / hexane to give an orange oil (4.9 g). The orange oil (1 g, 3.68 mmol) was dissolved in DMF (5 ml) containing imidazole (626 mg, 9.2 mmol). To this was added t-butyldimethyl-chlorosilane (468 mg, 4.42 mmol) and the reaction was stirred for 4 hours. The reaction solution was subsequently partitioned between ethyl acetate and water. The organic layer was separated, dried (sodium sulfate) and concentrated to give a yellow oil (~ 1.5 g). Subsequently, this oil was dissolved in ethyl acetate (10 ml) and 10% palladium on carbon (250 mg) were added and the reaction mixture was stirred under a hydrogen atmosphere for 45 minutes. The reaction mixture was then filtered through celite and the filtrate was concentrated to give an orange oil (1.42 g). The orange oil (700 mg, 4.9 mmol) was taken up in methylene chloride (5 ml) and pyridine (0.4 ml, 4.9 mmol). To this solution was added tosyl chloride (448 mg, 2.35 mmol) and n-dimethylaminopyridine (10 mg), and the reaction was stirred overnight. The reaction was partitioned between ethyl acetate and water. Subsequently, the organic layer was separated, dried (sodium sulfate) and concentrated to give an orange oil (800 mg). This oil was taken in THF (5 ml) and cooled to 0 ° C. To this solution was added t-butyl ammonium fluoride and the reaction was stirred for two hours. The reaction was partitioned between ethyl acetate and water. The organic layer was then separated, dried (sodium sulfate) and concentrated to give a yellow oil (440 mg). 1 H NMR (400 MHz, CDCl 3): d 7.37 (d, 2H); 6.92 (d, 2H); 6.85 (m, 3H); 6.79 (bs, 2H); 4.71 (bs, 1 H); 3.04 (s, 3H); 2.57 (t, 2H); 1.65 (m, 2H); 0.97 (t, 3H).

Step B: Preparation of ethyl 4- (3- (2-propyl-4- (4'-tolylsulfonamido-phenoxy) phenoxy) propoxy) mandelate The title compound was prepared according to the method described in example 22, Step C using 2-propyl-4- (4'-tolylsulfonamido-phenoxy) phenol (19.0 g, 62.0 mmol) and 4-3-bromopropoxy) -mandelate as starting materials.

Step C: Preparation of ethyl a-chloro-4- (3- (2-propyl-4 (-4'-tolylsulfonamido) phenoxy) -propoxy) phenylacetate The title compound was prepared according to the method described in the example 22, step D, using ethyl 4- (3- (2-propyl-4- (4'-tolylsulfonamido phenoxy) phenoxy) propoxy) mandelate (16.8 g, 30.18 mmol) as the starting material. 1 H NMR (400 MHz, CDCl 3): d 7.37 (d, 2H); 7.23 (m, 6H); 6.91 (d, 2H); 6.82 (m, 3H); 6.73 (bs, 2H); 5.27 (bs, 1 H); 4.2 (m, 2H); 3.93 (t, 2H); 3.84 (t, 2H); 2.85 (s, 3H); 2.57 (t, 2H); 1.93 (m, 2H); 1.63 (m, 2H); 1.05 (t, 3H); 0.95 (t, 3H).

Step D: Preparation of 5- [4- (3- (2-propyl-4 (4'-tolylsulfonamidophenoxy) phenoxy) propoxy) phene-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, step C (second paragraph), using ethyl α-chloro-4- (3- (2-propyl-4- (4'-tolylsulfonamidophenoxy) phenoxy) propoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.06 (bs, 1 H); 7.29 (d, 2H); 7.23 (m, 6H); 6.89 (m, 2H); 6.85 (m, 3H); 6.72 (bs, 2H); 5.3 (s, 1 H); 4.67 (s, 1 H); 4.01 (t, 2H); 3.84 (t, 2H); 2.88 (s, 3H); 2.57 (t, 2H); 1.98 (m, 2H); 1.63 (m, 2H); 0.97 (t, 3H).

EXAMPLE 74 5-r4- (3- (2-propyl-4-pyrazinyloxyphenoxy) propoxy) phenin-2,4-thiazolidinedione Step A: Preparation of 2-propyl-4-pyrazinyloxy-phenol The title compound was prepared according to the method described in Example 73, Step A by replacing chloropyrazine with 4-fluoro-nitrobenzene as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.36 (s, 1 H); 8.21 (s, 1 H); 8.1 (d, 1 H); 6.90 (d, 1 H); 6.82 (m, 1 H); 6.74 (d, 1 H); 5.67 (bs, 1 H); 2.55 (t, 2H); 1.59 (m, 2H); 0.95 (t, 3H).

Step B: Preparation of ethyl 4- (3- (2-propyl-4-pyrazinyloxyphenoxypropoxy) mandelate The title compound was prepared according to the method described in example 22, step C using 2-propyl-4-pyrazinyloxyphenol ( 19.0 g, 62.0 mmoles) and ethyl 4- (3-bromopropoxy) mandelate (19.5 g, 58.9 mmoles) (as prepared in example 22, step C) as starting materials.

Step C: Preparation of ethyl chloro-4- (3- (2-propyl-4-pyrazinylloxy-phenoxy) -propoxy) phenylacetate The title compound was prepared according to the method described in example 22, step D , using 4- (3- (2-propyl-4-pyrazinyl-oxyphenoxy) propoxy) ethyl mandelate (16.8 g, 30.18 mmol) as the starting material.

Step D: Preparation of 5-r4- (3- (2-propyl-4-p -razinylloxyphenoxy) propoxy) phenyl1-2,4-thiazolidinedione The title compound was prepared according to the method described in Example 1, Step C (second paragraph), using chloro-4- (3- (2- ethyl propyl-4-pyrazinyloxyphenoxy) propoxy) phenylacetate as the starting material. 1 H NMR (400 MHz, CDCl 3): d 8.35 (s, 1 H); 8.20 (s, 1 H); 8.07 (d, 1 H); 7.95 (bs, 1 H); 7.32 (d, 2H); 6.93 (m, 3H); 6.85 (m, 2H); 5.32 (s, 1 H); 4.17 (m, 4H); 2.55 (t, 2H); 2.26 (m, 2H); 1.57 (m, 2H); 0.90 (t, 3H).

EXAMPLE 75 5-r 3 - (3- (2-cyclopropylmethyl-4-phenoxy) propoxy) -phenin-2,4-thiazolidinedione Step A: Preparation of 2-cyclopropylmethyl-4-phenoxyphenol To a solution of 2-allyloxy-4-phenoxyphenol (PCT Application WO97 / 281-15) (1.0 g, 4.45 mmol) in ethyl ether cooled to 0 ° C was added diazomethane (20 ml of a 0.70 M solution in Et2O) under nitrogen. After 5 minutes of stirring, palladium acetate (cat, 2mg) was added. After 10 minutes, an additional amount of diazomethane (6 ml of a 0.70 M solution in Et 2 O). The reaction was stirred for 30 minutes at room temperature. The reaction mixture was filtered through a pad of celite, and the ether was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 10% EtOAc: hexane. Evaporation of the purified fractions and removal of the solvent in vacuo gave the title compound. 1 H NMR (400 MHz, CDCl 3): d 7.32-6.77 (ar, 8H); 4.82 (s, 1 H); 2.53 (d, 2H, J = 6.65 Hz); 0.55 (m, 2H).

Step B: Preparation of 5-r3- (3- (2-cyclopropylmethyl-4-phenoxy) propoxy) phenyl! 1-2,4-thiazo! Idinedione Using methyl 3- (3-bromopropoxy) mandelate and 2- cyclopropylmethyl-4-phenoxyphenol (as prepared in step A) as the starting materials for example 22, step B; the title compound was prepared according to the methods described in example 22, steps of B to D. 1 H NMR (400 MHz, CDCl 3): d 7.35-6.83 (ar, 12H); 5.33 (s, 1 H); 4.16 (m, 4H); 2.52 (d, 2H, J = 6.87 Hz); 2.27 (quint, 2H, J = 6.04 Hz); 0.47 (m, 2H); 0.12 (m, 2H).

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has the formula I: wherein, Ar 1 is (1) arylene or (2) heteroarylene, wherein the arylene or heteroarylene is optionally substituted with about 1 to 4 groups selected from Ra; Ar2 is (1) ortho-substituted aryl or ortho-substituted heteroaryl (2), wherein said ortho substituent is selected from R; and the aryl or heteroaryl is optionally substituted with about 1 to 4 groups independently selected from Ra; X and Y are independently O, S, N-Rb, or CH2; Z is O or S; n is 0 to 3; R is (1) C3-? 0 alkyl optionally substituted with 1-4 groups selected from halo or C3-6 cycloalkyl, (2) C3-? 0 alkenyl, or (3) C3-β cycloalkyl; R a is (1) C 1 -15 alkanoyl, (2) C 1-15 alkyl, (3) C 2-15 alkenyl, (4) C 2-15 alkynyl, (5) halo, (6) OR b, ( 7) aryl, or (8) heteroaryl, wherein said alkyl, alkenyl, alkynyl and alkanoyl are optionally substituted with 1-5 groups selected from Rc, and said aryl and heteroaryl are optionally substituted with 1 to 5 groups selected from Rd; Rb is (1) hydrogen, (2) C-O alkyl, (3) C2-10 alkenyl. (4) C2-10 alkynyl, (5) aryl, (6) heteroaryl, (7) aryl-C1-15 alkyl, (8) heteroaryl-C?-alkyl, (9) C-MS alkanoyl, (10) C 3-8 cycloalkyl, wherein alkyl, alkenyl, alkynyl are optionally substituted with one to four substituents independently selected from R °, and cycloalkyl , aryl and heteroaryl are optionally substituted with one to four substituents selected from Rd; or R c is (1) halo, (2) aryl, (3) heteroaryl, (4) CN, (5) NO 2, (6) OR f; (7) S (O) mRf, m = 0, 1 or 2, with the proviso that Rf is not H when m is 1 or 2; (8) NRfRf, (9) NRfCORf, (10) NRfCO2Rf, (1 1) NRfCON (Rf) 2, (12) NRfSO2Rf, with the proviso that Rf is not H, (13) COR, (14) CO2Rf, ( 15) CON (Rf) 2, (16) SO2N (Rf) 2, (17) OCON (Rf) 2, or (18) C3-8 cycloalkyl, wherein said cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 halo or alkyl groups of d-β; Rd is (1) a group selected from Rc, (2) C? _ ?alkyl, (3) C2-10 alkenyl, (4) C2-alqu o alkynyl. (5) aryl-C?-Βalkyl, or (6) heteroaryl-C alquilo-alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from Re; Re is (1) halogen, (2) amino, (3) carboxy, (4) C1-4 alkyl, (5) C1- alkoxy, (6) hydroxy, (7) aryio, (8) aryl-alkyl of C -? -, or (9) aryloxy; Rf is (1) hydrogen, (2) C2- [alpha] -10 alkyl, (3) C2- [alpha] alkenyl, or (4) C2- [alpha] alkynyl. (5) aryl, (6) heteroaryl, (7) aryl-C1-15 alkyl, (8) heteroaryl-C1-15 alkyl, (9) C-? -15 alkanoyl, (10) C3- cycloalkyl 8, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with one to four groups selected from Re; or a pharmaceutically acceptable salt thereof. 2. - A compound according to claim 1, further characterized in that Z is sulfur. 3. A compound according to claim 1, further characterized in that Ar1 is arylene optionally substituted with 1-4 groups selected from Ra. 4. A compound according to claim 3, further characterized in that Ar1 is phenylene optionally substituted with 1-2 groups selected from halogen and C1-4 alkyl. 5. A compound according to claim 1, further characterized in that X and Y are independently CH2, O or S. 6. A compound according to claim 5, further characterized in that X and Y are each O. 7 .- A compound according to claim 1, further characterized in that Ar2 is wherein Ra 'is selected from Ra, or 2 Ra' groups on adjacent carbon atoms taken together complete a 5 or 6 membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) m ( m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra. 8. A compound according to claim 7, further characterized in that R is C3- alkyl. 9. A compound according to claim 7, further characterized in that Ra 'is selected from ORb, aryl optionally substituted with 1 to 5 groups independently selected from Rd, and C?-15 alkyl optionally substituted with 1 to 5 groups independently selected from Rc. 10. A compound according to claim 7, further characterized in that 2 groups Ra 'on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 1-2 heteroatoms selected from N, O and S ( O) m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra. 1 - A compound according to claim 7, further characterized in that Ra 'is selected from O-phenyl wherein phenyl is optionally substituted with 1 to 4 groups selected from Rd, phenyl optionally substituted with 1 to 2 halogens, and alkyl of C? -5 optionally substituted with 1 to 5 groups independently selected from halogen, phenyl, and C3-8 cycloalkyl. 12. A compound according to claim 7, further characterized in that 2 groups Ra 'on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring selected from isoxazole, thiophene (S-oxide and S-dioxide) and furan each of which is optionally substituted with 1 to 2 groups selected from Ra. 13. - A compound according to claim 1, further characterized in that n is 1 or 2. 14. A compound according to claim 1, having the formula: wherein Ra 'is selected from Ra, or 2 Ra' groups on adjacent carbon atoms taken together complete a 5 or 6 membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) m (m is 0-2), said ring being optionally substituted with 1-2 groups selected from Ra; X, Y, Z, n, R and Ra are as defined in claim 1. 15. A compound according to claim 14, further characterized in that Z is S. 16. A compound according to claim 14 , further characterized in that Y is S or O, and X is O. 17. A compound according to claim 14, further characterized in that R is C3-4 alkyl. 18. - A compound according to claim 14, further characterized in that n is 1 or 2. 19. A compound according to claim 14, further characterized because Z is S; X is O; And it is (1) O or (2) S; R is C3-4 alkyl; Ra is (1) halogen or (2) C 1-5 alkyl; Ra 'is (1) O-aryl optionally substituted with 1 to 3 groups independently selected from Rd, (2) aryl optionally substituted with 1 to 3 groups selected from Rd, (3) C ?5 alkyl optionally substituted with 1 to 5 selected groups of Rc, or 2 Ra 'groups on adjacent carbon atoms taken together complete a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) m (m is 0-2 ), said ring being optionally substituted with 1-2 groups selected from Rd. 20.- A compound according to claim 1, further characterized in that it is selected from the group consisting of: 4i. W ^ -? ^? 5 > . i > -í ^ í- 4-. ^? ? ^ ^ * point of attachment of Y to the phenyl ring. ** c-Hex is cyclohexyl. TABLE 2 z Ra * YLX R ** Rd s H 4 O (CH2) 3O propyl 4 'H s 3-Cl 4 O (CH2) 3O propyl 4' H s 3-F 4 O (CH2) 3O propyl 4 'H s 3 -propyl 4 O (CH2) 3O propyl 4 'H s 3-Cl 4 S (CH2) 3O propyl 4' H s? C? C? C? C? C? CO C? C? C? C? C? O O C? C? C? C? C? ? ? ? ? •? T3 T3 3? ? ? ? o O O O O o o o o o o o o o O O O T3 TD "O 3 • or -s T3 -a 3 -s T s3 • or" O "O X3 T.3 -O 3 - ^ '. '- ^' F '. - ' Ji '. ^ J ^ Ji. - ^ 'Ji. -t ^ ^ • fc - £ - O ^ *. I- CO or o or X t-? ° TI ro O X X X X X X X z or O or X? X O? X? X X z Ra * Y-L-X R ** Rd S H 3 (CH 2) 5 O propyl 4 '4-OCH 3 s H 3 (CH 2) 5 O propyl 4' 4-F s H 3 O (CH 2) 5 propyl 4 '4-Ph s H 4 O (CH 2) 4 propyl 4' 4-OCH3 s H 3 O (CH2) 4 propyl 4 '4-F s H 3 O (CH2) 5 propyl 4' 4-CI s H 3 O (CH2) 3O propyl 4 '3-CH3-4-CI s H 4 O (CH 2) 3 O propyl 4 '4-CH 2 CH (CH 3) 2 s H 3 O (CH 2) 3 O propyl 4' 4-c-pentyl s H 3 O (CH 2) 3 O propyl 4 '4-CH (CH 3) 2 s 3-propyl 4 O (CH 2) 3 O propyl 4 '4-OCH 3 s H 4 O (CH 2) 4 O propyl 4' 4-OCH 3 s H 4 O (CH 2) 4 O propyl 4 '4-F s H 3 O ( CH2) 4O propyl 4'4-OCH3 s H3O (CH2) 4O propyl 4'4-CI s H 3 O (CH2) 3O propyl 4'4-SO2CH3 s H 3 O (CH2) 4O propyl 4'4 SO2CH3 s H 4 O (CH2) 3O propyl 5 'H s H 4 O (CH2) 3O propyl 3' H s H 3 O (CH2) 4O propyl 3 'H s H 3 O (CH2) 3O allyl 4' H s H 3 O (CH 2) 3 O 3 -F-propyl 4 'H s H 3 O (CH 2) 3 O Propyl 4' 4 -CO 2 CH 2 CH 3 s H 4 O (CH 2) 3 O propyl 4 '4-F s H 4 O (CH 2) 3O propyl 4 '4- (4'-tolyl sulfonamide) s H 3 O (CH 2) 3 O c-pr-CH 2 t 4' H TABLE 3 n Ra (1) Ra (2) 4 3 4-F-Ph H 3 3 2-naphthyloxy H 3 3 2-dibenzofuranyl H 3 3 phenoxy propyl 4 3 3-isoxazolyl H 3 4 3-isoxazolyl H 4 3 pyrazinyloxy H * Point of attachment of O to the phenyl ring. 21. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 22. The use of a compound as claimed in claim 1 for the manufacture of a medicament for treating, controlling or preventing diabetes mellitus in a mammal. 23. The use of a compound as claimed in claim 1 for the manufacture of a medicament for treating, controlling or preventing hyperglycemia in a mammal. 24. - The use of a compound as claimed in claim 1, for the manufacture of a medicament for treating, controlling or preventing hyperlipidemia in a mammal. 25. The use of a compound as claimed in claim 1 for the manufacture of a medicament for treating, controlling or preventing obesity in a mammal. 26. The use of a compound as claimed in claim 1, for the manufacture of a medicament for treating, controlling or preventing hypercholesterolemia in a mammal. 27. The use of a compound as claimed in claim 1 for the preparation of a medicament for treating, controlling or preventing hypertriglyceridemia in a mammal.