CZ20002286A3 - Arylthiazolidinedione derivatives - Google Patents

Abstract

The arylthiazolidinedione derivatives of the general formula (I) in which: the individual symbols are of specific importance, they are effective PPAR receptor agonists and can therefore be used in a form a pharmaceutical composition which also forms part of the solution, for the treatment, alleviation or prevention of diabetes, hyperglycemia, hyperlipidemia including hypercholesterolemia; hypertriglyceridemia, atherosclerosis, obesity, vascular restenosis and similar diseases, disorders and conditions in which they occur participating in PPAR.

Description

Technical field

Arylthiazolidinedione derivatives and pharmaceutically acceptable salts thereof. These compounds are particularly effective as PPAR agonists. The invention also relates to a process for the preparation of these substances and to a pharmaceutical composition containing them.

BACKGROUND OF THE INVENTION

Diabetes is a disease that is caused by a variety of causes and is manifested mainly by increased blood glucose concentration, hyperglycemia. If left untreated, disease development and increased and premature mortality occur due to an increased risk of damage to both small and large vessels, resulting in nephropathy, neuropathy, hypertension, retinopathy, stroke and heart disease. For this reason, controlling glucose concentration in the bloodstream is critical in the treatment of diabetes.

There are two recognized types of diabetes. In type I diabetes, or insulin-dependent diabetes, IDDM produces little or no insulin at all. In Type II non-insulin dependent diabetes mellitus (NIDDM), patients often have a blood insulin concentration that corresponds to healthy individuals and in some cases is higher. However, these patients have developed insulin resistance, usually sensitive to insulin, so that glucose and lipid metabolism in muscles, liver and adipose tissue is particularly affected and normal plasma insulin concentrations are insufficient to overcome tissue resistance.

• · · ·

Insulin resistance is not primarily due to a decrease in the number of insulin receptors, it is a defect in binding to the postinsulin receptor, which is not yet satisfactorily explained. The resulting insulin resistance results in insufficient glucose activation upon intake, insufficient oxidation and deposition in muscles, as well as insufficient suppression of lipolysis in adipose tissue and production and secretion of glucose in liver tissue.

Common treatments for NIDDM have not changed much in recent years and have limitations. Physical exercise and reduced food intake dramatically improves this type of diabetes, but patients are usually not willing to change their way of life. This type of diabetes usually occurs in people with a sedentary occupation and increased body weight, especially in the case of high fat intake. Increasing the plasma insulin concentration by administering sulfonylureas such as tolbutamide or glipizide that stimulate the pancreatic beta cells to secrete more insulin or inject insulin may ensure sufficient concentration of the substance to stimulate resistant tissues. However, with this method of treatment, there may be a dangerous decrease in blood glucose concentration, and usually insulin resistance also increases further, so that its increased concentrations are also insufficient. Biguanide derivatives increase the sensitivity of tissues to insulin and may have a beneficial effect. These substances, especially phenformin and metformin, can induce acidosis due to the presence of lactic acid as well as nausea and diarrhea.

Glitazones, such as 5-benzylthiazolidine-2,4-diones, are a newer group of substances with somewhat different ways to improve the symptoms of NIDDM. These substances substantially increase insulin, muscle, liver and adipose tissue sensitivity in the animal model for the disease and can completely correct elevated glucose, triglyceride and non-esterified fatty acid concentrations without the risk of hypoglycaemia.

Hyperlipidemia is a condition characterized by an abnormal increase in serum lipid concentrations. These are, in particular, cholesterol, triglycerides and phospholipids. These lipids are not in solution in blood plasma, but are bound to proteins and transported as macromolecular complexes, referred to as lipoproteins. These phenomena have been described in Merck Manual, 16th edition 1992, eg pages 1039-1040, and also in the publication "Structure and Metabolism of Plasma Lipoproteins" in Metabolic Basis of Inherited Disease, 6th Edition 1989, pages 1129-1138.

One form of hyperlipidemia is hypercholesterolemia, which is characterized by an increased concentration of LDL cholesterol. At the beginning of the treatment of this condition, the diet is often adjusted to a low intake of fat and cholesterol, while physical exercise is recommended. If these measures are not sufficient, medication is given. LDL is commonly referred to as "harmful" cholesterol, while HDL has a beneficial effect. Although it is desirable to lower the elevated LDL cholesterol concentration, it is also desirable to increase the HDL cholesterol concentration. Increased HDL concentrations have been shown to be associated with a lower risk of coronary artery disease as described by 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. Internal Med., 90, 85-91, 1979. An example of an HDL-enhancing agent is nicotinic acid, but the amount of acid required for this is associated with undesirable effects such as the formation of volatile rashes.

Peroxisome proliferation enhancers are substances with different structures that produce a dramatic increase when given to rodents • φ • · φ φ

φ • ΦΦΦ

the number of peroxisomes in the liver and kidneys and their enlargement, and at the same time the capacity of peroxisomes to metabolize fatty acids through increased expression of beta-oxidative cycle enzymes is also increased. Compounds of this class are, for example, fibrates, which also reduce the serum fat concentration, herbicides and some phthalates. Peroxisome proliferation can also be caused by dietary and physiological factors such as a fat-rich diet and a cold environment.

To date, three receptor subtypes have been shown to be activated by peroxisome proliferation enhancers. These receptors are called PPARs. These are alpha receptor, PPARalpha, gamma receptor, PPARgamma and delta receptor, PPARdelta. Identification of the PPARalpha receptor, which belongs to the nuclear hormone receptor activated by peroxisome proliferation enhancers, facilitated the analysis of the mechanism of proliferation enhancers. The PPARalpha receptor is activated by a variety of medium and long chain fatty acids and is involved in stimulating beta-oxidation of fatty acids. This receptor is also involved in the activity of fibrates and fatty acids in both rodents and humans. Derivatives of these substances, such as clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil, cause a substantial decrease in plasma triglyceride concentration and a slight decrease in LDL cholesterol and are used especially for the treatment of hypertriglyceridaemia.

The PPARgama subtype is involved in the activation of fat cell differentiation and is not involved in stimulating peroxisome proliferation in the liver. There are two isoforms of this receptor, PPARgamma 1 and PPARgamma2, which differ only in that the PPARgam2 form contains an extra 28 amino acid residues at the amino terminal terminus. DNA sequences for these isotypes have been described in Elbrecht et al., BBRC 224: 431-437, 1996. In mice, PPARgamma2 is expressed specifically in adipose cells. Tontonoz et al., Cell 79, 1147-1156, 1994 describes the physiological role of PPARgamma2 in inducing adipocyte differentiation. PPARgamma2 directs gene expression through interaction with other proteins and binding to hormone-influenced elements, eg, near the 5'-region of the genes involved.

As an example of a gene that responds to PPARgamma2 is a tissue-specific P2 adipocyte gene. Although peroxisome proliferation activators, including fibrates and fatty acids, also activate PPAR transcription efficiency, only prostaglandin J ₂ derivatives have hitherto been identified as natural ligands for the PPARgamma subtype, they may also bind with high affinity to a thiazolidinedione antidiabetic agent.

The human core receptor for the PPARdelta gene (hPPARdelta) was cloned from a human osteosarcoma cDNA cell bank and its sequence was fully described in A. Schmidt et al., Molecular Endocrinology, 6, 1634-1641, 1992. It is noted that PPARdelta is found in often referred to in the literature as PPARbeta or NUCD1, each of which denotes the same receptor. In Schmidt et al., The receptor is referred to as NUC1.

International patent application WO 96/01430 discloses a human PPAR subtype, hNUCIB. The amino acid sequence of this substance is different from the human PPARdelta, referred to as hNUC1, but differs by a single amino acid residue, namely the amine at position 292. According to in vivo experiments, the authors believe that hNUCIB suppresses hPPARα activity and thyroid hormone receptor activity. .

International patent application WO 97/28149 discloses that a group of PPARdelta agonists can increase plasma HDL concentrations. According to patent applications WO 97/27857, 97/28115, 97/28137 and 97/27847, some groups of substances may be used as anti-diabetic agents. Skupiny · · skupiny skupiny skupiny skupiny skupiny skupiny skupiny

6 weight loss agents, anti-sclerotic agents, and antihyperlipidemic agents, all of which may act through PPAR activation.

It has been reported that glitazones exert their effect through binding to an activated PPAR receptor and through the control of certain transcription elements for some of the above. It has also been shown that glitazones bind exclusively to the PPARgamma subtype of Hulin et al., Current Pham. Design, 1996, 2, 85-102.

All of the glitazones that have been tested until clinical trials in humans and almost all of the glitazones described in the literature have an aryl group at the 5-position of the thiazolidinedione bonded via one carbon atom. Although several compounds have also been prepared in which the 4- (oxy) phenyl group is bonded directly at the 5-position of the thiazolidinedione, they have not had hypoglycemic activity.

Thus, it was shown that 5- [5- [2- (2-benzoxazolylmethylamino) ethoxy] phenyl] -2,4-thiazolidinedione of formula (1) had no antihyperglycemic activity in ob / ob mice, then it was shown that relatively high PPARgamma activation is required by Cantello et al., J. Med. Chem., 1994, 37, 3977-3985 and Wilson et al., J. Med. Chem., 1996, 39, 665-668.

4444 • 4 • 4

4 “7 4 4 4 (444444 • ·· 4 4 4 4 · · 4 4 4 4 44 44 44 44 44 44

The other compound, 5- [4- (phenylethoxy) phenyl] -2,4-thiazolidinedione of Formula 2, had no antihyperglycemic effect in the mouse model of diabetes, although it reduced the activity of aldose reductase. According to Sohd et al., Chem. Pharm. Bull, 1982, 30, 3580-3600, and Sohda et al. Chem. Pharm. Bull. 1982, 30, 3601-3616. Examples of other aldose reductase inhibitors of the phenylthiazolidinedione group 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 according to Sohd et al., Chem. Pharm. Bull., 1982, 30, 3601-3616.

WO 97/22600 describes antihyperglycemic 5- [3- (carboxamido) phenyl] -2,4-thiazolidinediones of the general formula

(CH ₂ ) _n

O

X.

Ri

Rc ♦ 4 4444 ·· 44 44 44 * ♦ · · 4 4 4 4 4 44 4 4 4 4

4 4 4444

44 44 44

It has now been unexpectedly found that some substituted

5-aryl-2,4-thiazolidinediones are very potent PPAR agonists, especially alpha, delta and / or gamma subtypes, with dual effects on both alpha and gamma receptors being found particularly for the gamma subtype. They can be used for the treatment and prevention of diabetes, hyperglycemia, hyperlipidemia including hypercholesterolemia and hypertriglyceridemia, atherosclerosis, obesity, restenosis following vascular surgery and other diseases mediated through PPARalpha, delta and / or gamma receptors.

SUMMARY OF THE INVENTION

The present invention provides arylthiazolidinedione derivatives of the general formula I

YCH ₂ Ar ¹ - (CH 2) _n -CH ₂ -X ² wherein Ar ^_

Ar ¹ is a 1. Arylene or

2. a heteroarylene group; substituted by 1 to 4 groups of substituents R ^a ,

Ar ² is 1. ortho-substituted aryl or

2. an ortho-substituted heteroaryl, wherein the ortho substituents are selected from the group R and the aryl and heteroaryl groups are optionally substituted with R 2; further substituted with 1 to 4 groups independently selected from the group of substituents R ^a ,

9 4 98 • 9 4 4

94

4 9

4 4

X and Y independently represent O, S, NR ^b , or CH ₂ ,

Z is an oxygen or sulfur atom, n is an integer of 0 to 3,

R is C 1 -C 3 alkyl; substituted by 1 to 4 halogen and 3 to 6 carbon cycloalkyl groups,

2. C 3 -C 10 alkenyl; or

3. C 3 to C 8 cycloalkyl;

R ^a represents 1. alkanoyl of 1 to 5 carbon atoms,

2. alkyl of 1 to 15 carbon atoms,

3. alkenyl of 2 to 15 carbon atoms;

4. C 2 to C 15 alkynyl;

5. halogen atom,

6. OR ^b ,

7. aryl, or

8. heteroaryl, wherein the alkyl, alkenyl, alkynyl, and alkanoyl groups are optionally substituted. substituted with 1 to 5 R ^c groups, and the aryl and heteroaryl groups are optionally substituted with R 5 groups. substituted with 1 to 5 R ^d groups,

R ^b is 1. a hydrogen atom,

2. alkyl of 1 to 10 carbon atoms,

3. alkenyl of 2 to 10 carbon atoms;

4. C 2 to C 10 alkynyl;

5. aryl,

6. heteroaryl,

7. arylalkyl of 1 to 15 carbon atoms in the alkyl moiety;

8. heteroaryl having 1 to 15 carbon atoms in the alkyl moiety;

9. C 1 -C 15 alkanoyl;

10. C 3 -C 8 -cycloalkyl, wherein the alkyl, alkenyl, alkynyl radicals are optionally substituted; substituted with from 1 to 4 substituents R ^c and cycloalkyl, aryl and cycloalkyl, aryl and aryl groups; The heteroaryl radicals are optionally substituted with a heteroaryl moiety. substituted with 1 to 4 substituents independently selected from R ^d ,

R ^c is 1. halogen,

2. aryl,

3. heteroaryl,

4. cyano,

5. nitro,

6. OR ^f ,

7. S (O) _m R ^f , where m = 0, 1 or 2, provided that when m is 1 or 2, R ^{f has a} meaning other than H,

8. NR ^f R ^f

9. NR ^f COR ^f

10. NR ^f CO ₂ R ^f

11. NR ^f CON (R ^f ) ₂ ,

12. NR ^f SO ₂ R ^f , provided that R ^{f is} not H,

13. COR ^f ,

14. CO ₂ R ^f

15. CON (R ^f ) ₂

16. SO ₂ N (R ^f ) ₂

17. OCON (R ^f ) ₂ , or

18. cycloalkyl of 3 to 8 carbon atoms, wherein cycloalkyl, aryl and heteroaryl are optionally substituted; substituted with 1 to 3 halogen atoms or alkyl groups of 1 to 6 carbon atoms, R ^d represents a group R ^c ,

2. alkyl of 1 to 10 carbon atoms,

3. alkenyl of 2 to 10 carbon atoms;

4. C 2 to C 10 alkynyl;

5. arylalkyl of 1 to 10 carbon atoms in the alkyl moiety;

6. heteroarylalkyl of 1 to 10 carbon atoms in the alkyl moiety, wherein alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted with C 1 -C 10 alkyl; substituted with a group, independently selected from R ^e ,

9 99 •

88 · * 98

9 8 1

9 9 4 ·· ··

R ^e represents 1. halogen atom,

2. amino,

3. a carboxyl group,

4. alkyl of 1 to 4 carbon atoms,

5. C 1 -C 4 alkoxy;

6. hydroxy,

7. aryl,

8. arylalkyl of 1 to 4 carbon atoms;

9. aryloxy,

R ^f is 1. a hydrogen atom,

2. alkyl of 1 to 10 carbon atoms,

3. alkenyl of 2 to 10 carbon atoms;

4. C 2 to C 10 alkynyl;

5. aryl,

6. heteroaryl,

7. arylalkyl of 1 to 15 carbon atoms in the alkyl moiety.

8. heteroarylalkyl having 1 to 15 carbon atoms in the alkyl moiety

9. C 1 -C 15 alkanoyl;

10. cycloalkyl of 3 to 8 carbon atoms, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally cycloalkyl; substituted with 1 to 4 R ^e substituents as well as pharmaceutically acceptable salts thereof.

In one sub-group of compounds of formula I, Z is sulfur.

In another sub-group of compounds of formula I, Ar ^{1 is an} arylene group, respectively. substituted with 1-4 groups of R ^a. A preferred group is a phenylene group or a phenylene group. substituted with 1 to 2 groups selected from halogen and alkyl of 1 to 4 carbon atoms. The preferred value for an arylene group is a phenylene group.

·· · «« ·

Q * ·. «» · · .. .. .. .. .. .. .. .. .. ..

In another subgroup of compounds of Formula I, X and Y are CH 2, O, or S. Preferably, X and Y are oxygen.

In another subgroup of compounds of Formula I, Ar ^{2 is a} group of Formula

where

R is alkyl of 3 to 4 carbon atoms, respectively. substituted with 1 to 4 groups selected from halogen and 3 to 6 carbon cycloalkyl;

^And R is selected from the group R ^a or formed by two R groups ^and adjacent carbon atoms. 5- or 6-membered aromatic ring containing O to 2 heteroatoms selected from N, O and S (0) _m where m = O to 2, wherein the ring may be further substituted by 1-2 groups R ^and.

In a preferred subgroup of compounds, R ^{a is} selected from OR ^b ; substituted with 1 to 5 R ^d groups and alkyl of up to 15 carbon atoms; substituted with 1 to 5 R ^c groups. In another preferred subgroup of compounds, the two R groups ^and the adjacent carbon atoms together form a 5- or 6-membered aromatic ring containing 1 to 2 heteroatoms from N, O and S (O) _m , wherein m is 0 to 2, this circle is optionally. substituted with 1-2 groups R ^and. In another highly preferred embodiment, R ^and O are O-phenyl, wherein the phenyl moiety or the moiety is O-phenyl. substituted with 1 to 4 R ^d groups; substituted with 1 to 2 halogen atoms and alkyl of 1 to 5 carbon atoms, respectively. substituted with 1 to 5 substituents selected from the group consisting of halogen, phenyl and cycloalkyl of 3 to 8 carbon atoms.

• · »· · · Ό · · · ·

Ιο »··· ·· *« ** «» _<a

In another very preferred embodiment, they form 2 R groups ^and, together with the carbon atoms to which they are attached, a 5- or 6-membered aromatic ring selected from isoxazole, thiophene (S-oxide and S-dioxide) or furan; substituted by 1-2 groups R ^and.

In another group of compounds of formula I, n is an integer of 1 or 2.

A preferred embodiment of the compounds of formula (I) is represented by formula (Ia)

where

R ^a is selected from R ^a , or forms 2 R a ^and on adjacent carbon atoms together with these atoms a 5- or 6-membered aromatic ring containing 0 to 2 heteroatoms from N, O and S (O) _m , wherein m is 0 to 2; substituted with 1 to 2 groups R ^a ,

X, Y, Z, n, ^and R and R are as defined in formula I.

• · »4 * 4

4

4 • 444 44

44

4 4 4

4 4 ·

4 4 4 4 • 4 »4 • 4 44 ·· 44

4 · 4

4 4 4 4

4 4 4

4 4 4

Another subgroup of compounds of formula I ^to form compounds of formula I ^and (i)

Another subgroup of compounds of formula Ia are compounds of formula Ia (ii)

A preferred embodiment of the invention are compounds of formula Ia wherein Z is sulfur.

Another preferred embodiment of the invention are compounds of formula Ia wherein Y is sulfur or oxygen and X is oxygen.

·· * ·

Another highly preferred embodiment of the invention is a compound of formula (Ia) wherein R is alkyl of 3 to 4 carbon atoms.

Another very preferred embodiment of the invention is represented by the compounds of formula Ia in which R ^a represents O-aryl or O-aryl. substituted with 1 to 3 substituents from the group R ^d , aryl, respectively. substituted with 1 to 3 substituents from R ^d , or alkyl of 1 to 5 carbon atoms, respectively. substituted with 1 to 5 substituents from R ^c , or forming two R groups ^and on adjacent carbon atoms together with these atoms a 5 or 6-membered aromatic ring containing 0 to 2 heteroatoms from N, O and S (O) _m , wherein m is 0 to 2; substituted with 1-2 groups R ^and.

A very preferred embodiment consists of compounds of formula Ia in which Z represents a sulfur atom,

X is an oxygen atom,

Y is 1. an oxygen atom or

2. sulfur atom,

R is alkyl of 3 to 4 carbon atoms,

R ^a represents 1 halogen atom or

2. alkyl of 1 to 5 carbon atoms,

R ^a denotes 1. O-aryl, respectively. substituted with 1 to 3 R ^d groups,

2. aryl; substituted with 1 to 3 R ^d groups,

3. alkyl of 1 to 5 carbon atoms; substituted with 1-5 R ^c groups, or form two groups R ^and together with the adjacent carbon atoms to which they are attached, a 5- or

A 6-membered aromatic ring containing from 0 to 2 heteroatoms from the groups N, O and S (O) _m , wherein m = 0 to 2 and optionally 1 to 2; substituted with 1-2 groups R ^and.

Representative compounds of the invention are disclosed in 9,999

9999 99

99 99 99 • 9 9 · 9 9 9 9 • 9 99 9 9 9 • 9 9 © 9 9 9 9 9 ·

9 ··· 9999

99

next Tables 1 to 3. Table 1. R ^a 3 •in ^% 4 (B) -YLX — Κ / ¹ - _And ^z 0 = / ( ηνΆ- 0 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) 40 O / CH CH 2 C (CH 3) 3 3 O (CH 2) 40 O / CH (CH2) 2Ph 4 O (CH ₂ ) 3 O HE Ph 4 O (CH 2) 3 O HE CH 2 C (CH 3) 3 4 O (CH ₂ ) 3 O HE cf ₃ 4 O (CH 2) 3 O HE (CH ₂ ) ₂ Ph 4 O (CH ₂ ) 3 O HE (CH2) 4Ph 4 O (CH 2) 3 O HE CH2-c-Hex ** 4 O (CH 2) 3 O HE CH 2 C (CH 3) 2 Ph 3 O (CH 2) 40 HE cf ₃ 4 O (CH ₂ ) 3 O S / CH (CH2) 2Ph 3 O (CH 2) 40 S / CH (CH2) 2Ph 3 O (CH 2) 40 SO / CH (CH2) 2Ph 4 O (CH ₂ ) 3 O SO / CH (CH2) 2Ph 4 O (CH ₂ ) 3 O SO2 / CH Ph 3 O (CH 2) 40 SO2 / CH (CH2) 2Ph 4 O (CH 2) 3 O SO2 / CH (CH2) 2Ph instead of joining group Y to phenyl ring,

** c-Hex means cyclohexyl

Table 2.

OF Ra * Y-L-X with H 4 O (CH ₂ ) ₃ O with 3-Cl 4 O (CH ₂ ) ₃ O with 3-F 4 O (CH ₂ ) ₃ O with 3-propyl 4 O (CH ₂ ) ₃ O with 3-Cl 4 S (CH ₂ ) ₃ O with 3-Cl 4 O (CH ₂ ) ₄ O with 3-propyl 4 O (CH ₂ ) ₄ O with H 4 O (CH ₂ ) ₄₀ with H 3 O (CH ₂ ) ₃ O with H 3 O (CH ₂ ) ₄ O 0 H 3 O (CH ₂ ) ₃ O 0 H 4 O (CH ₂ ) ₃ O with H 4 O (CH ₂ ) ₃ O with H 4 O (CH ₂ ) ₃ O with H 4 O (CH ₂ ) ₃ O with H 4 O (CH ₂ ) ₃ O with H O O O (CH ₂ ) ₃ O with H 3 O (CH ₂ ) ₃ O with H 3 (CH ₂ ) ₄ O with H 4 (CH ₂ ) 40 with H 4 (CH ₂ ) ₄ O with H 3 (CH ₂ ) 40 with H 3 (CH ₂ ) ₅ O with H 3 (CH ₂ ) 50 with H 3 (CH ₂ ) ₅ O

R 4 ' —0— -Cf R ** Rd propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H propyl 4 ’ H Propyl 4 ’ _H propyl 4 ’ Έ Propyl 4 ’ 4-SO ₂ CH ₃ Propyl 4 ’ _4-CH3 propyl 4 ’ 4-CI propyl 4 ’ 4-Ph Propyl 4 ’ 4-OCH ₃ Propyl 4 ’ 4-F Propyl 4 ’ H propyl 4 ’ 4-OCH ₃ Propyl 4 ’ 4-CI propyl 4 ’ 4-CI Propyl 4 ’ H propyl 4 ’ 4-OCH ₃ propyl 4 ’ 4-F

• 000 »« · ♦ · 4 · 00 · · 9

0 9 9 ·· 99

OF Ra •and·· Y-L-X R Rd with H 3 O (CH ₂ ) 5 propyl 4 ’ 4-Ph with H 4 O (CH ₂ ) 4 propyl 4 ’ 4-OCH3 with H 3 O (CH 2) 4 propyl 4 ’ 4-F with H 3 O (CH ₂ ) 5 propyl 4 ’ 4-CI with H 3 O (CH ₂ ) 3 O propyl 4 ’ 3-CH3-4-C1 with H 4 O (CH 2) 3 O propyl 4 ’ 4-CH ₂ CH (CH 3) 2 with H 3 O (CH 2) 3 O propyl 4 ’ 4-C-pentyl with H 3 O (CH ₂ ) 3 O propyl 4 ’ 4-CH (CH 3) 2 with 3-propyl 4 O (CH ₂ ) 3 O propyl 4 ’ 4-OCH3 with H 4 O (CH ₂ ) 40 propyl 4 ’ 4-OCH3 with H 4 O (CH 2) 40 propyl 4 ’ 4-F with H 3 O (CH ₂ ) 40 propyl 4 ’ 4-OCH3 with H 3 O (CH 2) 40 propyl 4 ’ 4-CI with H 3 O (CH ₂ ) 3 O propyl 4 ’ 4-SO2CH3 with H 3 O (CH 2) 40 propyl 4 ’ 4-SO2CH3 with H 4 O (CH ₂ ) 3 O propyl 5 ’ H with H 4 O (CH ₂ ) 3 O propyl 3 ’ H with H 3 O (CH ₂ ) 40 propyl 3 ’ H with H 3 O (CH ₂ ) 3 O allyl 4 ’ H with H 3 O (CH ₂ ) 3 O 3-F-propyl 4 ’ H with H 3 O (CH ₂ ) 3 O propyl 4 ’ 4-CO 2 CH 2 CH 3 with H 4 O (CH ₂ ) 3 O Propyl 4 ’ 4-F with H 4 O (CH ₂ ) 3 O propyl 4 ’ 4- (4'-tolylsulfone ~) amide) with H 3 O (CH ₂ ) 3 O c-pr-CH ₂ T 4 ’ H place connection group Y to phenyl ring,

instead of attaching a phenoxy group to the phenyl ring, I * c-pr is cyclopropyl,

Table 3.

Ό

· * * * * * * * *

. _Λ · · · η g ······ • · · · · · · · * n Ra (l) Ra (2) 4 3 4-F-Ph H 3 3 2-n. Apthyloxy H 3 3 2-dib enzofuranyl H 3 3 phenoxy propyl 4 3 3-isoxazolyl H 3 4 3-isoxazolyl H 4 3 pvrazinyloxy H * Connect instead atom oxygen to phenyl ring.

The term "alkyl" and, in the case of other groups derived therefrom, such as alkoxy or alkanoyl, means carbon chains, linear or branched or combined. Examples include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

Alkenyl is a carbon chain which contains at least one inter-carbon double bond and which is linear, branched or combined. Examples include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

Alkynyl is a carbon chain containing at least one inter-carbon triple bond and which is linear, branched, or combined. Examples are ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptinyl and the like.

Cycloalkyl is a mono- or bicyclic saturated carbon ring system, each ring having from 3 to 10 carbon atoms. The term also includes cycloalkyl fused to an aryl group in which the condensation occurred in the non-aromatic moiety. As an example

4 4 4 4 4

4

4444 44 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Aryl and also arylene mean a mono- or bicyclic aromatic ring system which contains only carbon atoms in the ring. The term also includes aryl groups fused to a monocyclic cycloalkyl radical or a monocyclic heterocyclic group when the condensation site is in the aromatic moiety.

The heterocyclic radical is a fully or partially saturated ring containing at least one heteroatom selected from nitrogen, sulfur and oxygen, each of which contains 3 to 10 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl and the like.

Heteroaryl and heteroarylene are mono-, bi- or tricyclic aromatic ring systems containing at least one nitrogen, oxygen and sulfur heteroatom in the ring, including SO and SO ₂ groups, each ring containing 5 to 6 carbon atoms. Exemplary heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl, benzisoxazolyl , benzofuranyl, benzothiophenyl (including S-oxides and dioxides) furo (2,3-b) pyridyl, quinolyl, indolyl, isoquinolyl, dibenzofuran and the like.

A halogen atom is a fluorine, chlorine, bromine or iodine atom.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

·. ··· .. · · .. ·· .. ·

By &quot; ortho-substituted &quot; is meant that a substituent attached to an atom in a ring is bound to an atom adjacent to a site of attachment to the rest of the molecule.

The pharmaceutical composition containing the active compounds according to the invention also forms part of the invention. This composition may contain, in addition to the active ingredients, inert ingredients, i. carrier and other excipients. As an active ingredient, such a composition may also contain a combination of the active ingredients, their complexes and those resulting from the dissociation of the ingredients or from their interaction or interaction.

Optical isomers, diastereomers, geometric isomers and tautomers.

The compounds of formula I may contain one or more centers of asymmetry and may therefore exist as racemates, racemic mixtures, individual enantiomers, mixtures of diastereomers and as individual diastereomers. The invention includes all isomeric forms of the compounds of Formula I.

Some of the compounds described contain olefinic double bonds and thus include both geometric isomers E and Z.

Some of the compounds described may exist with different hydrogen bonding sites, so they are tautomers. Examples of such materials are ketone and its enol. The invention includes both individual tautomers and mixtures thereof of Formula I.

The compounds of formula (I) may be separated into diastereoisomeric pairs, enantiomer pairs, for example by fractional crystallization from a suitable solvent such as methanol or ethyl acetate, or from a mixture of these solvents. The pair of enantiomers thus obtained can be: · 4444 • · 4 4 4 4 4 4 • 4 · 4 4 4 4 4 4 · 4 • 4 44 # 4 4444 • 444 44 444 4 «4

...... ** can be separated into individual stereoisomers in the usual manner, for example using an optically active acid as a separating agent.

The enantiomer of a compound of formula I or Ia can also be directly prepared 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 aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, zinc and the like salts. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts with primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, salts with cyclic amines, and basic ion exchange resins. Examples are salts with arginine, betaine, caffeine, choline, Ν, Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, histamine, glucamine, glucamine, glucamine, glucamine , lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the derivative of the invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Of these acids, 4,444,444,154 are possible

4 4

4

4444 44 mention acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, almond, methanesulfonic, mucic, pantic, nitric, pamo, sulfuric, tartaric, p-toluenesulfonic and the like. Particularly preferred acids are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

It is to be understood that when referring to derivatives of formula (I) throughout the application, the term "pharmaceutically acceptable salts" of the compounds of formula (I) is also to be understood.

Use

The derivatives of the invention are potent antagonists of various receptor subtype activators which can be activated by peroxisome proliferating agents, particularly PPARalpha, PPARgamma and / or PPARdelta receptors. The derivatives of the invention may be potent agonists of one subtype of these receptors, e.g. PPARgamma, or may be antagonists of more than one subtype, e.g. they may have a dual effect on PPARalpha / gamma. The derivatives of the invention can be used to treat or prevent diseases, disorders or conditions mediated through activation of individual subtypes or combinations of PPAR receptor subtypes. In particular, the present invention relates to the treatment of such diseases, disorders or conditions in mammals, including humans, which are administered an effective amount of a compound of Formula I. These conditions may be 1. diabetes, 2. hyperglycemia, 3. obesity, 4. hyperlipidemia, 6. hypercholesterolemia, including increased HDL concentration, 7. atherosclerosis, 8. vascular restenosis, 9. irritable bowel syndrome, 10. pancreatitis, 11. abdominal obesity, 12. adipose cell tumors, 13. malignant tumors

9999

9 9 9 9 9 9 ♦ Φ »φ φ 9 9 9 9 9 9

9 9 9 9 9

99 99 tuk odolnost · · · φ φ φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

The derivatives of the invention are very suitable for the treatment or prevention of hypercholesterolemia, for this purpose an effective amount of both PPARalpha and PPARgamma agonists are administered. Preferably, a dual action agent is used which is co-administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and rivastatin.

Administration and dosage range

For administration to mammals, especially humans, any suitable route of administration may be selected. For example, the compounds of the invention may be administered orally, rectally, topically, parenterally, eye, lung, nasal mucosa, and the like. Dosage forms include tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. the route of administration of the compounds is oral.

The effective dosage may vary for a particular compound over a wide range depending on the route of administration, the condition being treated and its severity. The appropriate dose is always determined by the attending physician.

In the treatment or prevention of diabetes and / or hyperglycemia or hypertriglyceridaemia or other disease in which the compounds of formula I are effective, the desired results are usually obtained when the active compounds are administered at a daily dose of 0.1 to 100 mg / kg body weight. , the derivatives are preferably administered simultaneously or in divided doses of two to six sub-doses of 9,9999

OC 999 9999 9999 * ··· · * ·· · * 9. 99 during the day or in a sustained release form. For most large mammals, the total daily dose is in the range of 1.0 to 1000 mg, preferably 1 to 50 mg. Thus, for a 70 kg human, the total daily dosage will generally be in the range of 7 to 350 mg. Doses can be adjusted for optimal results.

Pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising active derivatives of Formula I together with a pharmaceutically acceptable carrier. The pharmaceutical composition according to the invention may contain the active compound in free form or in the form of a pharmaceutically acceptable salt thereof and, in addition to a conventional carrier, it may contain other additives normally employed. The term "pharmaceutically acceptable salts" refers to salts with pharmaceutically acceptable non-toxic inorganic or organic bases or acids.

The pharmaceutical composition of the invention may be for oral, rectal or topical administration, for parenteral administration including subcutaneous, intramuscular and intravenous administration, for administration to the eye, to the lungs, for example by inhalation through the nose or mouth or for nasal mucosa administration. the case will depend on the nature and severity of the disease being treated and the nature of the active ingredient. The derivatives of the invention may be formulated in a unit dosage form.

For practical use, the derivatives of formula (I) may be admixed as an active ingredient with a pharmaceutical carrier in a conventional manner.

The carrier will vary according to the dosage form being prepared. For the manufacture of oral compositions, for example, water, glycols, oils, alcohols, flavorings, color preservatives, and the like in the case of liquid compositions such as suspensions, elixirs and solutions may be used as carriers. or solid carriers such as starches, sugars, microcrystalline cellulose, granulating agents, glidants, binders, disintegrating agents and the like can be used in the case of solid compositions such as powders, hard and soft gelatin capsules or tablets. A solid pharmaceutical composition for oral administration is a highly preferred form of the composition of the invention.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage form for administration of the active ingredients. If desired, tablets may be provided with the usual coatings of aqueous or non-aqueous solutions. The pharmaceutical composition of the invention should contain at least 0.1% by weight of the active ingredient. The amount of active ingredient may vary, usually in the range of 2 to 60% by weight, based on the total weight of the dosage form. The amount of active ingredient in the dosage form must be such that an effective dosage will be obtained. Another suitable dosage form is, for example, nasal drops or sprays for nasal administration.

Tablets, pills, capsules and the like may contain binders such as gum tragacanth, gum acacia, corn starch or gelatin, excipients such as dibasic calcium phosphate, a disintegrant such as corn starch, potato starch or alginic acid, glidants such as magnesium stearate and sweeteners. , such as sucrose, lactose or saccharin. In the case of a capsule, the composition may further comprise a liquid carrier such as an oil.

A variety of other materials can be used to form a coating or to modify the physical form of the compositions. E.g. tablets may be coated with shellac, sugar or both. Syrups or elixirs may contain, in addition to the active ingredient, sucrose such as φφφφφφφ · · · ·φφφΦΦφφφφφφφφφφφφφ

sweetener, methyl paraben and propyl paraben as preservatives and, in addition, coloring and flavorings such as cherry or orange flavor.

The derivatives of formula 1 can also be administered parenterally. Solutions and suspensions of the active derivatives can be prepared in water and / or water. with a wetting agent such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof with oils. Under normal conditions of storage and use, such compositions will contain preservatives to prevent the growth of microorganisms.

Pharmaceutical dosage forms suitable for injection are sterile aqueous solutions or dispersions as well as sterile powders for the extemporaneous preparation of sterile solutions or dispersions. In all cases, the dosage form must be sterile and must be fluid to the extent that easy syringability exists. Further, the dosage form must be stable under the conditions of manufacture and storage and must be preserved against contamination by microorganisms such as bacteria or fungi. As the carrier, a solvent or dispersion medium containing, for example, water, ethanol, polyol, such as glycerol, propylene glycol and liquid polyethylene glycol, as well as mixtures of these substances and vegetable oils may be used.

Use of combination of active substances

The derivatives of formula (I) may be used in combination with other active agents, which may also be useful in the treatment, prevention or at least amelioration of the conditions in which the derivatives of formula (I) are used. These additional agents may be administered in conventional manner and in conventional amounts simultaneously with, prior to or after administration of the derivatives of Formula I.

4 4 · «4 * 4 4 • · • 4

4 4 ••• 44 44 »44

4 4 4 • 44

4 4 4

4 * * · 4 4 • 4 4 4

4 4 4

When a compound of formula (I) is administered concomitantly with one or more other agents, it is preferable to administer all the active agents in the form of a pharmaceutical composition containing derivatives of the general formula (I) and other active agents. In some cases, all of the active ingredients may be used at lower doses as compared to the single use doses.

Examples of other active ingredients which can be combined with the derivatives of formula I and administered separately or in a common pharmaceutical formulation are, for example, the following:

a) insulin sensitivity enhancers including (i) PPARgamma agonists such as glitazones such as troglitazone, pioglitazone, englitazone, MCC555, BRL49653 and the like, and compounds disclosed in WO 97/27857, 97/28115 and 97 / 27847 and (ii) biguanides such as metformin and phenformin,

(b) insulin or insulin-like substances;

(c) sulfonylureas such as tolbutamide and glipizide or related substances;

d) alpha-glucosidase inhibitors such as acarbose;

e) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin and other statins; (ii) sequestering agents such as cholestyramine, coiestipol and dialkylaminoalkyl derivatives of cross-linked dextran (iii) nicotinyl alcohol, nicotinic acid or salts thereof; (iv) PPARalpha agonists such as fenofibric acid derivatives such as gemfibrozil, clofibrate, fenofibrate and benzafibrate; (v) cholesterol absorption inhibitors such as beta-sitosterol and acyltransferase acylCoAA inhibitors and cholesterol such as melinamide and (vi) probucol,

f) PPARdelta agonists, as described, for example, in WO 97/28149

(g) anti-obesity agents such as fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide X5 inhibitors and beta ₃ adrenergic receptor agonists;

h) bile acid transport inhibitor in the small intestine.

Biological tests

A. In vitro white fat test

In this assay, the efficacy of the derivatives of the invention to increase the incorporation of labeled ¹⁴ C-glucose into glycogens of adipose tissue WAT after insulin activation for 5 hours in an in vitro system is measured. All assays were performed in medium 199 containing 1% bovine serum albumin, 5 mM HEPES, antibiotics (100 units / ml penicillin, 100 micrograms / ml streptomycin sulfate and 0.25 micrograms / ml amphotericin B). The epididimal fat pads are divided by scissors into small fragments of approximately 1 mm diameter.

100 mg of ground WAT fragments are incubated in a total volume of 0.9 ml of the above medium containing 1 mU / ml insulin and test substance in a tissue culture incubator at 37 ° C in 5% carbon dioxide atmosphere with shaking for 3 hours. ¹⁴ C-labeled glucose is then added and incubated for a further 2 hours. Then centrifuge the tubes at low speed, remove the infranatant and add M sodium hydroxide solution. After addition of the base, the mixture is incubated for another 10 minutes at 60 ° C to dissolve the tissue. The resulting tissue hydrolyzate is applied to Whatman filter paper strips, which are then rinsed with 66% ethanol and then 100% acetone to remove unincorporated ¹⁴ C-glucose from labeled bound glycogen. The dried filter papers are then incubated in an amyloglucosidase solution to cleave glucogen to glucose. Scintillation fluid is added and the labeled carbon activity is determined on a scintillation counter. Test substances that have increased activity well above that obtained only when incubated with insulin are considered to be

9 »9999

9

99

9 9 9

9 9 9

9 9 9

9 9 9

99 ·· 99

9 9 1

9 99

9 9 9

9 9 fl «9

9 effectively enhances insulin action. The active substances were titrated and the concentration at which 50% of the maximum insulin potentiation or activation, which was designated as EC50, was determined.

B. Gal-4 hPPAR transactivation

(a) Plasmids

Constructs for expression of chimeric receptors, pcDNA3-hPPARgamma / GAL4, pcDNA3-hPPARdelta / GAL4, and pcDNA3-HPPARalpha / GAL4 were prepared by depositing GAL4 transcription factor DBD from yeast into the ligand binding domain, LBD in hPPARgamma, hPPARgamma, and hPPARgamma. The pUAS (5X) -tk-luc reporter construct was generated by depositing five copies of the GAL4 element upstream from the herpes virus thymidine kinase promoter and the luciferase reporter gene. Plasmid pGMV-lacZ contains the galactosidase Z gene under the control of the cytomegalovirus promoter.

b) Cell culture and transactivation

COS-1 cells were seeded at x 10 ³ cells / well in 96-well tissue culture plates, containing wells in Dulbecco's Dulbecco's modification, high glucose DMEM, and 10% activated carbon-treated fetal calf serum (Gemini) BioProducts, Calabasas, CA), the medium contains non-essential amino acids, 100 units / ml penicillin G and 100 mg / ml streptomycin sulfate at 37 ° C in a humidified atmosphere containing 10% carbon dioxide. After 24 hours, a transaction was performed using Lipofectamine (GIBCO BRL, Gaithersburg, MD) according to the manufacturer's instructions. The procedure was carried out in such a way that the mixtures for transfection of each well contained 0.48 microliters of Lipofectamine, 0.00075 micrograms pcDNA3-PPAR / GAL4 as expression vector, 0.045 micrograms pUAS (5X) -tk-luc as

99

9 9 9

9 99 • 9 4999 * 9

9

9 • 999 99

9 9 9

99 • 9 99

4 9 4

9 9 9

9 9 9

A reporter vector and 0.0002 micrograms of pCMV-lacZ for internal control of transactivation efficiency. The cell material was incubated in the transfection mixture for 5 hours at 37 ° C in an atmosphere containing 10% carbon dioxide. The cells were then incubated for approximately 48 hours in fresh DMEM with a high glucose content and 5% charcoal-treated fetal calf serum, non-essential amino acid, 100 units / ml penicillin G and 100 mg / ml streptomycin sulfate ± increasing concentrations of test substance. Since the test compounds were dissolved in DMSO, control cells were incubated at an equivalent DMSO concentration, the final DMSO concentration was greater than or equal to 0.1%, a concentration that had no effect on transactivation. The disrupted cells were then obtained using Reporter Lysis Buffer (Promega, Madison, WI) according to the manufacturer's instructions. Luciferase activity in cell extracts was determined using luciferase assay buffer (Promega, Madison, WI) using an ML3000 luminometer (Dynatech Laboratories, Chantilly, VA). Beta-galactosidase activity was determined using beta-D-galactopyranoside (Calbiochem, San Diego, CA).

C. In Vivo Assays

Male db / db mice aged 10-11 weeks, C57B1 / KFJ (Jackson Labs, Bar Harbor, ME) were caged in five cages and fed (Purina) and water ad libitum. Animals and their feed were weighed every two days. 0.5% carboxymethylcellulose ± test substance at the indicated dose. Active ingredient suspensions were freshly prepared each day. Blood was drawn from the tail vein throughout the test at intervals of 3-5 days, and glucose and blood triglyceride concentrations were determined. The Boehringer Mannheim Hitachi 911 • φ φφφφ was used for the determination

9 »

Φ φ φ φ • • φ φ »» »φ φ φ φ φ φ φ φ φ φ φ φ

(Boehringer Mannheim, Indianapolis, IN) using heparinized plasma diluted 1: 6 in volume with saline. Heterozygous mice of the same age were used as controls.

The derivatives of formula (I) may be prepared by the procedures outlined in the following Schemes. The general symbols shown in the schemes have the same meaning as in the general formula I, unless expressly stated otherwise.

Scheme 1

H ₃ COOC-CH ₂ - Ar ¹ -Y-CH ₂ - (CH ₂ ) _n -CH ₂ -X-aH (Al)

LiHMDS, THF, TMSCI, NBS

b. wherein Z = S, thiono, methoxyethanol

HCl, reflux

O _Ar LY-CH ₂ - (CH ₂ ) _n -ΟΗ ₂ -χ — Ar ² (I; Z = S)

The alpha-bromination of an aryl acetate-type intermediate A1 with a halogenating agent such as N-bromosuccinimide in the presence of a base gives a halogenated intermediate in which the ring can be closed with thiourea in which Z is sulfur in the presence of a strong aqueous acid solution or sodium acetate in alcohol such as 2-methoxyethanol at higher temperature. In this way, the resulting arylthiazolidinones of formula (I) in which Z is a sulfur atom are obtained.

4444

4 4

4 «4 * • * • 4 • 44

4445 44 ·· • 4 4 4

4 4'4

4 44 44 • 4 4 4

4 4 4 * 4 4

Scheme 2

HX — Ar ² (Bl)

LH ₂ C- (CH ₂ ) _n -CH ₂ -L '(I)

H ₃ COOC-CH ₂ -Ar ¹ -YH + LH ₂ C- (CH 2 -CH 2 X-Ar ² (B2) (Cl)

Cs ₂ CO ₃ , DMF

H ₃ COOC-CH ₂ -Ar ¹ -Y-CH ₂ - (CH ₂ ) _n -CH ₂ -X-Ar ² (Al)

Cs ₂ CO ₃ , DMF

H ₃ COOC-CH ₂ -Ar ¹ -Y-CH ₂ - (CH ₂ ) _n -CH ₂ -L ⁺ HX-Ar (C2) (B1)

AND

LH ₂ C- (CH ₂ ) _n -CH-L '(I)

H ₃ COOC-CH ₂ - Ar ^{1 -} YH (B2)

L and L ’are the same or different leaving groups • · * · · ♦ tt *

9 ·

9 • 9 · ·

Scheme 2 shows the synthesis of intermediate A1, which contains an Ar ¹ and Ar ² group linked by a bridge of up to 4 atoms. Intermediate A1 can be prepared by first linking a T bridge with two terminal leaving groups to an Ar ¹ or Ar ^{2 group} , in which L and L 'are independently a common leaving group such as a halide, preferably a bromide or a sulfonyloxy group such as a mesylate or tosylate. Another aryl group is then coupled in the presence of an inorganic base such as cesium carbonate in DMF to give the intermediate aryl A1 ester containing said bridge. The bridge starting material and the two other starting materials B1 and B2 are commercially available or can be prepared by known methods. For example, compounds of formula B2 can be obtained by the methods disclosed in WO 97/27857, 97/28115 and 97/28137.

Scheme 3 OH

H ₃ COOC-CH-Ar ¹ -YH + LH ₂ C- (CH ₂ ) _n ^{CH 2} X Ar ²

Cs ₂ CO ₃ , DMF

OH

HqCOOC-CH-Ar ¹ -Y-CH 2 - (CH ₂ ) _n -ΟΗ-—-Ar (A2) where Z = O urea, sodium methoxide, methanol, reflux where Z = S

and thionyl chloride, pyridine, toluene

b. thiourea, sodium acetate, ethanol reflux and 2N HCl, reflux

O

Aj-1-y-CH ₂ - (CH ₂ ) _n -CH ₂ -X-Ar (I; Z = O, S) '

In Scheme 3, an appropriately substituted mandelic acid ester B3 is reacted with an Ar ² derivative having a leaving group L and a starting material C1 in the presence of an inorganic base such as cesium carbonate. The resulting product A2 is cyclized by treatment with urea in the presence of a base such as sodium methoxide to give the desired product of formula I wherein Z is an oxygen atom. The hydroxy group of compound A2 can also be converted to the corresponding chloride by treatment with thionyl chloride, and the resulting compound is then subjected to ring closure in the same manner as in Scheme 1 to give compounds of formula I wherein Z is sulfur. The starting materials for carrying out Scheme 3 are commercially available or can be prepared in a known manner.

Scheme 4

HX-Ar ₂

El

1) (Tf) ₂ O, Pyridine

2) HY-CH ₂ (CH ₂ ) n CH ₂ CH (Y = O)

Pd (PPh ₃ ) ₄ , piperidine,

HY-CH - (-C = CAr ₂ (y = O) p 9 ^H z) ⁿ

1) H ₂ , Pd / C, Ethanol

2) (Ms) ₂ O, Pyr, CH ₂ Cl ₂

-MsO-C- (-C-X-Ar ₂₎

H3COOC-CH ₂ -Ar ¹ -YH ^H 2 ^{CH 2 -) n} (X = _CH2)

B1 (Y = O) Cl

Cs ₂ CO ₃ , DMF

HXOOC-CH ₂ - Ar ¹ - Y - CH ₂ - (CH ₂ ) _{n -} CH ₂ X Ar ₂ Al

HX-Ar ₂ (X = O) B2 Cs ₂ CO ₃ , DMF · 9 · 9 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

9999 99 99 99 ·· 9999

9 9 · • Φ ··

H, COOC-CH ₂ - Ar ¹ -Y-CH ₂ - (CH ₂ ) n -CH ₂ OMs (Y = CH ₂ ) 22 |

1) H _2, Pd / C, ethanol

2) (Ms) ₂ O, Pyr, CH ₂ Cl ₂

HoCOOC _-Αη-CH2-C = C (CH ₂₎ n CH ₂ -XH (X = O)

D2

HC = C (CH ₂ ) n -CH ₂ -XH (X = O) Pd (PPh ₃ ) ₄ , CuBr, Et ₃ N

H ₃ COOC-CH ₂ -Ar ¹ -L E2

L = leaving group (Tf) ₂ O = trifluoromethanesulfonic anhydride (Ms) ₂ O = methanesulfonic anhydride

Scheme 4 illustrates the synthesis of intermediate A1 in which Ar ¹ and Ar ² are linked by a bridge of up to 4 atoms in which one of X or Y is oxygen. The palladium catalyzed addition of the alkyne to the aryl bromide E1 or triflate E2 is then carried out to form compounds D1 or D2. Their hydrogenation at atmospheric pressure yields saturated compounds C1 or C2, which is combined with B1 or B2 in the presence of an inorganic base such as cesium carbonate in dimethylformamide to afford the aryl acetate intermediate A1. The starting materials for the synthesis of Scheme 4 are commercially available or can be prepared by known methods.

»4 4 ** 4 <4 4 4 • 4 4 4

4 •• * 44

JŠLÍ-S-SLZ ____ 2_S_2_Y_S _ ^ _ S_5LI ____ Z_Z_E_É_1 _? _ 5_3

The following examples, which are described below, are given only to demonstrate the invention, and are not to be construed as limiting the claims of the invention in any way.

Example)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxy-phenoxypropoxy) -phenyl) -2,4-thiazolidinedione

Stage A)

Preparation of methyl 4- (3-bromopropoxy) phenylacetate

A solution prepared by dissolving 20.0 g (0.12 mol) of methyl 1-4-hydroxyphenyl acetate, 97.20 g (0.48 mol), 1.3 dibromopropane, and 43.10 g. (0.13 mol) of cesium carbonate in 250.0 ml of dried dimethylformamide was stirred at room temperature overnight.

* · ··> se

Then, the reaction mixture was partitioned between ethyl acetate and 0.2N hydrochloric acid solution, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and then dried with sodium sulfate. The organic layer was then filtered, and concentrated to an oily substance which was chromatographed on silica gel using dichloromethane: hexane (2.0: 1.0) as eluent.

The title compound was obtained.

¹ H-NMR, (400 MHz, CDCl 3): (nuclear magnetic resonance spectra) δ, 7.17, (d, 2H, J = 8.70 Hz), 6.84, (d, 2H, J = 8.70 Hz), 4.07, (t, 2H, J = 5.80 Hz), 3.66, (s, 3H), 3.58, (t, 2H, J = 6, 50 Hz), 3.55, (s, 2H), 2.31, (quint., 2H,

J = 6.30 Hz).

Step B)

Preparation of methyl 4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -phenylacetate

A solution prepared by dissolving 11.0 g, (38.58 mmol) of methyl 4- (3-bromopropoxy) phenylation of the salt obtained in the above step (A) above, further 8.0 g, (35, 4-phenoxy-2-propylphenol, (International Patent Application, WO -97 / 28.115), 8 12.0 g, (36.82 mmol) of cesium carbonate, in 80.0 ml of dimethylformamide, was Stir overnight at 40.0 ° C.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and then dried over sodium sulfate.

After filtration and evaporation of the organic layer, it was obtained # 99 * 9

9 ·

9

9

9 9

9999 99 »9 ·· • 9 9 * 9

9 «

99 • 9 99 «9 9 9 • 9

9 9 9

9 9 9

The oil was chromatographed over silica gel, eluting with 10% ethyl acetate in hexane to give the title compound.

¹ H-NMR _γ (400 MHz, CDCl 3):

delta, 7.30-7.18, (m, 4H), 7.02-6.70, (m, 8H), 4.17 (t, 2H, J = 6.30 Hz), 4.11, (t, 2H, J = 6.00 Hz), 2.53, (t, 2H, 7.40 Hz), 2.26, (quint., 2H, J = 6.30 Hz) 1.55, (hex, 2H, 5.60 Hz), 0.89, (t, JH, J = 7.30 Hz).

Stage C)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -phenyl / -2,4-thiazolidinedione

A solution prepared by dissolving 27.36 mL of (27.36 mmol of 5, lithium bis (trimethylsilyl) -8mide) in 80.0 mL of dried tetrahydrofuran was mixed with 5.94 mL at minus 78.0 ° C. (46.76 mmol) trimethylsilyl chloride.

Then, a solution prepared by dissolving 10.80 g (24.87 mmol) of methyl 4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -phenylation of the tate obtained in the reaction mixture was added dropwise. of the preceding step B) above in 15.0 ml of tetrehydrofurnau, and the reaction mixture was stirred at minus 78.0 ° C for 2.0 hours.

Then, after the addition of 4.65 g (26.12 mmol) of N-bromosuccinimide, the reaction mixture was allowed to warm to room temperature overnight. Thereafter, the tetrahydrofuran was evaporated, and the resulting residue was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was washed once with water, and the organic layer was washed once with water.

Φ · • φ · φ φ φ

·· · ho · · · ho · φ · φ ·

It was then dried over sodium sulfate, filtered, and evaporated.

Methyl-alpha-bromo-4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -phenylacetate was obtained as an oily consistency.

The resulting oil-like residue was dissolved in 100.0 ml of methoxyethanol and 2.84 g (37.31 mmol) of thio urea and 2.14 g were added to the resulting solution. (26.12 mmol) of sodium acetate, and the resulting reaction mixture was heated at 115.0 ° C, for 5.0 hours.

After addition of 19.43 ml of 6N hydrochloric acid, the reaction mixture was heated to 115.0 ° C for an additional 5.0 hours.

Subsequently, the reaction mixture was partitioned between ethyl acetate and water, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and dried over sodium sulfate, and after filtration evaporated to an oily substance which was chromatographed over silica gel using of 1% methanol in dichloromethane as eluent.

The title compound was obtained.

¹ H-NMR (4.00 MHz, CB € 'l _3):

delta, 8.01, (g.s.,), IH), 7.32 - 7.24 (m., 4H) , 7,02 - 6,79, ( m., 8H), 5.32, (s, 3H). 4.17, (t, 2H, J = 6.30 Hz), 4 11 (t, 2H, J) = 6.00 Hz) 2.53, (t. , 2H, 7.40 Hz), 2,26, ( quint., 2H, J = 6.30 Hz), 1.55, (hex. , 2H, 5.60 Hz), 0,89, ( t, 3H, J = 7.30 Hz).

Example 2) ·· • ····

ÝY ···· *

• fc ·································

Preparation of 5- / 4- (3- (7-propyl-3-phenyl-6-benzo) - 4,5-isoxysolyloxypropoxy) -phenyl) -2,4-thiazolidinedione

Stage A)

Preparation of methyl 4- (3- (7-propyl-3-phenyl) -6-benzo [4,5] -isoxazoyloxy) -propoxy) -phenyl acetate

The reaction procedure described above in Example 1), Step Efc), was carried out using 7-propyl-3-phenyl-6-hydroxy-benzo [4,5] -30X8Zul, (International Patent Application, WO-97 / 28.137). as a starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCl 3):

.delta. 7.92 (dd, 2H, J = 7.90, 2.60 Hz), 7.64 (d, 1H,

J = 8.70 Hz), 7.52 (m, 3H), 7.18 (d, 2H, J = 8.60 Hz), 7.01, (d, 2H, J) 8.80 Hz), 6.8 & (dd, 2H, q / q, 2.10 Hz), 4.26, (t, 2H, J = 6.10 Hz), 4.18, (t. 2H, J = 6.00 Hz), 3.67, (s, 3H), 3.55, (s, 2H), 2.90, (t, 2H, J =

7.30 Hz) 2.31, (quint., 2H, J = 6.30 Hz), 1.71, (hex., 2H,

J = 5.70 Hz), 0.92 (t, 3H, J = 7.30 Hz), • 9 ·

• t 9 9 9 9 9 9

Grade ffi)

Preparation of 5- [4- (3- (7-propyl-3-phenyl-6-benzo [4,5,5] oxazolyloxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C, using meth, yl-4- (3- (7-propyl-3-phenyl-6-benz- [4,5] -oxoxolyolyloxy) -propoxy) - Phenylacetate obtained as described in Step A ') above, as a starting material, the title compound is prepared. ¹ H-NMR, (400 MHz, CRCl 3):

delta,. 8.23 (broad b, 1H), 7.92 (dd 2H, J = 7.90, 2.60 Hz), 7.64 (d, 1H, J = 8.70 Hz) 7.52, (m, 3H), 7.31, (d, 2H, J = 8.60 Hz), 6.98, (d, 2H, J = 8.80 Hz) 6.92 (dd, 2H, J = 8.70, 2.10 Hz), 4.26, (t, 2H, J = 6.10 Hz),

,, 4.20 _(t.,; ,, 2H J = 6.00 Hz), 3.67 (s., 3H), 3.55 (a.,

2H), 2.90 _r (t., 2H, "J = 7.30 Hz), 2.31 ,, quint., 2H, J =

6.30 Hz), _1.71 (hex, 2H, J = 5.70 Hz), 0.92 (t, 3H, 1H);

J = 7.30 Hz).

Mass apectrometry-chemical ionization (GI-MS):

m / e = 503.0 (M + 1);

Example 3)

Preparation of 5- / 4- (3- (7-propyl-3-neopentyl-6-benzo- (4,5) -isoxazolyloxy) -propoxy) -phenyl) -2,4-thiazolidinedione

Stage A)

Preparation of methyl 4- (3- (7-propyl-3-neopentyl-6-benzo / 4,5-isoxszolyloxy) propoxy) phenylacetate

An analogous procedure to that described in Example 1 above, Step 8), using 7-propyl-3-neopentyl-6-hydroxybenz (4,5) -oxazole, (International Patent Application, WO-97)

28.137), as a starting material, the desired title compound.

¹ H-NMR (400 MHz, CDCl 3):

delta, 7.34, (d, 1H, J = 8.70 Hz) 7.17, (d.d., 2H, J = 8.70,

2.10 Hz), 6.90 (d, 1H, J = 8.70 Hz), 6.86 (d, d, 2H, J =

8.70, 2.10 Hz), 4.23 (t, 2H, J = 6.00 Hz), 4.18, (t, 2H,

J = 6.00 Hz), 3.67, (a, 3H), 3.54, (s, 2H), 2.85, (t,

2H ₍ J = 7.20 Hz), 2.78, (a, 2H), 2.28, (quint., 2H, J =

6.30 Hz), 1.6N _r (hex., 2H, J - 5.90 Hz), 1.02 (s. 9H), 0.92 (t., 3H, J = 7.30 Hz).

Grade H) · · · 9 ·· 9 ty

Preparation of 5- [4- (3- (7-propyl-3-neopentyl-6-benzo [4,5] -oxoxolyolyloxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C, using methyl 4- (3- (7-propyl-3-neopentyl-16-benzo [4,5] isoxazolyloxy) propoxy) phenylacetate, as obtained from the above-described Step A) as a starting material, the title compound is obtained. H-.mR ¹ _r (400 WIZ .. CHC1 _3):

9H), 0.92. (t, ,, 3H, J = 7.30 Hz).

Example 4)

Preparation of 5- [4- (3- (7-propyl-3-trifluoromethyl-6-benzo [4,5] -isoxazoloyloxy) -propoxy) -phenyl] -2,4-thiazolidinedione

H

O

4 4 · * * * · *

Stage A)

Preparation of methyl 4- (3- (7-propyl-3-trifluoromethyl-6-benzo [4,5] isoxazolyloxy) propoxy) phenylacetate

An analogous procedure (described above in Example 1), Step E), using 7-propyl-3-trifluoromethyl-6-hydroxybenz- (4,5) -isoxazole, (International Patent Application, WO-97)

28.137), as a starting material, the desired title compound.

¹ H-NMR, (400 MHz, SLOCl-j):

δ, 7.53, (d, 1H, J = 8.20 Hz), 7.18, (d.d., 2H, <1 =

8.70, 2.10 Hz), 7.05 (d, 1H, J = 8.80 Hz), 6.86 (dd, 2H, 1-8.70, 2.10 Hz), 4.27, (t, 2H, J = 6.00 Hz), 4.18, (t, 2H, J = 6.00 Hz), 3.65, (s, 3H), 3.54 , (a. 2H),

2.88, (t, 2H, J = 7.20 Hz), 2.30, (quint., 2H, J = 6.30 Hz), 1.66, (hex, 2H, J = 5) 90 Hz), 0.92 (t, 3H, J 7.30 Hz).

Step B)

Preparation of 5- / 4- (3- (7-propyl-3-trifluoromethyl-6-benzo- (4,5) -isoxazolyloxy) -propoxy) -phenyl) -2,4-thiazolidinedione

An analogous procedure to that described in Example 1 above, Step G), using methyl 4- (3- (7-propyl-3-trifluoromethyl-6-benzo / 4,5) -isoxazolyloxy) propoxy The phenyl compound obtained in the preceding step (A) above as a starting material is prepared as a title compound.

9 ··· / ··· «>

• 9

9999 • 9

9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9

99 ¹ H-NMR (400 MHz, CDCl 3)?

delta, (d.d.

6.92., (T., (T »,

1.66 ..

8.05 ,, I (š.s., 1H), 7.53. (d, 1H, J) = 8.80 Hz), 7.32, , 2H, J = θ JO, 2.10 Hz), 7,06, ( d., 1H, J = 8.60 Hz), (d.d., 2H, J = 8.70, 2.10 Hz), 5, 32, (s, 1H) 4,27, 2H, J = 6, 10 Hz , 4.18, ( t. · 2H, J = 6.10 Hz), 2,85, 2H, J = 7.50 Hz ), 2.28, ( kvint., 2H, J = 6.30 Hz (hex. 2H, J = 5.90 Hz), 0,92, ( t., 3H, J = 7.30 Hz).

m / z, 512.30, (M + NH4)

Mass spectrometry-Cl:

Example 5)

Preparation of 5- [4- (3- (7-propyl-3-phenethyl-6-benzo [4,5] -isoxazoloyloxy) propoxy) phenyl] -2,4-thiazolidinedione

Grade A) • 0 ·

0 • · ······

0

0 •• 00 00

• 0 0 0 ·· 00

Preparation of methyl 1-4- (3- (7-propyl-3-phenyl-6-benzo [4,5] -oxazolyloxy) propoxy) phenylacetate

Using the analogous procedure described above for Example 1), Step B), using 7-propyl-3-phenethyl-6-hydroxy-benzo [4,5] -isoxzole was used. (International Patent Application, WO-97/28 * 137,), as a starting material, the title compound is prepared.

¹ H-NMR, (400 MHz, CDCl 3):

δ 7.28-7, -16, (m, 8H), 6.88 - 6.84, (m, 3H), 4.21, (t, 2H, J = 6.00 Hz) 4.16, (t, 2H, J = 6.00 Hz), 3.67, (s, 3H), 3.54, (s, 2H), 3.22-3.12, ( m., 4H), 22.85, (t, 2H, J = 7.20 Hz), 2.29, (quint., 2H, J = 6.30 Hz),

1.66, (hex, 2H, J = 5.90 Hz), 0.92, (t, 3R, J = 7.30 Hz).

P r es B)

Preparation of 5- / 4- (3- (7-propyl-3-phenethyl-6-benzo- (4,5) -isoxazolyloxy) -propoxy) -phenyl) -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C) above, using methyl 4- (3- (7-propyl-3-trifluoromethyl-6-benzo [4,5] -isoxazoloyloxy)) (propoxy) -phenyl acetate as the starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, ODCl ₃ ):

delta, 8.10, (bs, 1H), 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 = 7.20 Hz), 2.29, (quint. , 2H, J - 6.30 Hz), ·· ···· · ··

1.66 (hex, 2H, J = 5.90 Hz); 0.92, (t, 3H, J = 7.30 Hz).

CI-mass spectrometry: m / z, 531.50, (M + 1)

Example 6)

Preparation of 5- / 4- (3- (7-propyl-3-phenylbutyl-6-benzo- (4,5) -osoxazolyl-oxy) -propoxy) -phenyl) -2,4-thiazolidinedione

Stage A)

Preparation of methyl 4- (3- (7-propyl-3-phenylbutyl-6-benzo [4,5] -isoxazolyloxy) propoxy) phenylacetate

Using the analogous procedure described above for Example 1), Step B), the title compound was prepared using 7-propyl-3-phenylbutyl-6-hydroxy-benzo [4,5] -isoxazole as starting material. compound.

44 · · ♦> ·> 44 ···· ·

• • • 44 • <

• 4 • · ·· 44

I • · I

4

4 44

4

4

4 • 4 ¹ H-NMR, (400 MHz, CDG1-j):

delta. 7.31 * (d, 1H, J = 8.60Hz). 7.26 - 7.13. (m. 8H)

6.88 - 6.84 (m, 2H), 4.21, (t, 2H, J = 6.00 Hz), 3.67,

2.91 (t, 2H, J = 7.40 Hz),

2.66, (t, 2H, J = 7.20 Hz),

1.90 - 1.70 ,. (m, 4H), 1.66, (t, 3H, J = 7.30 Hz).

(t, 2H, J = 6.00 Hz), 4.16, (s, 3H), 3.54, (a, 2H), 2.82, (t, 2H, J = 7) 50 Hz), 2.29 (quint. 2H, J = 6.30 Hzl (hex, 2H, J 5.90 Hz), 0.92,

Step B)

Preparation of 5- [4- (3- (7-propyl-3-phenylbutyl-6-benzo [4,5] -isoxazolyl oxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1 (Step C) above, methyl (3- (7-propyl-3-phenylbutyl) 6-benzo [4,5] -isoxazolyloxy-1-propoxy) -phenyl acetate was used, . obtained as a starting material from the previous step (A) above, as a starting material, the desired title compound, ¹ H-NMR (400 MHz, CDCl 3):

δ, 8.10, (b, 1H), 7.32-7, -29, (m, 3H), 7.26-7.20 (m, 2H). 7.17-7.11, (δ, 3H), 6.93 - 6.87, (m, 3H), 4.23-4, -16, (m, 4H), 2.91, (t, 2H, J = 7.40 Hz), 2.82, (t, 2H, J = 7.50 Hz), 2.66, (t, 2H, J = 7.20 Hz) 2.29, (quint., 2H, J = 6.30 Hz), 1.90-1.70, (m, 4H), 1.66, (hex, 2H, J = 5.90 Hz) 0.92, (t, 3H, J = 7.30 Hz).

Mass spectrometry-GI:

m / e, 559.70 (M + 1);

• 9

9 «9 * · 4 · Α ··

999 · ·· ·· <

• 9 9 9 9 9 9 9

* · 99 9 «« · 9 • · 9 • 9 9 · · 9 9 ♦ · 99

SO

Example 7)

Preparation of 5- / 4- (3- (7-propyl-3-phenylbenzofursn-6-yl) oxy) propoxy) phenyl] -2,4-thiazolinedione

Stage A)

Preparation of methyl 4- (3- (7-propyl-3-phenyl-benzofuran-6-yl) propoxy) phenylacetate

Using the analogous procedure described above for Example 1), Step Η), the desired title compound was prepared using 6-hydroxy-7-propyl-3-phenylbenzofuran (International Patent Application WO-97 / 27.857) as the starting material. said compound.

@ ¹ H-NMR, < 400 MHz. ODCl ^:

delta, 7, .69, (a., 1H). 7.68-7.59, (m, 2H), 7.54, (d,

1H, J = 8.50 Hz), 7.45-7.13 (m, 3H), 7.18-7.15, (m,

2H), 6.92 (d, 1H, J = 8.50 Hz), 6.90 - 6.85, (m, 2H),

4.21. 4.16, (m, 4H), 3.67, (a, 3H), 3.54, (a, 2H),

2.88, (t, 2H, J = 7.40 Hz), 2.29, (quint., 2H, J = 6.30, φ · H);

·· # · φφ ·· · · ·

φ · · · · · · · ·

Ηζ), 1.66, (hex., 2Η, J = 5.90 Hz), 0.92, (t., 3Η, J =

7.30 Hz).

Step B)

Preparation of 5- [4- (3- (7-propyl-3-phenyl-benzofuran-6-yl) -propoxy) -phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C, using methyl 4- (3- (7-propyl-3-phenylbenzo-furan-6-yl) -propoxy) -phenylacetate obtained under from Step A) as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 8.18, (bs, 1H), 7.69, (s, 1H), 7.63-7.59, (m, 2H), 7.55, (d, 1H) , J = 8.50 Hz), 7.45 to 7.40 (m., 2H), 7.36 to 7.27 (r. 2H), 6.90 to 6.55 _r (r. , 3H), 5.31 (a.,

1H), 4.21-4, 16, (m, 4H), 3.67, (s, 3H), 2.88, (t,

2H, J = 7.40 Hz), 2.29, (quint., 2H, J = 6.30 Hz), 1.66, (hex, 2H, J = 5.90 Hz), 0.92, . (t, 3H, J = 7.30 Hz).

Example 8)

Preparation of 5- / 4- <3- (7-propyl-3-phenylbenzothiophen-1,1-dioxide-6-yl) oxy] -benzyloxy) -phenyl-2,4-thiazolidinedione • · 4 • 4 ···

9 4 9 4

F2.

Stage A)

Preparation of methyl 4- (3- (7-propyl-3-phenyl-benzothiophen-1,1-dioxide-6-yl) -propoxy) -phenylscetate

Using the analogous procedure described above for Example 1), Step B), the title compound was prepared using 6-hydroxy-7-propyl-3-phenylbenzothiophene-1,1-dioxide as the starting material.

¹ H-NMR (400 MHz, ODCl 3):?

δ, 7.50-7.42, (m, 4H), 7.31, (d, 2H, J = 8.80 Hz),

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83, (m, 3H),

6.46, (a, 1H), 4.21-4.16, (m, 4H), 3.67, (s, 3H),

3.54, (s, 2H), 2.95, (t, 2H, J = 7.40 Hz), 2.29 (quint, 2H, J = 6.30 Hz), 1.71 (hex, 2H _r J = 5.90 Hz). 1.01, (t _r 3H, J = 7.30 Hz).

Degree

B) 9944 • r • * # #

Preparation of 5- [4- (3- (7-propyl-3-phenyl-benzothiophen-1,1-dioxide-6-yl) -propoxy) -phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C, using methyl 4- (3- (7-propyl-3-phenylbenzothiophen-1,1-dioxide-6-yl) propoxy) phenylacetate, obtained as described above in Step A) above as a starting material, to obtain the title compound.

@ ¹ H-NMR (400 MHz, GdCl3): .delta.

delta, 8.05, (bs, 1H), 7.50-7.42, (m, 4H), 7.31, (d,

2H, J = 8.80 Hz), 7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92 6.83, (m, 3H), 6.46 , (a., 1H), 5.32, (s, 1H), 4.21, 4.16, (m, 4H), 2.95, (t, 2H, J = 7.40 Hz) , 2.29, (quint.

2H, J = 6.30 Hz 1.71, hex, 2H. J = 5.90 Hz), 1.01, (t, 3H, J = 7.30 Hz).

CI-mass spectrometry: m / e, 567.30, (M + NH4);

Example 9)

Preparation of 5- / 4- (3- (7-Propyl-3-cyclohexylmethyl-6-benzo [4,5] -isoxazolyloxy) -propoxy) -phenyl] -2,4-thiazolidinedione

About 4 * 4. ί * »44 ·» # ♦ 44 ·· í # *

S t u p e A)

Preparation of methyl 4- (3- (7-propyl-3-cyclohexylmethyl-6-benzo [4,5] oxazolyloxy) propoxy) phenylacetate

In analogy to the procedure described in Example 1 (Step B) above, using (3-cyclohexylmethyl-6-hydroxy-7-propyl) -benz- (4,5) -oxazole as starting material, the desired product was prepared. the title compound: ¹ H-NMR, (400 MHz, CDG 1?):

delta,. 7.36, (d, 1H, J = 8.60 Hz), 7.32, (d.d., 2H, J =

6.70, 1.90 Hz), 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 = 6.30 Hz), 2.77, (d, 2H, J = 7.0 Hz), 2.29, (quint.,

2H, J = 6.30 Hz), 1.85-1.00, (m, 13H), 0.89, (t, 3H,

J = 7.30 Hz

P r es B)

Preparation of 5- [4- (3- (7-propyl-3-cyclohexylmethyl-6-benzo [4,5] isoxazolyloxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C above, using methyl 4- (3- (7-propyl-3-cyclohexylmethyl-6-benzo- [4,5] -isoxazolyloxy) -propoxy) - of the phenylacetate obtained in Step A) above, as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, OR? 1?):

.delta., 8.25, (s, 1H), 7.36 (d, 1H, J = 8.60 Hz), 7.32, i (dd, 2H, J = 6.70, 1, 90 Hz), 6.93 - 6.88, (m, 3H), 5.32, ^f (s, 1H), 4.23 - 4.17, (ra, 4H), £ 84, (t, 2H, J = 6.30)

Hz), 2.77, (d, 2H, J = 7.00 Hz), 2.29, (quint., 2H, J =

6.30 Hz), 1.85-1.00, (ra., 13H), 0.89, (t., 3H, J = 7.30Hz)

·· ···· • · • «1 · • · 7. f '. t • · • · • · • · ·

Example 1 8 d 10?)

Preparation of 5- / 4- (3- (2-propyl-4- (4-fluorobiphenyloxy) -propoxy) -phenyl)

2,4-thiazolidinedione

Si t u fo e A)

Preparation of methyl 4- (3- (2-propyl- (4-fluorobiphenyloxy) propoxy) phenyl acetate)

Using the analogous procedure described above for Example 1), Step B), the title compound (R) was prepared using 2-propyl-4- (4-fluorophenyl) phenol as the starting material.

4 * 94 • • 9 949 9 9 9 »* 1 «4 · 9 • · * .9 / * 9 • 9 9 9 • 9 9 9 9 9 9 9 • 9 • 9 9

’Η-ΝΜΚ, (400MHz, CDCl ^):

.delta., 7.32-7.24, (m, 4H), 7.02 - 6.79, (m, 7H), 4.20, 4.16, (m, 4H), 3.80, (a., 3H), 3.70, (a., 2H), 2.53, (t,

2H, 7.40 Hz), 2.26, (quint., 2H, J = 6.30 Hz), 1.55, (hex.,

2H, 5.60 Hz), 0.89, (t, 3H, J = 7.30 Hz).

Step B)

Preparation of 5- / 4- (3- (2-propyl- (4-fluorobiphenyloxy) -propoxy) -phenyl) phenyl) -2,4-thiazolidinedione

An analogous procedure to that described in Example V), Step C), was the use of methyl 4- (3- (2-propyl- (4-fluorobiphenyloxy) propoxy) phenylacetate) obtained as described above in Step A above. ), as a starting material, the title compound of the title compound (400 MHz, GDC1):

δ, 8.01, (b, 1H), 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, 7.40 Hz), 2.26, (quint., 2H, J-6) 30 Hz), 1.55, (hex, 2H, 5.60 Hz), 0.89, (t, 3H, J = 7.30 Hz).

Feed 11)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-chlorophenyl / -2,4-thiazolidinedione *** ♦ 44 ··

Stage A)

Preparation of 4- (3-bromopropoxy) -3-propylphenyl-phenyl ether

A solution prepared by dissolving 12.0 g (52.60 mmol) of 4-phenoxy-2-propylphenol, followed by 31.86 g. (157.81 mmol) of 1,3-dibromopropane. and 18.0 g (55.23 mmol) of cesium carbonate in 110.0 mL of dimethylformamide was stirred at room temperature overnight.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and then dried with sodium sulfate. After filtration, the organic layer was evaporated. The oily residue was chromatographed on silica gel using dichloromethane: hexane. (1.0: -1.0) as eluent.

The title compound was obtained.

Step B)

Preparation of methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-chlorophenylacetate ce * ΤΜ * ··· »· • 0

*

/ ·

8

5 £

A solution prepared by dissolving 2.50 g (7.18 mmol) of 4- (3-bromopropoxy) -3-propylphenyl 1-phenyl ether obtained in the above-described Step A), further 1.42 g, (7, Methyl 3-chloro-4-hydroxyphenylacetate, and 2.43 g (7.45 mmol) of cesium carbonate were stirred overnight at 40.0 ° C.

Then the reaction mixture was partitioned between ethyl acetate and 0.2N hydrochloric acid solution, and after separation of the organic and aqueous phases, the organic layer was washed twice with water and then dried with sodium sulfate. After filtration, the organic layer was evaporated, and the residue, as an oily substance, was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane.

The title compound was obtained.

¹ H-NMR, (400 MHz, GDE 1):

δ, 7.24-7, 29, (m, 3H), 7.10, (dd, 1H, J = 8.40,

2.10 Hz), 7.00 ,. (t, 1H 'J = 7.30 Hz), 6.92-6.80, (m,

6H), 4.22 (t, 2H, J = 6.10 Hz), 4.16, (t, 2H, J = 6.00 Hz), 3.67, (a. 3H), 3.52, (s, 2H), 2.53, (t, 2H, J = 7.40 Hz), 2.30, (quint., 2H, J = 6.30 Hz), 1.55, (hex, 2H, 5.60 Hz), 0.89, (t, 3H, J = 7.30 Hz).

G)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-chlorophenyl / -2,4-thiazolidinedione

In an analogous manner to that described in Example 1 above,

Step G), using methyl 4- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -3-chlorophenylate, obtained from the above step (výše) as starting material ,

• • · • · • 4 4 ♦ ·· · • • ^ 9-V-W W * · · 4 »9 and". t *, 9 9 44 —W-w — r— • ♦ · · • «· · • ♦ · · · • · 99 4 9 • * 4 4

to obtain the title compound.

¹ H-NMR (400 MHz, GTUGI):?

delta, 8.46 (bs, 1H), 7.42 (d, 1H, J = 2.30 Hz), 7.29 7.23, (nu, 3H), 7.02-6, 80 (m, 7H), 5.27 (s, 1H),

4.24, (t, 2H, J = 6.10 Hz), 4.15, (t, 2H, J = 6.00 Hz),

3.67, (s, 3H), 3.52, (s, 2H), 2.53, (t, 2H, J = 7.40

Hz), 2.30, (quint., 2H, J = 6.30 Hz), 1.55, (hex, 2H, 5.60)

Hz), 0.89, (t, 3H, J = 7.30 Hz).

Example. 12)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-fluorophenyl / -2,4-thiazolidinedione

Stage A)

Preparation of methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3r fluorophenylacetate, -, - < - &gt;

• · · 4 »4 4 • 4 «» 4 4 4 · ».T«, » »». t *. 4 4 • 4 44 4 4 4 4 4444 44 44 44 4 * 4 »

€ 0

Using the analogous procedure described above for Example 11), Step B), the title compound was prepared using methyl 3-fluoro-4-hydroxyphenylacetate as the starting material.

¹ H-NMR (400 MHz, ODCl 3):?

δ, 7.23-7.28 "(m, 3H), 7.11 (dd, 1H, J = 8.40,

2.03 Hz) 7.03, (t, 1H, J = 7.30 Hz), 6.92-6.82, (m,

6H) ,. 4,, 24,. (t, 2H, J = 6.10 Hz), 4.14, (t, 2H, J = 6.00 Hz), 3.66, (s, 3H), 3.52, ( s, 2H). 2.51 _R (t., 2H, J =

7.40 Hz), 2.31 _r (quint., 2H, J = 6.30 Hz), 1.54 _r (hex., 2H,

5.60 Hz), 0.86 _r (t, 3H, J = 7.30 Hz).

Step B)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-fluorophenyl / -2,4-thiazolidinedione

An analogous procedure to that described above in Example 1), Step C), using the methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-fluorophenylacetate obtained in the foregoing, above of Step A), as a starting material, the desired title compound.

¹ H-NMR (400 MHz, CM 4):

delta, 7.98, (bs, 1H), 7.42, (d, 1H, J = 2.30 Hz), 7.29, 7.23. (m, 3H), 7, O 2 - 6.80 "(m, 7H), 5.27, (s, 1H), 4.24 (t, 2H, J = 6.10; Hz), 4.15, (t, 2H (J = 6.00 Hz), 3.67, (s, 3H), 3.52, (s, 2H), 2.53 (t, 2H _, J = 7) 40 Hz),

2.30. (Quint., 2H, J = 6.30 Hz), 1.55, (hex, 2H, 5.60 Hz), 0.89, (t., 3H, J = 7.30) Hz).

• ♦ · • · · · · · · · ·

Example 13) I * I * i * r * t * t

Gl • · <·· ··

Preparation of 5- / 4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -3-propyl-phenyl / -2,4-thiazolidinedione

Stage A)

Preparation of methyl-4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -3-propynylphenate

In an analogous manner to that described in Example 11), Step B), the title compound was prepared from methyl 4-hydroxy-3-propylphenylacetate as the starting material.

¹ H-NMR, (400 MHz, CDCl ₃ ):

δ, 7.31-7.25, (m, 2H), 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 = 6.30 Hz), 1.61 1.55, (m, 4H), 0.96 - 0.86, (m, 6H).

9 9

9

9

9 9 9

9 9 9

S t u p e η Β)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-propylphenyl / -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C, using methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-propylphenylacetate obtained in Step B above. ), as a starting material, the title compound (1).

¹ H-NMR (400 MHz, CDCl 3):?

delta, 8.04, (bs, 1H), 7.28-7.24, (m, 2H), 7.18, (dd ,,);

(m, 6H),

Example 14)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) -propylthio) -3-chlorophenyl 1 / -2. 4-thia zolidinedione

Cl ^w - · 44 · · · · · · · · · · · ·

• 4 4 49

Φ ΦΦΦΦΦΦ

ΦΦΦΦ Φ Φ ΦΦΦΦ

ΦΦΦΦ ΦΦ ΦΦ φ φ · φ φ φ φ φ φ φ φ φφ / 3

S t u ρ e Α)

Preparation of methyl 3-chloro-4- (3-bromopropylthio) phenylacetate

To a solution prepared by dissolving 8.50 g (0.0295 mol) of methyl 3-chloro-4-dimethylcarbamoylthio-phenylacetate in 30.0 ml of methanol, 7.0 ml (0.034 mol) was added. Of a 25% solution of sodium methoxide in methanol, and the resulting reaction mixture was heated to reflux under reflux for 2.0 hours.

Thin Layer Chromatography (TLC) analysis showed residual carbamate used as starting material.

A further 1.0 mL of sodium methoxide in methanol was added to the reaction mixture, and the mixture was stirred at reflux for an additional 30.0 minutes. After cooling to room temperature, the thiolate solution was added dropwise to the solution obtained by dissolving 12.0 ml (0.12 mol),

1,3-dibromopropane in 30.0 ml of methanol, and the resulting reaction mixture was heated to reflux for 3.0 hours, and then cooled to room temperature.

After the reaction mixture was allowed to stand overnight, the reaction was stopped by pouring the mixture into ice-cold water. After the pH of the mixture was adjusted to 1.0 with concentrated hydrochloric acid, the mixture was extracted in the form of an aqueous solution first with 0.20 liter, then twice with 1.0 liter of ethyl acetate each time.

The combined organic layers were washed successively with water, and brine. and dried over anhydrous magnesium sulfate, filtered, and concentrated.

The resulting residue was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane.

The title compound was obtained.

¹ H-NMR, (CDCl ₃ ):

delta, 7.25 - 7.32 ,. (m., 2H), 7.15, (d.d., 1H, J = 8.10, 9 · 9)

9

9

9 9

4999 98 «99 9 9 9 9

9 9 9 9 4

9 4 9 4 4 5

44

6'Ý

1.80 Hz), 3.71 (s, 3H), 3.57. (3., 2H), 3.55, (t, 2H, J = 7.70 Hz), 3.10, (t, 2H, J = 7.70 Hz 5, 2.18, (m 2H,

Level EL ·)

Preparation of methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) -3-chlorophenylacetate

A solution prepared by dissolving 2.50 g (7.18 mmol) of 4- (3-bromopropoxy) -3-propylphenyl-phenyl ether, followed by 1.42 g (7.11 mmol) of methyl 3-chloro-4- hydroxyphenylacetate, and 2.43 g, (7.45 mmol) of cesium carbonate, ve. Dimethylformamide (20.0 mL) was stirred at 40.0 ° C overnight.

The reaction mixture was then partitioned between ethyl acetate 8N, 2N hydrochloric acid, 8 after separation of the organic and aqueous phases, the organic layer was washed twice with water, and dried over sodium sulfate, filtered and evaporated to an oily substance which The residue was chromatographed on silica gel, eluting with 10% ethyl acetate in hexane.

The title compound was obtained.

¹ H-NMR, (400 MHz, CDCl 3):

.delta., 7.24-7.29, (m, 3H), 7.10 (dd, 1H, J = 8.40,

2.10 Hz), 7.00 (t, 1H, J = 7.30 Hz), 6.92-6.80, (m,

6H), 4.22, (t, 2H, J = 6.10 Hz), 4.16, (t, 2H, J = 6.00 Hz), 3.67, (a, 3H), 3.52, (a, 2H), 2.53, (t, 2H, J =

7.40 Jz), 2.30, (quint., 2H, J = 6.30 Hz), 1.55, (hex.,

2H, 5.60 Hz), 0.89, (t, 3H, J = 7.30 Hz).

G)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) -3-chlorophenyl / -2,4-thiazolidinedione

In an analogous manner to that described in Example 1 above, Step C), using the methyl 4- (3- (2-propyl-4-phenoxyphenoxy) propylthio) -3-chlorophenyl acetate, obtained above of Step B), as a starting material, the title compound is obtained.

@ 1 H-NMR (400 MHz, CDCl3):

delta, 8.60 (bs, 1H), 7.42. (d, 1H, J = 2.30 Hz), 7.29 -

0,89 ,. (T., _{3H r} J = 7.30 Hz) »

Example 15)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -3-chlorophenyl / -2,4-thiazolidinedione

HN,

Cl y ^s • O

*

Α Σ Σ · · · Λ · · · · · · · ·

9 4 9 9 4 5

9

9 9 9 9 9

9 9 9 9 9

9999 99 99 99

9 9 «

9 9 9

49

GG

Grade Α)

Preparation of 4- (4-bromobutoxy) -3-propylphenyl-phenyl ether

A solution of 25.0 g (0.11 mol), 4-phenoxy-2-propylfen.srlu _of further 70.99 g (0.33 mol) of 1,4-dibromobutane and 39 », 28 g ( 0.12 mol) of cesium carbonate in 250.0 ml of dried dimethylformamide was stirred at room temperature overnight.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with sodium sulfate, filtered and evaporated.

The resulting oil-like residue was chromatographed over silica gel using dichloromethane: hexane (1.0: 1.0) as eluent.

The title compound was obtained.

P r es B)

Preparation of methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenylation

A solution prepared by dissolving 5.70 g _r (15.75 mmol) of 4- (4-bromobutoxy) -3-propylphenyl-1-phenyl ether obtained in the above step (A) described above, further 3.0 g (15.00 mmol) of methyl 3-chloro-4-hydroxyphenyl acetate; and 5.38 g (16.50 mmol) of cesium carbonate in 50 ml of dimethylformamide was stirred at 40.0 ° C overnight.

The resulting reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was washed twice with water, and after

• Φ * * »·· ·. · * • * * • · <· <* · <· « • • • · · * 9 · • Φ • • • · • t · · • ♦ • · c · · · ·· ·· »· ··

dried over sodium sulfate, filtered and evaporated.

The resulting residue as an oil was chromatographed on silica gel. elution with 10% ethyl acetate in hexane.

The title compound was obtained.

@ ¹ H-NMR (400 MHz, GCl3): .delta.

.delta., 7.28-7.24, (m, 3H), 7.10, (dd, 1H, J = 8.40,

2.20 Hz), 7.02-6.98, (m, 1H), 6.92-6.76, (m, 6H), 4.09, (t, 2H, J-5, 70 Hz), 4.01, (t, 2H, J = 5.80 Hz),

3.67, (a, 3H), 3.52, (s, 2H), 2.53, (t, 2H, J = 7.40 Hz), 2.02, (m, 4H) 1.55, (hex, 2H, 5.60 Hz), 0.89, (t, 3H, J = 7.30 Hz).

G e G)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenyl]

2,4-thiazolidinedione

In an analogous manner to that described in Example 1, Step C, above. using methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenylacetate obtained as described above in Step B) as the starting material, the title compound was obtained.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 8.12, (bs, 1H), 7.42, (d, 1H, J = 2.40 Hz), 7.28 7.23, (m, 3H), 7.02 6.75 (m, 7H), 5.28 (s, 1H),

4.09, (t, 2H, J = 5.70 Hz), 4.03, (t, 2H, J = 5.80 Hz),

3.67, (s, 3H), 3.52, (s, 2H), 2.53, (t, 2H, J = 7.40 Hz)

2.02, (m, 4H), 1.55, (hex, 2H, 5.60 Hz), 0.89, (t, 3H,

J = 7.30 Hz) »

Example 16)

• • · • • 4 4 · 4 Ϊ · · * · • Ml * · 4 · ♦ ·· • • • 4 • 4 ^ • • 4 44 4 · »4 • • • 4 44 4 4 4 4 4 4

Preparation of 5- (4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-chlorophenyl)

2,4-thiazolidinedinedione

Stage A)

Preparation of methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-propylphenylate

An analogous procedure to that described in Example 15, Step A) above was using methyl 3-propyl-4-hydroxyphenylacetate. as a starting material, the title compound is obtained.

1 H-NMR, (400 MHz, δ, 7.31-7.25, (m, 2H), 7.04-6.76, (m, 9H), 4.02 4.00, (m ., 4H), 3.67, (a., 3H), 3.55, (s, 2H), 2.61, 2.53, (m, 4H), 2.03-1.98, ( m., 4H), 1.66-1.55 (m.,

4H) ,. 0.98 - 0.90, (m, 6H).

Step B)

Preparation of 5- / 4- (4- (2-propyl-4-phenoxy-phenoxy) butoxy) -3-propylphenyl / -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C), using the methyl 4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -3-propylphenylacetate obtained in the preceding Step A above. ), as a starting material, the title compound.

¹ H-NMR (400 MHz, ODCl 3):?

.delta., 8.14 (s, 1H), 7.29-7.24, (m, 2H), 7.19-6.12,

Example. 17)

Preparation of 5- [4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenyl] -2,4-thiazolidinedione

-O ··

T-D · · * *--------

Stage A ')

Preparation of Methyl 1-4- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenyl acetate

Using the analogous procedure described above for Example 15), Step A), the title compound was prepared using methyl 4-hydroxyphenylate as starting material.

¹ H-NMR (400 MHz, ODG ₁₃ ):

.delta., 7.32-7.23, (m, 5H), 7.02 - 6.76, (m, 7H), 4.02 4.00, (m, 4H), 2.54 (t, 2H, J = 6.40 Hz), 2.01-1.94, (m, 4H), 1.56, (hex, 2H, J = 6.70 Hz), 0, 90, (t., 3H,

J = 7.40 Hz).

P r es B)

Preparation of 5- / 4- (4- (2-propyl-4-phenoxyphenoxy) -butoxy) -phenyl / -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C), using methyl 4- (4- (2-propyl-4-phenoxyphenoxy) buroxy) phenylacetate obtained in the preceding step A), as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, QDG 1?):

δ, 8.01, (bs, 1H), 7.32-7.23, (m, 5H), 7.02-6.76, (m, 7H), 5.32, ( s, 1H), 4.02-4.00, (m, 4H), 2.54 (t, 2H, J 6.40 Hz), 2.01-1.94, (m, 4H), 1.56, (hex-,

2H, J = 6.70 Hz), 0.90, (t, 3H, J = 7.40 Hz).

1 i k 1 β and 18)

Preparation of 5- [3- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -phenyl] -2,4-thiazolidinedione.

S t u p e A)

Preparation of methyl 3- (3- (2-propyl-4-phenoxyphenoxy) propoxy) phenylacetate

Using the analogous procedure described above for Example 11), Step B), the title compound was prepared using methyl-3-hydroxyphenylacetate as the starting material.

¹ H-NMR (400 MHz, O 3 O 3):

2.27, (quint., 2H, J = 6.30 Hz), 1.56, C hex, 2H, J = 7.20 Hz), 0.96, (t, 3H, J = 7.30 Hz).

> 2-

Stage Β)

Preparation of 5- / 3- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -phenyl / -2,4-thiezolidinedione

The answerlogic procedure described above for Example 1), Step G), using methyl-3- (3- (2-propyl-4-phenoxyphenoxy) propoxy) phenylation, was the tate obtained in the foregoing, described above. Step A), as a starting material, the title compound is prepared.

¹ H-NMR, (400 MHz, GDCl 3):

δ, 8.48, (bs, 1H), 7.32-7.24, (m, 3H), 7.02-6.79, ((m, 9H), 5.30, (a, 1H), 4.16, (t, 2H, J = 6.20 Hz), 4.11, (t, 2H, J = 6.10 Hz), 3.67, ( s, 3H), 3.57 (s, 2H)

2.55, (t, 2H, J = 6.20 Hz), 2.27, (quint., 2H, J = 6.30 Hz),

1.56, (hex, 2H, J = 7.20 Hz), 0.96, (t, 3H, J = 7.30 Hz).

Example 19)

Preparation of 5- / 3- (4- (2-propyl-4-phenoxyphenoxy) -butoxy) -phenyl] -2,4-thiazolidinedione

O

···· · · ·· · ·

Stage A)

Preparation of methyl 3- (4- (2-propyl-4-phenoxyphenoxy) butoxy) phenylacetate

Using the analogous procedure described above for Example 15), Step A), the title compound was prepared using methyl-3-hydroxyphenylacetate as the starting material.

¹ H-NMR, (400 MHz, GDCl 3):

δ, 7.31-7.22, (m, 5H), 7.01 - 6.76, (m, 7H), 4.01 4.00, (m, 4H), 2.54, (t, 2H, J = 6.40 Hz), 2.00-1.94, (m, 4H), 1.55, (hex, 2H, J = 6.70 Hz), 0 , 91, (t., 3H,

J = 7.40 Hz).

P r es B)

Preparation of 5- / 3- (4- (2-propyl-4-phenoxy-phenoxy) -butoxy) -phenyl / -2,4-thiazolidinedione

In an analogous manner to that described above under (Example 1), Step G), methyl-3- (4- (2-propyl-4-phenoxyphenoxy) butoxy) -phenylate was obtained as above. of Step A), as a starting material, the title compound is obtained.

¹ H-NMR (400 MHz ^ _r CDCl-):

delta, 7.93 ,. (bs, 1H), 7.31-7.22, (m, 5H), 7.00 - 6.75, (m, 7H), 5.31, (a, 1H), 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 (6.70 Hz), 0.91 (t, 3H, J = 7.40 Hz).

· · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 20)

Preparation of 5- [3- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -phenyl] -2,4-oxazolidinedione

S t u p e A)

Preparation of methyl 3- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -mandelate (mandelate ~ 2-hydroxy-2-phenylethanoet)

A solution prepared by dissolving 253.0 mg (1.39 mmol) of methyl 3-hydroxymandelate, followed by 500.0 mg (1.44 mmol) of 4- (3-bromopropoxy) -3-propylphenylphenyl ether and 475. 1.0 mg, (1.46 mmol) of cesium carbonate in 5.0 mL of dried dimethylformamide was stirred at room temperature overnight.

Then, the reaction mixture was partitioned between ethyl acetate and 0.2N hydrochloric acid, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and after being dried with sodium sulfate, filtered and evaporated.

The resulting oil-like residue was chromatographed on silica gel using dichloromethane: hexane (1.0: 1.0) as eluent.

The title compound was obtained.

¹ H-NMR (400 MHz, CDCl 3):?

delta, , 7.29 - 7,24, ( m. , 3H), 7.03 - 6, (m., 9H ), 5.12, (d., 1H ,. J = 5.70 Hz ) 4,18, (t, 2H) J = 6.20 Hz) , 4,13, (i.e., 2H, J = 6.10 Hz > » 3,40, (d, 1H) J = 5.70 Hz) , 2,55, (i.e., 2H, _J = 6.20 Hz ) 2,27 ,. (quint., 2H, J - 6.30 Hz), 1,56, (hex., 2H, J = 7, 20 Hz) , °> 96 ,, ( t., 3H, J = 7 , 30 Hz).

Step B)

Preparation of 5- [3- (3- (2-propoxy-4-phenoxyphenoxy) -propoxy) -phenyl] -2,4-oxazolidinedione

The solution prepared by mixing. 194.0 mg of methyl 3- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -mandelate obtained as described above in Step A) above, 39.0 mg of urea and 0.90 ml (0.5M) sodium methoxide was heated at reflux overnight.

Then the reaction mixture was partitioned between ethyl acetate and water, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with sodium sulfate, filtered and evaporated.

The residue as an oil was chromatographed on silica gel, eluting with 3% methanol in dichloromethane.

The title compound was obtained by ¹ H-NMR (400 MHz, OPCl ₃ ):

.delta., 7.3: 4, (t, 1H, J = 7.60 Hz), 7.30-7.24, (m, 2H), 7.03-6, 79, (m, 9H), 5.74, (s, 1H), 4.18, (t, 2H, J =

20.6 Hz), 4.13 (t. _R 2H, b = 0, 1O Hz), 2.55 (t., 2H, J = 6.20 Hz), 2.27 ,. (quint., 2H, J = 6.30 Hz), 1.56, (hex, 2H, J 7.20 Hz), 0.96, (t, 3H, J = 7.30 Hz).

• 9 9 9 9

999 99 999 99

99 · · · · 999 · · 999 99 99 ·· ·· ··

Η

Example; 21)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxy-phenoxy) -propoxy) -phenyl] -2,4-oxazolidinedione

Stage A)

Preparation of ethyl 4- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -mandelate

Using the analogous procedure described above for Example 20), Step A), the title compound was prepared using ethyl 4-hydroxymandelate as starting material.

¹ H-NMR, (400 MHz, GBCl ₃ ):

.delta., 7.32-7.24, (m, 5H); 7.01, (t, 1H, J = 7.40 Hz),

6.92 - 6.79 ,. (M.,. 6H) 5, _O3; (D., 1H, "J = 5.70 Hz), 4.26 (quart. 2H ,," J = 7.40 Hz), 4 18 _{r r} (t. 2H _r "J = 6.20 Hz) ,

4.13. (T, 2H, J = 6.10 Hz), 3.36 (d, 1H, J = 5.70 Hz),

2.55., (T, _r 2H, J = 6.20 Hz), 2.27, - (quint., 2H, J = 6.30 Hz),

1.56., (Hex., 2H, J = 7.20 Hz), 1.21, (t, 3H, J = 7.20 Hz),

0.96 _F (t, 3H, J = 7.30 Hz).

444 4

44 44

4 4 ♦ 4 4 * · 445

4444 44

4 9 4 4 4 ·· «4

Stage Β)

Preparation of 5- / 4- (3- (2-propyl-4-phenoxyphenoxy) -propoxy) -phenyl / -2,4-oxazolidinedione

In an analogous manner to that described in Example 20, Step B, above, using ethyl 4- (3- (2-propyl-4-phenoxyphenoxy) propoxy) -methanate obtained under the preceding Step A) above was used. The title compound was prepared as a starting material.

¹ H-NMR (400 MHz, CDCl 3):

δ, 7.32-7.24, (m, 5H), 7.01, (t, 1H, J = 7.40 Hz),

6.92-6.79, (m, 6H), 5.74, (a, 1H), 4.18, (t, 2H, J =

6.20 Hz), 4.13, (t, 2H, J = 6.10 Hz), 2.55, (t, 2H, J =

6.20 Hz), 2.27, (quint., 2H, J = 6.30 Hz), 1.56, (hex, 2H, J = 7.20 Hz), 0.96, (t, 3H, J = 7.30 Hz).

Example 22)

Preparation of 5- / 4- (3- (2-propyl-4- (4-methylsulfonyl) -phenoxyphenoxypropoxy) -phenyl) -2,4-thiszolidinedione

^ SO ₂ CH ₃ ·· 4 44 9

44 44 44

4 9 4 4 4 4 4 4 4 ·

4 9 4 9 9 4

9 4 9 4 9 4

4 4 9 9 9

49 4 94 9 9 99

Stage A)

Preparation of 2-propyl-4- (4-methylsulfonyl) phenoxyphenol

Grade A’P

Preparation of 4-allyloxyphenol

To a solution prepared by dissolving 33.00 g (0.30 mol) of hydroquinone and 45.60 g (0.33 mol) of potassium carbonate in 250.0 ml of dried dimethylformamide and stirred at 40.0 ° C for 30.0 minutes, 5.20 mL (0.06 mol) of allyl bromide was then added, and the resulting reaction mixture was stirred overnight.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid, and after separation of the organic and aqueous phases, the organic layer was washed with water, and after drying with sodium sulfate, filtered and evaporated.

The resulting oily residue was chromatographed on silica gel using hexane: ethyl acetate (4.0: 1.0) as eluent to give the desired 4-allyloxyphenol.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 6.74, (dd, 4H, J = 9.00 Hz, 12.50 Hz), 6.03, (m, 1H), 5.37, (dd, 1H, J = 1.30 Hz) 15.70 Hz, 5.25, (dd, 1H, J = 1.30 Hz, 9.00 Hz), 4.64, (bs, 1H), 4.46, (d, 2H (J = 5.30 Hz).

Grade A2) · · ··· ····· · · «

I · ··

Preparation of 4- (4-methylsulfonyl) -phenoxyphenyl-allyl ether A solution prepared by dissolving 4.30 g, (28.70 mmol),

4-allyloxyphenol obtained in the above step (A) above, followed by 5.00 g (28.70 mmol) of 4-fluorophenylmethylsulfone and 4.80 g (34.45 mmol) of potassium carbonate , in 50.0 ml of dried Ν, Ν-dimethylacetamide was heated at reflux overnight.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was evaporated, and the resulting residue, as an oil, was chromatographed on silica gel using hexane: ethyl acetate (5.0: 1.0) as eluent.

The desired 4- (4-methylsulfonyl) -phenoxyphenyl-allyl ether was obtained.

¹ H-NMR, (400 MHz, GDCl 3):

δ, 7.84, (d, 2H, J = 8.90 Hz), 7.00, (m, 6H), 6.08, (m, 1H), 5.44, (dd, 1H) J = 1.50 Hz, 15.50 Hz), 5.31 (dd, 1H, J = 1.40 Hz, 8.80 Hz), 4.45, (d, 2H, J = 5, 60 Hz), 3.02, (s, 3H).

Grade A ^)

Preparation of 2-allyl-4- (4-methylsulfonyl) -phenoxyphenol

A solution prepared by dissolving 5.20 g (0.12 mol) of 4 ((4-methylsulfonyl) -phenoxy) -phenyl-allyl ether obtained as described above in Step (A) above in dried 1.2. -dichlorobenzene, bvl heated to 180.0 ° C overnight, 4 ··· 44

Sat

After evaporation of the solvent from the reaction mixture in vacuo, the resulting residue was chromatographed on silica gel using hexane: ethyl acetate (4.0: 1.0) as eluent.

The desired 2-allyl-4- (4-methylsulfonyl) -phenoxyphenol- ¹ H-NME, (400 MHz, CDCl 3) was obtained:

δ, 7.84, (d, 2H, J = 8.90 Hz), 7.34, (s, 1H), 7.01, (dd, 2H, J = 9.80 Hz, 2.00 Hz), 6.84 ,. (d, 2H, J = 2.20)

5.97, (m, 1H), 5.18, (d, 1H, J = 1.40 Hz). 5.15, (dd, 1H, J = 1.50 Hz, 5.80 Hz), 4.93, (s, 1H), 33.38, (d, 2H, J = 6.50 Hz) , 3.02, (s, 3H).

Grade A ^)

Preparation of 2-propyl-4- (4-methylsulfonyl) -phenoxyphenol

A solution prepared by mixing 3.80 g (12.40 mmol) of 2allyl4- (4-methylsulfonyl) phenoxyphenol obtained as described above in Step A) and 5% palladium on charcoal, ( 1.20 g), in 50.0 ml of ethyl acetate, was stirred at room temperature under a hydrogen atmosphere for 3.0 hours.

The reaction mixture was then filtered through diatomaceous earth, and after washing through a short pad of silica gel, it was concentrated in vacuo.

The desired 2-propyl-4- (4-methylsulfonyl) phenoxyphenol was obtained as an oily consistency which was used without further purification.

¹ H-NMR, (400 MHz, GDC1):

δ 7.86 (d, 2H, J = 8.90 Hz), 7.02 (d, 2H, J = 9.90)

6.84, (s, 1H), 6.78, (d, 2H, J = 1.00 Hz), 4.73, (s, 1H); 3.02, (3., 3H), 2.56, (t, 2H, J = 7.50 Hz),

1.62, (quint., 2H, J = 7.50 Hz), 0.95 "(t, 3H, J = 7.40 Hz).

• · · · · · · · · · · «·· * '· * · · · ·. »·. ·. ··· «« «·. * ·. «..

Step B)

Preparation of ethyl 4- (3-bromopropoxy) -mandelate

A solution prepared by dissolving 19.60 g (0.10 mol) of ethyl 4-hydroxymandelate, followed by 60.75 g (0.30 mol) of 1,3-di-bromopropane and 35.75 g of ( 0.11 mol) of cesium carbonate in 200.0 ml. of dried dimethylformamide was stirred at room temperature overnight.

The reaction mixture was then partitioned between ethyl acetate and 1.0 N hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was washed twice with water, once with brine, and then dried with sodium sulfate, filtered, and the solvent was removed in vacuo.

The resulting oily residue was chromatographed on silica gel, eluting with a gradient of from 100% hexane to dichloromethane: hexane (2.0: 1.0). The title product was obtained.

¹ H-NMR, (400 MHz, CDCl 3):

.delta., 7.30, (m, 2H); 6.86 (m, 2H), 5.82 (d, 1H,

J = 5.60 Hz). 4.20, (m, 2H), 4.08, (t, 3H, J = 5.60 Hz), 3.58, (t, 2H, J = 0.016 ppm), 3.37 (d, 1H, J 5.60 Hz), 2.29, (m, 2H), 1.21, (t, 3H, J = 7.20 Hz).

«· · T t t t t t t t t t t t t t

99

β.

Stage Ο)

Preparation of ethyl 4- (3- (2-propyl-4- (4-methylsulfonyl) -phenoxyphenoxypropoxy) -mandelate

Solution, prepared by mixing + 9.0 g (62.00 mmol),

2-propyl-4- (4-methylsulfonyl) -phenoxyphenol (obtained under Step A above), and 9.40 g. (68.20 mmol) of potassium carbonate and 100.0 ml of dimethylformamide were stirred at 40.0 ° C for 0.50 hours.

Was then added to the reaction mixture ethy1-4- (3-bromopropoxy) mandelá.t ,, (obtained under the foregoing, the above Stage b) (19.50 g of _.gamma. -? .- 58.90 <mfeolu) and this reaction mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and 1.0 N hydrochloric acid, and after separating the organic and aqueous phases, the organic layer was washed twice with water, once with brine, and dried over sodium sulfate, filtered and the solvent was removed in vacuo. removed.

The resulting residue, as an oily substance, was chromatographed on silica gel using ethyl acetate: hexane: dichloromethane (1.0: 4.0: 5.0) as the eluent.

The title compound was obtained by ¹ H-NMR (400 MHz, CDCl 3):

δ, 7.30 * (m, 2H), 6.86, (m, 2H), 5.82, (d, 1H,

J = 5.60 Hz), 4.20, (m, 2H), 4.08, (t, 3H _, J = 5.60 ppm)

3.58 (t, 2H, J = 6.40 Hz), 3.37 (d, 1H, J = 5.60 Hz),

2.29, - (m, 2H), 1.21, (t, 3H, J = 7.1, 20 Hz).

Grade H) φ> φ φφ ·

99 · ·· 99 Φ * · Φ

Φ ΦΦ Φ Φ Φ • ΦΦΦ Φ φφ φ

99,999 99 ·

9Φ9 9 Φ φ «»

ΦΦ ΦΦ «φ

Preparation of ethyl alpha-chloro-4- (3- (2-propyl-4- (4-methylsulfonylphenoxy) propoxy) phenylacetate)

To a solution prepared by mixing 16 ', 80 g, (30, 18 mmol) of ethyl 4- (3- (2-propyl-4- (4-methylsulfonyl) phenoxy-phenoxypropoxy) -mendelate) (obtained in 2.58 ml, (36.51 mmol), pyridine, and 160.0 ml, toluene, were added 2.88 ml (39.54 mmol), thionyl chloride, and the resulting reaction mixture was stirred overnight.

Then the mixture was partitioned between ethyl acetate and water, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and once with brine, and after drying with sodium sulfate, filtered.

Removal of the solvent from the filtrate under vacuum gave an oil-like residue which was filtered through a pad of silica gel using acetone: hexane (1.0: 4.0) as the scavenger.

The title compound was obtained.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 7.86, (m, 2H), 7.35, (m, 2H 5, 7.03, (m, 2H)),

6.92 (m, 2H), 6.87 (bs, 3H), 5.12, (bs, 1H),

4.20, (m, 6H), 3.05, (s, 3H), 2.59, (t, 2H, J = 7.60 Hz), 2.31, (m, 2H) 1.60, (m, 3H), 1.25, (m, 3H), 0.93, (t, 3H, J = 7.20 Hz).

Step E)

Preparation of 5- / 4- (3- (2-propyl-4- (4-methylsulfonyl) -phenoxy) -phenoxy) -propoxy) -phenyl] -2,4-thiazolidinedione φφφφφφφφφφφφφφφ φ φ · · · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ f f f f

In an analogous manner to that described in Example 1 above, Step C, (second stage), using ethyl-alpha-chloro-4- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) propoxy) 1) of the phenylacetate obtained in the preceding step (D) above as a starting material, to obtain the title compound.

¹ H-NMR, (400 MHz, GDCl 3):

delta , 8,18, _r (bs, 1H 7.84 (d. 2H) J = 8.90 Hz ), 7.35, (a., 2H, J = 8.70 Hz), 6.99 (d, 2H, J) = 8.70 Hz), 6,92, (d., 2H, J = 9.80 Hz), 6.84 (s, 3H), 5.35 (a., 1H), 4,12, (i.e., 2H, J = 6.60 Hz), 4.08, (t, 2H, J = 6.30 Hz), 3,02, (3., 3H), 2.57, (t, 2H, 7.50 Hz): >, 2.28, (k. , 2H,

J = 6.40 Hz), 1.57, (hex, 2H, 5.80 Hz), 0.91, (t, 3H, J = 7.50 Hz).

Example 23)

Preparation of 5- / 4- (3- (2-propyl-4- (4-methylphenoxy) phenoxypropoxy) phenyl) -2,4-thiazolidinedione

O

0 '

About 9 9 9 9 9 4 4 4 9 9 9 9 9 9 9 4 9 4 9 4 4 4 4 9

9 4 9 4 4 4 4 9 4 • 449 99 44 44 44 44

Stage A)

Preparation of 2-propyl-4- (4-methylphenoxy) -phenol

Stage I)

Preparation of 4v (4-methylphenoxy) -benzaldehyde

A solution of 4.52 g (40.29 mmol), 4-methylphenol, further 5.00 g (40.29 mmol), 4-fluorobenzaldehyde _r and 6.70 g (48.35 mmol) of potassium carbonate, in 40.0 ml of dimethylacetamide, was heated at reflux for 12.0 hours.

After the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed with brine, and after drying with sodium sulfate, filtered and concentrated.

The resulting oily residue was chromatographed on silica gel, eluting with 15% ethyl acetate / hexane.

The title compound was obtained.

Grade A ^)

Preparation of 4- (4-methylphenoxy) phenol

A solution prepared by dissolving 9,00 g (41,63 mmol),

4- (4-methylphenoxy) -benzsldehyde, (obtained as described above in Step A 1 above), in 75.0 ml, chloroform, 4444

44 44 44

9 4 9 6 9 9 4 6 9 9 • 4 9 9 49 9 4 6 4 • 4 4 5

45 4 4 4 4 4 4 4 4

4444 44 99 44 99 99

SH was mixed with 15.80 g (52.00 mmol) of m-chloroperbenzoic acid (46-85% product), and the resulting reaction mixture was stirred at room temperature for 3.0 hours.

The reaction mixture was then washed successively with saturated aqueous sodium bisulfite, saturated aqueous sodium bicarbonate, and water. After separation of the organic and aqueous phases, the organic layer was concentrated, and the resulting residue, as an oily consistency, was taken up in 10.0 ml of methanol containing a few drops of concentrated hydrochloric acid, and this solution was stirred at room temperature for 1 hour. 0 hours.

After removal of the solvent under vacuum, the resulting oily consistency residue was chromatographed on silica gel using 20% ethyl acetate in hexane as eluent.

The title compound was obtained.

Grade A ^)

Preparation of 4- (4-methylphenoxy) phenyl-allyl ether

Solution prepared by dissolving 4,75 g (23,30 mmol),

4- (4-methylphenoxy) -phenol (obtained under the above Step A), 4.17 g, (30.30 mmol), potassium carbonate, and 2.22 ial, (25.60 mmol), of allyl bromide, in 50.0 ml of dimethylformamide, was stirred at 60.0 ° C for 5.0 hours.

The reaction mixture was then cooled, and neutralized

1N hydrochloric acid solution, was extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic extract was washed with brine, and after drying with sodium sulfate, filtered, and concentrated.

• · · ·

The resulting residue, as an oily substance, was chromatographed on silica gel using 15% ethyl acetate in hexane as eluent.

The title compound was obtained.

§ t up e n A ^)

Preparation of 4- (4-methylphenoxy) -2-allylphenol

The solutions prepared by dissolving 4.00 g (16.37 mmol) of 4- (4-methylphenoxy) phenyl-ethyl ether in 50.0 ml of 1,2-dichloro-benzene were heated at reflux for 20 min. 0 hours.

After cooling the solution, the solvent was removed in vacuo, and the resulting residue, as a crude oil, was chromatographed on silica gel, eluting with 15% ethyl acetate in hexane.

The title compound was obtained.

Grade A ^)

Preparation of 2-propyl-4- (4-methylphenoxy) phenol

A solution prepared by dissolving 2.30 g (9.42 mmol) of 4- (4-methylphenoxy) -2-allylphenol (obtained in the above step A) and 5% palladium on activated carbon, (0.90 g), in 30.0 mL, of the ethyl acetate * was stirred at room temperature under a hydrogen atmosphere for 3.0 hours.

• ·

• · · · · · · ·

The reaction mixture was then filtered through a small pad of silica gel, and the filtrate was concentrated in vacuo.

The title compound was obtained and used further without further treatment.

¹ H-NMR. (400 MHz, CDCl3):

.delta., 7.19, (d, 2H), 6.86,. (d, 1H), 6.83, (dd, 2H 5, 6.72, - (d, 2H), 4.61, (a, 1H), 2.53, (t, 2H), 2.30, (a, 3H), 1.61 "(hex, 2H), 0.96" (t, 3H).

Step B)

Preparation of methyl-4- (3- (2-propyl-4- (4-methylphenoxy) -phenoxy) -propoxy) -phenylate

In an analogous manner to that described in Example 1), Step B, using 9.0 g (62.00 mmol) of 2-propyl-4- (4-methylphenoxy) -phenol, and 19, 50 g, (58.90 mmol) of methyl 4- (3-bromopropoxy) phenylacetate (obtained under Example 1), Step A), and described above), as starting materials, the desired title compound was prepared. said compound.

¹ H-NMR, (400 MHz, CDCl 3): δ, 7.18, (d, 2H), 7.07, (d, 2H), 6.85, (m, 5B),

6,76 ,. (d, 1H), 6.70, (d, 1H), 5.33, (s, 1H), 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., 2H),

1.59, (hex, 2H), 0.89, (t, 3H).

• · ··· · «Γ?

Stage C)

Preparation of 5- [4- (3- (2-propyl-4- (4-methylphenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

An analogous procedure to that described in Example 1 above, Step C), using methyl 4- (3- (2-propyl-4- (4-methylphenoxy) phenoxy) propoxy) phenylacetate, (19.50) g (58.90 mmol) (obtained under Step B above) as a starting material, the title compound is obtained.

¹ H-NMR (400 MHz, CUC 1 H):

Example 24)

Preparation of 5- / 4- (3- (2-propyl-4- (4-chlorophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 23 above, the title compound was prepared using 4-chlorophenol, as opposed to 4-methyl phenol, in Step A).

¹ H-NMR, (400 MHz, CDCl 3):

δ, 8, -19, (bs, 1H), 7.33, (d, 2H), 7.22, (d, 2H),

6.93, (d, 2H), 6.85, (d, 1H), 6.84, (d, 2H), 6.80, (dd, 2H), 5.32, (s. 1H, 4.18, (t, 2H), 4.11, (t,

2H), 2.54, (t, 2H), 2.37, (quint., 2H), 1.55, (hex, 2H) 0.89, (t, 3Hi).

Examples 25)

Preparation of 5- / 4- (3- (2-propyl-4- (4-phenyl) phenoxy) phenoxy) propoxy) phenyl / -2,4-thiazolidinedione

In analogy to the procedure described in Example 23 above, the title compound was prepared using 4-phenylphenol, in contrast to 4-methylphenol, in Step A).

• ·

H-NMB (400 MHz, GDCl3):

delta. 8.01, (bs, 1H). 7.54. (D, 2H). 7.50. (d, 2H)

7,40, (i.e., 2H), 7.32, (d., 2H), 6,91, (d., 2H), 6.98, 6,87, (d., 1H), 5,28, (a., (i.e., 2H), 2,56, (i.e., 2H), 2H) ,. Qý 92, (i.e., 3H) ..

2H), 7.31. (T., _{1H) r} 6.98 (d. (D., 1H), 6.85 (dd, 1H),

1H), 4.05, (t, 2H), 4.00,

1.99, (quint., 2H), 1.59, (hex.

Example 26)

Preparation of 5- / 3- (3- (2-propyl-4- (4-methoxyphenoxy) -propoxy) -phenyl)

2,4-thiezolidinedione

In an analogous manner to that described in Example 23 above, it was prepared using 4-methoxyphenola, as opposed to 4-methylphenol. in Step A) as the starting material, -, p. methyl (4- (3-bromopropoxy) phenyl) methyl, (Step B), the desired title compound.

• 9,999 ·· 99 • 9,9 9 · 9 9 9 »9 ·

9 99 99 999 ·

999 99,999 · 9 9

99,999 9 · 99

9999 99 99 99 99 99 ¹ H-NMR (400MHz, CDCl 3):

delta, 8,09 , (bs, 1H), 7.31, ( t, 1H ), 7.23, (m, 1H), 7,25, (d.d ^1H , 6.95 (d, 1H) ), 6.89 , (d., 2H), 6 , 83, (d., 2H), 6.78 (d, 1H); 6.75, (d., 1H), 6.72 (d . d ·, 1H), 5.31, (s, 1H), 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)

Preparation of 5- [3- (3- (2-propyl-4- (4-fluorophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 26 above, the title compound was prepared using 4-fluorophenol as opposed to 4-methoxyphenol as the starting material.

¹ H-NMR. (400 NHz, CDCl3):

δ, 8.01, (bs, 1H), 7.54, (d, 2H), 7.49, (d, 2H) ······· φ · · · · · · · · · ·

7.40, (t, 1H b 7.31 (d, 1H) ), 7.29, (d., IH) 6,95, (overlapping) d. (2H), 6.87, ( a., iH) 6.85 (d. d, 1H 5.32, (p., 1H b 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)

Preparation of 5- / 4- (4- (2-propyl-4-phenoxy-phenoxy) -butyl) -phenyl / -2,4-thiazolidinedione

Stage A)

Preparation of methyl 4-bromophenylacetate

The mixture, prepared by mixing 10.0 g (46.50 mmol) of 4-bromophenylacetic acid with 125.0 mL of methanol and 5.0 mL of sulfuric acid, was heated at reflux overnight. The reaction mixture was then concentrated and partitioned between ethyl ether and saturated aqueous sodium bicarbonate.

• 44

4 44 4 4 44

4 4 4 4 4 4 · ·

4 44 44 4444

443 44 443 44 4

43 4 ··· 4444

4444 44 44 44 44 44

After separation of the organic and aqueous phases, the organic layer was washed with water, brine and dried over sodium sulfate, filtered and evaporated.

The title compound was obtained as an oily consistency.

¹ H-NMR. (400 MHz, _:; GDC1 ₃ ) ::

δ, 7.42, - (d, 2H, J = 8.30 Hz), 7.13 ,. (d., 2H, J = 8.30 Hz), 3.67, (s, 3H), 3.56, (s, 2H).

Stage fi)

Preparation of methyl 4- (4-hydroxyl-1-butynyl) -phenylacetate

A solution prepared by dissolving 1.45 g. (6.35 mmol) of methyl 4-bromophenylacetate obtained in the previous step (A) above, followed by 0.89 g (12.70 mmol) of 1-hydroxy-3-butyne, 0.293 g, Tetrakis (triphenylphosphine) palladium (0), 0.109 g. (12.0 mol%). of copper (I) bromide, in 12.50 mL of triethylamine, was purged with nitrogen, and heated to reflux for hodiny8 for 1.0 h.

The reaction mixture was then concentrated and partitioned between ethyl ether and saturated aqueous ammonium chloride solution. After separation of the organic and aqueous phases, the organic layer was washed with water and brine, and dried over magnesium sulfate. was filtered and evaporated.

The resulting oily residue was chromatographed on silica gel using chloroform: ethyl acetate (10.0: 1.0) as eluent.

The title compound was obtained by ¹ H-NMR (400 MHz, GDCl 2):

··· · ·· · 99 · «··

δ, 7.34, (d, 2H, J = 8.30 Hz), 7.12, (d, 2H, J = 8.30 Hz), 3.79, (t, 2H, J = 6.20 Hz), 3.67, (s, 2H), 3.59, (s, 3H), 2.67, (t, 2H, J = 6.20 Hz).

Grade 0)

Preparation of methyl- (4- (4-hydroxybutyl) -phenylate)

Solution prepared by dissolving 1,38 g. (6.35 mmol) of methyl (4- (4-hydroxyl-1-butynyl) phenyl acetate) obtained in the above step (výše) above in 25.0 ml of ethanol was degassed and purged with nitrogen, and 10% palladium on charcoal was added.

The reaction mixture was then degassed and purged with hydrogen, followed by stirring under a hydrogen atmosphere at room temperature for 2.0 hours, and then filtered through diatomaceous earth.

Evaporation of the filtrate gave the title compound, ¹ H-NMR, (400 MHz, GBCl ₃ ):

.delta., 7.13-7.18, (m, 4H), 3.62-3.66, (m, 5H); 3.57, (a, 2H), 2.60, (t, 2H, J = 7.20 Hz), 1.59-1.68, (m,

4H), 1.40 ,. (bs, 1H).

Step D)

Preparation of methyl 4- (4- (2-propyl-4-phenoxy-phenoxy) -butyl-phenyl acetate)

99 «·

9,999 «9 * 9«

9 99 99 9999

999 99 999 99 ·

99,999,999

9999 99 99 99 99

A solution prepared by dissolving 0.395 g (1.80 mmol) of methyl (4- (4-hydroxybutyl) -phenylation of the tate obtained in the preceding step C), further 0.470 g (2.70 mmol), methanesulfonic anhydride, 0.001 g, (catalytic amount), 4- (dimethylamino) -pyridine, and 0.267 ml, (2.70 mmol). pyridine, in 2.0 mL, dichloromethane, was stirred at room temperature for 1.0 hour.

Then the reaction mixture was concentrated, and after dilution with ethyl acetate, it was washed twice with water, and with brine. After separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and after filtration was evaporated, to give an oil-like residue.

AND

The oily consistency obtained above was added to the reaction mixture, prepared by mixing 0.483 g (2.12 mmol), 4-phenoxy-2-propylphenol, δ 0.749 g, (2.30 mmol). cesium carbonate, in 2.0 mL, dimethylformamide, 8 the resulting mixture was stirred at 60.0 ° C overnight.

The reaction mixture was then partitioned between ethyl acetate and 0.45M citric acid solution (2-hydroxypropane-1,2,3-tricarboxylic acid). After separation of the organic and aqueous phases, the organic layer was filtered and evaporated to a residue as an oily substance which was chromatographed on silica gel. eluent toluene: hexane (1.0: 1.0).

The title compound was obtained. ¹ H-NMR (400 MHz, δ, 7.27-7.18, (m, 7H), 6.92-6.75, (m, 5H) 3.93, (b.s., 2H), 3.67, (s, 3H), 3.58, (s, 2H), 2.67, (b, s, 2H); 2H), 2.54, (t, 2H, J = 7.30 Hz), 1.81, (bs, 4H), 1.56, (m, 2H), 0.90 ,. (t, 3H, J = 7.30 Hz).

·· · ♦ ··

S t u ñ e Ε)

Preparation of 5- / 4- (4- (2-propyl-4-phenoxy-phenoxy) -butyl) -phenyl / -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C, using methyl (4- (4- (2-propyl-4-phenoxyphenoxy) buty) -phenylacetate) obtained in Step D above. ), as a starting material, the title compound.

¹ H-NMR (400 MHz "CDCl 3):"

Example 29)

Preparation of 5- / 4- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butyl) phenyl / -2,4-thiazolidinedione

H ···· ·· ·· 44 ··

4 4 9 4 4 4 4 4 4 9

4 4 4 49 4 4 9 4

4 4 4 4 4 4 4 9 9 9 9

4 9 4 9 9 4

9999 49 94 49 9 9 94

In an analogous manner to that described in Example 28 above, 2-propyl-4- (4-methoxy-phenoxy) -phenol was prepared, starting from step 2, as opposed to 2-propyl-4-phenoxy-phenol, as the starting material. , the title compound.

¹ H-NMR, (400 MHz, GOCl ₃ ):

δ, 7.98, (bs, 1H), 7.34, (m, 2H), 7.24, (m, 3H), 6.71-6.90, (m, 6H) ), 5.34, (b, 1H), 3.91, (bs, 2H), 3.77, (a, 3H), 2.69, (b, 2H) ' 2.52, (t, 2H, =

7.30 Hz), 1.81, (bs, 4H), 1.57, (m, 2H), 0.89, (t,

3H, J = 7.30 Hz).

Mass spectrometry-GI: m / e, 528.30, (M + Na) &lt; + &gt;

Example 1 a d 30)

Preparation of 5- / 4- (4- (2-propyl-4- (4-chlorophenoxy) phenoxy) butyl) phenyl)

2,4-thiazolidinedione

O

Cl

O

0000

00 00 0 0 0 0000 0 »0 · 0 0 00 00 0 0 0 0 0 000 00 0 · 0 · 0 · 0 00 0000 0000 0000 00 00 00 0 · 00

In an analogous manner to that described in Example 28 above, it was prepared using 2-propyl-4- (4-chlorophenoxy) -phenol, as opposed to 2-propyl-4-phenoxyphenol, in Step D.) as the starting material, the desired compound-title.

¹ H-NMR, (400 MHz, GDCl 3):

δ, 7.98, (b, 1H), 7.32, (m, 2H), 7.19, (m, 3H), 6.75-6.84, (m, 6H) ), 5.35, (s, 1H), 3.93, (b.s., 2H), 2.69, (b.s., 2H), 2.54, (t, 2H, J = 7.60 Hz), 1.81, (bs, 4H), 1.55, (m, 2H), 0.90, (t, 3H, d = 7.30 Hz).

CI-mass spectrometry: m / e, 532.20, (M + Na) J

Example 1 a d 31)

Preparation of 5- [3- (4- (2-propyl-4- (4-chlorophenoxy) phenoxy) butyl) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 28 above, the title compound was prepared, with the following: 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 9 9 99

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9999 99 99 99 99 99/00 but instead of methyl (4-bromophenyl acetate) in Step B), methyl (3-bromo) -phenylate was used as the starting material and D) _R was Miette; ^ - * 4.7fěňoxy propyl-phenol, used as starting material 2-propyl-4- (4-chlorophenoxy) phenol.

¹ H-NMR. (400 MHz, CDC1 _3):

delta ,, 8, 20 ,. (bs, 1H). 7.32 to 7.20 (m., 5H), 6.85 to 6.75 (m., 6H), 5.33 _r (s., 1H), 3.93 ,. (bs, 2H), 2.70, (bs,

(2H), 2.54 ,. (t, 2H, J = 7.60 Hz), 1.81, (bs, 4H), 1.55, (m, 2H), 0.90, (t, 3H, J = 7.30 Hz). .

CI MASS :: m / e, 532 .20 (M + Na) + _t

Example 3'2)

Preparation of 5- / 3- (5- (2-propyl-4-phenoxy-phenoxy) pentyl) phenyl / -2,4-thiazolidinedione

About · ** · ** ·

99 ·· ·· • · 9 9 9 9 9 9 9 9 9

9 9 9 99

9 9 9 9 9 9 9 9 9 9 9 9 9 9

9999 99 99 99 99 99

The title compound was prepared in an analogous manner to that described in Example 28 above, except that in place of methyl-4-bromophenylation of theta,

B ^; methyl-3-bromo-ethylacetate was used as the starting material, and 4-pentyn-1-ol was used instead of 3-butyn-1-ol.

¹ H-NMR, (400 MHz, C 18 H 18):

delta,. 8.11, (bs, 1H), 7.32-7.22, (m, 6H), 7.21-6 (m, 6H), 5.33, (s, 1H) ), 3.91, (t, 2H, 6.30 Hz), 2.65 (t, 2H, 7.60 Hz), 2.52, (t, 2H), 1.83-1, 50, (m, 8H 0.89, (t, 3H, 7.30 Hz)).

CI-mass spectrometry: m / e, 490.30, (M + 1)

70,

Example 33)

Preparation of 5- [3- (5- (2-propyl-R- (4-methoxyphenoxy) phenoxy) pentyl) phenyl] -2,4-thiazolidinedione

· · «· Φ · · · φ · φ · φ · φ · ·

9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9

99 99 99 99 99 99 / 02A analogous procedure to that described in Example 28 above gave the title compound, except that methyl-4-bromophenylacetate was used in step B) as the starting material methyl methyl. 3-bromophenylacetate, and in the same step B) instead of 3-butyn-1-ol was used instead of 4-pentyn-1-ol, and in step D), 2-propyl-4-phenoxyphenol was used as starting material -4- (4-methoxyphenoxy) phenol

¹ H-NMR, (400 MHz, GBCl 3):

delta, 8.19 (bs, 1H), 7.34, (m, 1H), 7.21, (τη, 3H),

6.90-6.71 (m, 7H), 5.30 (s, 1H); 3.91, (t, 2H, J =

6.30 Hz), 3.76, (s, 3H), 2.64, (t, 2H, J = 7.60 Hz), 2.51, (t, 2H, J = 7.60 Hz), 1.81-1.59, (m, 8H), 0.89, (t, 3H, J = 7.30 Hz).

CI-mass spectrometry: m / e, 519.30, (M +)

Example; 1 and d 34)

5- (3- (5- (2-propyl-4- (4-fluorophenoxy) phenoxy) pentyl) phenyl) -2,4-thiazolidinedione

O «9

44 ·· * 4 4 4 9 9999 9949

9 99 99

49 »99,999 * 9 9

99,999,999

9945 44 49 49 49 44

In analogy to the procedure described in Example 28 above, the title compound was prepared except that methyl-3- was used as the starting material in step B) instead of methyl 1-4-bromophenylate. bromophenylacetate, and in the same Step B) instead of 3-butyn-1-ol, 3-pentyn-1-b1 was used, and in Step D), 2-propyl-4-phenoxyphenol was used as the starting material, 4- (4-Fluorophenoxy) -phenol.

¹ H-M 5 R, (400 MHz, COCl 2):

delta, 8.33 (bs, 1H), 7.34 (m, 1H), 7.21 (m, 3H),

6.90 - 6.71, (m, 7H), 5.30, (s, 1H), 3.90, (t, 2H, 6.30 Hz), 2.64, (t, 2H, 7.60 Hz), 2.51, (t, 2H, 7.60 Hz), 1.82-1.59, (m, 8H), 0.89, (t, 3H, 7 , 30 Hz).

CI-mass spectrometry: m / e, 507.20 (M +)

Example 35)

Preparation of 5- [3- (5- (2-propyl-4- (4-phenylphenoxy) phenyl) pentoxy) phenyl]

2,4-thiazolidinedione

About ····

4 · · 44 44 4444 4444

4 44 44 4444

443 44 443 44 4

44 4444 4444

4444 44 44 44 44 44 .454

Stage A)

Preparation of 5- (2-propyl-4- (4-phenylphenoxy) phenyl) -pentyn-1-ol

Solution prepared by dissolving 1,0 g (3,30 mmol). 4- (4-phenylphenoxy) -2-propylphenol, followed by 0.832 mL (4.95 mmol) of trifluoromethanesulfonic anhydride and 0.400 mL (4.95 mmol) of pyridine in 3.0 mL of dichloromethane were stirred in temperature range from 0 ° - to room temperature, overnight.

The reaction mixture was then concentrated, diluted with ethyl acetate and then washed twice with water, and once with brine. After separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and after filtration it was evaporated to an oil-like residue.

A solution prepared by dissolving 1.30 g (3.03 mmol) of an oily consistency prepared in the above operation, further 0.567 ml (6.10 mmol) of 4-pentyn-1-ol, 0.175 g. (0.151 mmol), tetrakis (triphenylphosphine) -palla dia (O), in 3.0 mL of pyridine, was purged with nitrogen, and then heated at 80.0 ° C, overnight.

Then the reaction mixture was concentrated, and partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. After separation of the organic and aqueous phases, the organic layer was washed with water and brine, and then dried with sodium sulfate, filtered and evaporated.

The resulting oily residue was chromatographed on silica gel using toluene: ethyl acetate. (10.0: 1.0) as eluent.

The title compound was obtained.

¹ H-NMR, (400 MHz, CDCl ₃ ):

δ, 7.55, (m, 5H), 7.41, (t, 2H, δ = 7.30 Hz), 7.32, (m, 2H), 7.05, (m, 2H), 6.78, (m, 1H), 3.82, (t,

2H, J = 6.10 Hz), 2.68, (t, 2H, J = 7.60 Hz), 2.55, (t,

4444 • 4 4

4,444 «4444

4 44

444 44 444 4 t 4

44,444 4,444

4444 44 44 44

2H, J = 6.90 Hz), 1.86, (t, 2H, J = 6.22 Hz), 1.62, (m, 2H), 0.94, (t, 3H, J = 7.30.

Step B)

Preparation of 5- (2-propyl-4- (4-phenyl-phenoxy) -phenyl) -pentanol

In analogy to the procedure described above for Example 28), Step C), the title compound was prepared using 5- (2-propyl-4- (4-phenyl-phenoxy) -phenyl) -pentyn-1-ol obtained in of the preceding step A) as starting material.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 7.55, (m, 5H), 7.41, (t, 2H, J = 7.30 Hz), 7.32, (m, 2H), 7.05, - (m. (2H), 6.78, (m, 1H), 3.65, (t, 2H, J = 6.50 Hz), 2.61-2.52, (m, 4H), 1, 63-1.44 (m, 8H), 0.95 (t, 3H, J = 7.30 Hz).

Grade O)

Preparation of methyl- (3- (5- (2-propyl-4- (4-phenylphenoxy) phenyl) pentoxy) -phenate ylation)

In analogy to the procedure described in Example 28 above, Step D), the title compound was prepared using 5- (4- (4-phenyl-phenoxy) -2-propyl-phenyl) -1-pentanol and methyl-3-ol. hydroxyphenylacetate as starting materials.

«9 99 β» 99 • 9 9 · 99 · 9999

9 99 99 · 9 · 9

999 99 999 99

99 9999 9999 • 999 99 99 9 9 99 99 ¹ H-NMR (400 MHz, GDCl3):

delta 7.55 (m., 4H), 7.42 (t., 2H, J = 7.30 Hz), 7.38 (m. _r 1H), 7.02 to 7.11 " (m, 4H), 6.79-6.86, (m, 5H),

3.95, (t, 2H, J = 6.40 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 = 7.30 Hz).

Grade O)

Preparation of 5- [3- (5- (2-propyl-5- (4-phenyl-phenoxy) -phenyl) -pentoxy) -phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step O), the title compound was prepared using methyl- (3- (5- (2-propyl-4- (43-phenylphenoxy) phenyl) pentoxy)). of the phenylacetate obtained as part of the preceding step C) as starting material.

@ 1 H-NMR (400 MHz, GDCl3): .delta.

delta,. 7.55 - 7.51 ,. (m, 5H), 7.50-7.38, (m, 2H), 7.29

7,24 ,. (m, 1H), 7.10-7.01, (m, 3H), 6.86-6.81, (m,

6H) ,. 5.25 (s, 1H), 3.95, (bs, 2H), 2.60-2.52, (m,

4H), 1.80 ,. (m, 2H), 1.60-1.54, (m, 6H), 0.96, (t,

3H, 7.30 Hz).

CI-mass spectrometry: m / e, 588.30, (M + Na) J

Example 36)

9999 • 9, 9, 9, 9, 9

9

€ 9 9 9 9 9

9 9 9 9 9 9 • • 99 99 · 99 99 «9

9 9 9

9 9 9

9 9 9

9 «99

Preparation of 5- / 4- (4- (2-propyl-4- (4-methoxyphenoxy Kenyl) butoxy) phenyl) -2,4-thiazolidinedione

In analogy to the procedure described in Example 35 above, the title compound was prepared except that, instead of 4- (4-phenyl If enoxy) -2-propylphenol, it was used as the starting material in Step A). material 4- (4-methoxyphenoxy) -2-propylphenol, and in the same Stage A) in the second part, instead of 4-pentyn-1-ol, 3-butyn-1-ol was used as the starting material ¹ H-NMR, (400 MHz) , CDCl ^:

δ, 8.51, (bs, 1H), 7.31, (δ, 2H), 7.24 - 6.74 / m,

9H), 5.32, (s, 1H), 3.96, (t, 2H, 6.30 Hz), 3.78, (s,

3H), 2.61, (t, 2H), 2.51, (t, 2H), 2.02-1.59, (nr.

6H), 0.92, (t, 3H, J = 7.30 Hz).

CI-mass spectrometry: m / e, 505.60, (M &lt; + &gt;) * 9 &lt; tb &gt;

• _ _ ·· ·· · · · · · ««

Example 37)

Preparation of 5- [3- (4- (2-propyl-4- (4-fluorophenoxy) phenyl) butoxy) phenyl]

2,4-thiezolidinedione

In analogy to the procedure described in Example 35 above, the title compound was prepared except that 4- (4-phenylphenoxy) -2-propylphenol was used as the starting material 4- (4-fluorophenoxy) -2-propylphenol, and in the same Stage A) (second part), 3-butyn-1-ol was used as starting material instead of 4-pent-1-ol.

@ 1 H-NMR (400 MHz, CDCl3): .delta.

Mass spectrometry-CI:

m / e, 517.20, (M + Na);

• · · · · · · · · · ·

Example 38)

Preparation of 5- / 3- (5- (2-propyl-4- (4-chlorophenoxy) phenyl) pentoxy) phenyl / -2,4-thiazolidinedione

In analogy to the procedure described in Example 35 above, the title compound was prepared except that, instead of 4- (4-phenylphenoxy) -2-propylphenol, it was used as the starting material in Step A). 4- (4-chlorophenoxy) -2-propylphenol.

¹ H-NMR (400MHz, CDCl ₃ ):

delta, 8.07,. (bs, 1H), 7.31-6.71, (m, 11H), 5.31, (s, 1H), 3.96, (t, 2H), 2.61- 2.51 (m, 4H), 1.83 (m,

2H), 1.62-1.51, (m, 6H), 0.94, (t, 3H, J = 7.30 Hz).

CI-mass spectrometry: m / e, 546.20, (M + Na)

Example 39) / 770

Preparation of 5- / 3- (3- (2-propyl-4- (3-methyl-4-chlorophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolinedione

The title compound was prepared in an analogous manner to that described in Example 23 above except that 4-chloro-3-methylphenol was used as the starting material instead of 4-methylphenol.

¹ H-NMR (400 MHz, GDCl 3):?

delta,. 8.04, (bs, 1H). 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 at 7.40 Hz), 2.26, (quint., 2H, J = 6.30 Hz), 1.60, (hex, 2H) J = 5.60 Hz). 0.89, (t, 3H _, J = 7.30 Hz).

GI-MS: m / e 544.0. (M + NH4) J

Example 40) z // // · · ····

Preparation of 5- [4- (3- (2-propyl-4- (4-isobutylphenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

The title compound was prepared in an analogous manner to that described in Example 23 above, except that 4-isobutylphenol was used as the starting material in Step A) instead of 4-methylphenol.

¹ H-NMR (400 MHz, CDCl ₃ ):?

δ, 7.89, (bs, 1H), 7.34, (d, 2H), 7.06, (d, 2H),

7.04-6.78 (m, 7H), 5.35 (s, 1H), 4.20 (t, 2H),

4.16, (t, 2H), 2.54, (t, 2H, J = 7, < 0 Hz), 2.41 (d, 2H),

2.25, (t, 2H), 1.81, (m, 1H), 1.57, (m, 4H), 1.23, (t,

3H, J = 7.30 Hz), 0.90, (m, 9H).

Mass spectrometry-CIr. m / e, 533.35 (M &lt; + &gt;);

Example 41) • ·

Preparation of 5- [3- (3- (2-propyl-4- (4-cyclopentylphenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

In analogy to the procedure described in Example 23 above, the title compound was prepared except that in step A) the starting material, 4-cyclopentylphenol, was used instead of 4-methylphenol.

¹ H-NMR, (400 MHz, GDCl 3):

delta, 9.79, (bs, 1H), 7.39, (t, 1H), 7.18, (d, 2H), 7.16-6.81, (m, 8H) ), 5.34, (s, 1H), 4.21, (t, 2H, J =

6.20 Hz), 4.16 (t, 2H, J = 6.00 Hz), 2.95, (quart., 1H),

2.56, (t, 2H, J = 7.40 Hz), 2.30, (t, 2H, J = 6.00 Hz), 2.07, (bw, 2H), 1 80 - 1.54 _(m.,, 8H), 0.90 (m., 3H,

7.30 Hz).

MS-01: m / e, 545.38 (M &lt; + &gt;);

Example 42) 9 9

»· · <

»· ·« ·· ··

Preparation of 5- [3- (3- (2-propyl-4- (4-isopropylphenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

In analogy to the procedure described in Example 23 above, the title compound was prepared except that 4-isopropylphenol was used as the starting material in step A) instead of 4-methylphenol.

(400 MHz, CDG.l _3):

δ, 8.23, (bs, 1H), 7.27, (d, 2H), 7.16, (d, 2H), 6.90, (d, 2H), 6, 90 - 6.80, (m, 5H), 5.34, (s, 1H), 4.21, (t, 2H, J = 6.20 Hz), 4.15, (t, 2H, J = 6.10 Hz), 2.98, (quatt, 1H), 2.57, (t, 2H, J = 7.80 Hz), 2.30;

(t, 2H), 1.64, (m, 2H), 1.26, (m, 6H), 0.96, (t,

3H, J = 7.40 Hz).

CI-mass spectrometry: m / e, 521.20, (M + H) +

Example. 43) ····

Preparation of 5- (3- (3- (2-propyl-4- (naphthyloxy) phenoxy) propoxy) phenyl)

2,4-thiazolidinedione

The title compound was prepared in an analogous manner to that described in Example 23 above except that 2-naphthol was used as the starting material in Step A instead of 4-methylphenol.

(400 MHz, CDG1-j):

.delta., 8.05, (s, 1H), 7.83, (d, 2H), 7.66, (d, 1H), 7.46-7.39, (m, ,,); 2H) ,. 7.38-7.20, (m, 2H), 6.92-6.78, (m, 3H), 5.35 "(s, 1H), 4.29" (m, 4H), 2.59, (t, 2H, J = 7.40 Hz) ,. 2,35 ,. (t, 2H), 1.69 (quart, 4H), 0.99 (t, 3H).

CI-mass spectrometry: m / e, 528.30, (M + H);

Example 44)

Preparation of 5- / 3- (3- (2-propyl-4- (dibenzfuran-2-yloxy) phenoxy) propoxy) phenyl / -2,4-thiazolidinedione

The title compound was prepared in an analogous manner to that described in Example 23 above except that 2-hydroxydibenzofuran was used as the starting material in step A) instead of 4-methylphenol.

’Η-ΝΜΡ, (400MHz, CDCl ^):

δ, 7.99, - (bs, 1H), 7.87, (d, 1H), 7.66 - 7.46, (m, 4H), 7.38 - 7.22, (m, 2H), 6.92-6.78, (m, 3H), 5.35, (s, 1H), 4.22, (t, 2H), 4.17, (t. (2H), 2.59, (t, 2H, J = 7.40 Hz), 2.35, (t, 2H), 1.69, (quart., 2H), 0.99, ( t, 3H).

CI-mass spectrometry: m / e, 567.30, (M + NH4)

Example. 45)

0/6 • 4 '«« · 4 44 • 4 4

4 44

4 4 4 4 4

44

• 4 4 4

4 4 4 4

4 4 4

44

Preparation of 5- / 3- (3- (2,6-bispropyl-4-phenoxypropoxy) phenyl) -2,4-thiazolidinedione

S t u p e A)

Preparation of 2,6-bispropyl-4-phenoxyphenol

To a solution prepared by dissolving 4-phenoxy-2-propylphenol (International Patent Application-Wo-97 / 28.115) in dimethyl formamide was added potassium carbonate and silyl bromide, and the resulting reaction mixture was stirred at room temperature for 5.0 hours.

Then, the reaction mixture was cooled, and neutralized with 1N hydrochloric acid solution was extracted with ethyl acetate. After separation of the organic and aqueous phases, the organic layer was washed with brine, 8 after drying with magnesium sulfate, filtered 8 and concentrated.

The resulting oily residue was chromatographed on silica gel, eluting with 15% ethyl acetate in hexanes to give 2-propyl-4-phenoxyphenyl-1-allylether.

In the above-described operation, the pure 2-propyl-4-phenoxy-allyl ether obtained was used for the treatment of

• 4 4 4

4 44

4 4 4

44 «4

4 4 4

4 4 4

4 4 4 4

44 of the title compound in analogy to the procedures described above for Example 23), Step A 1), and A 1).

¹ H-NMR, (400 MHz, ODCl ₃ ):

δ, 7.31-6.69, (ar., 7H), 4.49, (s, 1H), 2.54, (t,

4H (J = 7.47 Hz), 1.59, (m, 4H), 0.96 (t, 6H, J = 7.33 Hz).

Grade H?)

Preparation of 5- / 3- (3- (2,6-bispropyl-4-phenoxypropoxy) phenyl) -2,4-thiazolidinedione

Using methyl 3- (3-bromopropoxy) -mendelate, and 2,6-bispropyl-4-phenoxyphenol obtained as described above in Step A) as starting materials, for further processing by analogous procedures to those described above. above in Example 22), Steps B) through D), b) prepared the title compound.

¹ H-NMR (400 MHz, CDCl 3):

delta, 7.36 - 6.69, ( ar. , 11H), 5.35, (s, 1H) ), 4.26 , < 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 (i.e., 6H, J = 7.36 Hz ).

Example 46) * · »··· z //

Preparation of 5- [4- (3- (7-propyl-3-neophyll-6-benzo [4,5] isoxazolyloxy) propoxy) phenyl] -2 '_; 4-thiazolidinedione

S t u p e A)

Preparation of methyl-4- (3- (7-propyl-3-phenyl) 6-benzo-4,5-isoxazolyloxy-1-propoxy) -phenyl acetate

In an analogous manner to that described in Example 1), Step B, above, it was prepared using 7-propyl-3-neophyll-6-hydroxy-benzo [4,5] -isoxazole, (International Patent Application, WO-97). 28.137), as a starting material, the title compound.

@ ¹ H-NMR (400 MHz, CDCl3): .delta.

δ, 7.38, (d, 2H, J = 7.32 Hz), 7.30-7.16, (ar., 9H), 6.85, (d, 2H, J = 8, 67 Hz), 6.67, (d, 1H, J = 8.75 Hz).

6.50, (d, 1H, J = 8.70 Hz), 5.15. (m, 4H). 3.66, (p.,

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).

* · «« ·· • ·

9

4 4 • 94 9 4 4 • 4 4

9 4 4

9 4 4

4 4

4 4 4 4 4

4 49

Ml

Stage Β)

Preparation of 5- [4- (3- (7-propyl-3-neophyll-6-benzo [4,5] isoxazolyloxy) propoxy) phenyl] -2,4-thialidinedione

In an analogous manner to that described in Example 1), Step C, using methyl 4- (3- (7-propyl-3-neophyll-6benz- [4,5] -isoxysolyloxy) propoxy) -phenyl was used as the phenyl. The title compound is prepared as a starting material from the above obtained step A) as described above.

¹ H-NMR. (400 MHz, GDCl3);

delta, 8.02, (bs, 1H), 7.38-7.16, (ar., 9H), 6.90, (d, 2H, J = 8.71 Hz), 6 66 (d, 1H, J = 8.79 Hz), 6.49 (d,

1H, J = 8.78 Hz), 5.32, (s, 1H), 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 Hz), 1.43, (s,

6H), 0.91, (t, 3H, J = 7.45 °).

Example 47)

Preparation of 5- [3- (4- (7-propyl-3-trifluoromethyl-6-benzo [4,5] isoxazolyloxy) butoxy) phenyl] -2,4-thiazolidinedione

O

• 0 «···

7Ζ0 · · · 8 Ί 0 0 · · »· 0 ··

0 0 0

0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 ·· 00

Stage A)

Preparation of ethyl 3- (4- (7-propyl-3-trifluoromethyl-6-benzo [4,5] isoxyloxy-oxy) butoxy) -methylate, m -ndellate-2-hydroxy- 2-phenylethanoate)

An analogous procedure to that described in Example 22 above, Step C), using 7-propyl-3-trifluoromethyl-6-hydroxybenz- [4,5] -isoxazole, (International Patent Application-WQ-97)

28,137), and methyl 3- (4-bromobutoxy) -mandelate, as starting materials, the desired title compound.

¹ H-NMR, (400 MHz, CDCl 3):

delta, 7,50, (d., 1H, J = 8.50 Hz), 7.27 - 6.83, (ar., 5H), 4,28 - 4,24 ,. (m.,. 2H), 4j 17-4.021 (m, 4H) 2.89 (i.e., 2H, J = 7.41 Hz), 1,22, ( t, 3H, J = 7.16 Hz), 0.94, ( IN·, 3H, J = 7.41 Hz).

Step B)

Preparation of ethyl alpha-chloro-3- (4- (7-propyl-3-trifluoromethyl-6-benzo [4,5] -isoxazolyloxy) butoxy) phenylacetate

An analogous procedure to that described in Example 22 above, Step D), using ethyl 3- (4- (7-propyl-3-trifluoromethyl 6-benzo [4,5] -9Oxazolyloxy) butoxy) butenolate, as obtained from the above-described Step A) as a starting material, the title compound is obtained.

¹ H-NMR (400 MHz, CDCl ₃ ):

delta, 7.50, (d, 1H, J = 8.50 Hz), 7.27 - 6.83, (ar., 5H),

5,28, (p., 1H). 4.28 - 4.24, (m. 4H) ,. 2,89, (i.e., 2H, J = 7.41 Hz) Hz), 0,94 " (i.e.,. 3H, [delta] = 7.41 Hz)

From 4.17 to 4.031, (m. _{R (t.,;} 3H, J = 7.16

Stage ¢)

Preparation of 5- [3- (4- (7-propyl-3-trifluoromethyl-6-benzo [4,5] -isoxezolyloxy) butoxy) phenyl] -2,4-thiazolidinedione

An analogous procedure described above for Example 22), Step E), using ethyl-alpha-chloro-3- (4- (7-propyl-3-trifluoromethyl-6-benzo / 4,5) -isoxazolyloxy) butoxy 5-phenylacetate, as a starting material, obtained as described above in Step B) above, the title compound is obtained.

¹ H-NMR, (400 MHz, CDCO 3):

δ, 8.18, (bs, 1H), 7.50, (d, 1H, J = 8.14 Hz), 7.32 6.88, (ar., 5H), 5.31 ( _s , 1H), 4.16, (t, 2H, 5.78),

4.04 (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 = 7.36Hz)

Example 48)

Preparation of 5- [4- (3- (2-propyl-4- (4-methoxyphenoxy) phenoxy) propoxy) -3-propylphenyl] -2,4-thiazolidinedione // 2.

···· ·· ·· ··

I · · · · · · · · · · · · »·« · «·« · «

S t u ρ e n A)

Preparation of 4- (3-bromopropoxy) -3-propylphenylphenyl ether

In an analogous manner to that described in Example 11), Step A) above. using 2-propyl 1-4- (4-methoxyphenoxy) phenol (prepared as described in Example 23 above), Step A) using 4-methoxyphenol) as the starting material, the desired product was prepared as described above. the title compound.

Degree &)

Preparation of methyl 1-4- (3- (2-propoxy-4- (4-methoxyphenoxy) phenoxy) propoxy) -3-propylphenylacetate

In an analogous manner to that described in Example 11 above,

Step B), using methyl 4-hydroxy-3-propylphenyl lacetate. and 4- (3-bromopropoxy) -3-propylphenylphenyl ether, obtained as described in Step A) above, as starting materials, to obtain the title compound.

• 444

44

¹ H-NMR. (400MHz, EDCl-j):

.delta., 7.09-6.74, (ar., 10H), 4.19-4.14, (m, 4H), 3.81, (a, 3H), 3.70 ,. (a., 3H), 3.56, (g, 2H), 2.60-2.54, (quint., 4H, J = 7.60 Hz 1, 2.29, (quint., 2H) , J = 6.0 Hz),

1.59, (quint., 4H, J = 7.70 Hz ', 0.93, (quart., 6H, J = 6.70Hz).

Grade O

Preparation of 5- / 4- (3- (2-propyl-4- (4-methoxyphenoxy) phenoxy) propoxy) 3-propylphenyl / -2,4-thiazolidinedione

An analogous procedure to that described in Example 1 above, Step C), using methyl 4- (2- (2-propyl-4- (4-methoxyphenoxy) phenoxy) propoxy) -3-propylphenylacetate, as obtained from the above-described step B) as a starting material, the title compound is obtained.

¹ H-NMR (400 MHz, CDCl 3):

delta, 7.89, (bs, 1H), 7.29-6.74, (ar., OH), 5.34. (a., 1H) 4.20, (t, 2H, J = 6.10 Hz). 4,15 ,. (t, 2H, 5.80 Hz, 3.81, (s, 3H), 2.61-2.53, (m, 4H), 2.30, (quint., 2H,

J = 6.10 Hz), 1.57 (m, 4H), 0.92, (m, 6H)

Example 49)

Preparation of 5- [4- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) phenyl] -2,4-thisbididinedione m.p.

c c t t · · t t r <, <- c <

t <t t c '' <

t, t ·. ·.

c c c <

t C (i c c c c

C · l c

Stage A)

Preparation of ethyl 1-4- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) mandelate

An analogous procedure to that described in Example 22 above, Step C), using ethyl 4- (4-bromobutoxy) -mandelate, and 2-propyl-4- (4-methoxyphenoxy) -phenol (prepared as described above) in Example 23), Step A), using 4-methoxyphenol) as the starting materials, the title compound was prepared.

¹ H-NMR, (400 MHz, ORCl 2):

δ, 7.31-7.29, (m, 2H), 7.02-6.76, (m, 9H), 5.09 5.07, (d, 1H, J = 5.70) Hz), 4.27-4.04, (m, 2H), 4.02 3.96, (m, 4H), 3.36, (d, 1H, J = 5.80 Hz), 2.53, (t,

2H, J = 7.41 Hz), 0.90, (t, 3H, J = 7.32 Hz).

Step B)

Preparation of ethyl alpha-chloro-4- (4- (2-propyl-4- (4-methoxy-4-methoxyphenoxy) butoxy) phenylacetate

424

An analogous procedure to that described in Example 22 above, Step D), using ethyl 4- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) butylate (obtained in the foregoing, of Step A), as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, GDCl 3):

δ, 7.40-7.38, (d, 2H, J = 8.78 Hz), 6.91-6.72, (ar., 9H), 5.28, (s, 1H), 4.23 - 4.17, (m, 2H), 4.04 - 3.96, (m, 4H), 2.53, (t, 2H, J = 7.61 Hz), O, 90, (t, 3H, J = 7.36 Hz).

Stage C)

Preparation of 5- [4- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 22), Step E, above, ethyl-alpha-chloro-4- (4- (2-propyl-4- (4-methoxy) phenoxy) phenoxy) butoxy) -phenylene was used. of the title compound (obtained under Step B above), as a starting material, the title compound of formula (I); ¹ H-NMR ,, (400 MHz ,, GDC1 _3):

delta ,, 8.18 ,. (bs, 1H), 7.40-7.38, (d, 2H, J = 8.78 Hz),

6.91-6.72, (ar., 9H), 5.32, (s, 1H), 4.04-3.95, (m,

4H), 2.53, (t, 2H, J = 7.61 Hz), 1.95, (m, 4H), 1.56, (sext., 2H, 7.50), 0.90 (t, 3H, J = 7.36 Hz).

• · · · ·

1 k 1 and d 50)

Preparation of 5- / 4- (4- (2-propyl-4- (4-fluorophenoxy) phenoxy) butoxy) phenyl] -2,4,4-thiazolidinedione

Stage A)

Preparation of ethyl 4- (4- (2-propyl-4- (4-fluorophenoxy) phenoxy) butoxy) mandelate, (mandelate = 2-hydroxy-2-phenylethanoate),

An analogous procedure to that described in Example 22 above, Step C) was using 2-propyl-4- (4-fluorophenoxy) -phenol (prepared as described in Example 26 above using 4-fluorophenol), and of ethyl 1-4- (4-bromobutoxy) -mandelate as starting materials, the title compound is obtained.

¹ H-NMR (400 MHz, CDCl 3):?

δ, 7.31, (.delta., 2H), 6.98-6.74, (ar., 9H), 5.10, (d,

1H, J = 5.78 Hz), 4.25-4.11, (m, 2H), 4.09-3.97, (m,

4H), 3.36, (d, 1H, J = 5.77 Hz), 2.54, (t, 2H, J = 7.57)

Hz), 0.90, (t, 3H, J = 7.37 Hz).

::

Stage ft)

Preparation of ethyl-.alpha.-chloro-4- [4- (2-propyl-4- (4-fluoro-ethoxy) -phenoxy) -butoxy) -phenyl acetate

An analogous procedure to that described in Example 22 above, Step D), using ethyl 4- (4- (2-propyl-3- (4-fluorophenoxy) phenoxy) butoxy) butylate (obtained in the foregoing, of Step A), as a starting material, the title compound is obtained.

¹ H-NMR, (400MHz, GDC 4):

δ, 7.40, (d, 2H), 6.98 - 6.75, (sr, 9H), 5.28, (s,

1H), 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).

Grade 0)

Preparation of 5- / 4- (4- (2-propyl-4- (4-fluorophenoxy) phenoxy) butoxy) phenyl) -2,4-thiazolidinedione

An analogous procedure to that described in Example 22 above, Step E), using ethyl-alpha-chloro-4- (4- (2-propyl-4- (4-fluorophenoxy) phenoxy) butoxy) phenylacetate (obtained in as a starting material, the title compound (R) was prepared as described above.

¹ H-NMR, (400 MHz, GHG ₁₃ ):

delta, 8.08, (bs, 1H), 7.32, (s, 1H), 7.30, (s, 1H), 6.98-6.74, (ar., 9H), 5.33, (s, 1H), 4.04, (t, 2H,

J = 5.82 Hz), 3.98, (t, 2H, J = 7.68 Hz), 2.54, (t, 2H,

J = 7.60 Hz), 2.28 (k, 2H, J = 6.40 Hz), 1.55, (hex.

2H (J = 7, -40 Hz), 0.90, (t, 3H, J = 7.30 Hz).

• ·· ·

Example 51)

Preparation of 5- / 3- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) phenyl 1 / -2,4-thiazolidinedione

Stage A)

Preparation of 4- (4-bromobutoxy) -3-propyl- (4-methoxyphenyl) -phenyl ether

In an analogous manner to that described in Example 15 above, Step A) was carried out using 2-propyl-4- (4-methoxyphenoxy) -phenol (prepared as described above in Example 23), Step A using 4- methoxyphenol), as a starting material, the title compound.

Step B)

Preparation of methyl 3- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) phenylacetate

99

9 9

9 9 «9

9 9 99 9

99

Μ

Using the analogous procedure described above for Example 15), Step Β), the title compound was prepared using methyl 3-hydroxyphenylacetate and 4- (4-bromobutoxy) -3-propylphenyl-4-methoxyphenyl ether as starting materials. compound. @ 1 H-NMR. (400MHz, CDQ1):

delta,. 7.24-7.19, (m, 2H), 6.91, 91-6.93, (ar., 9H), 4.02 3.96, (m, 4H), 3.77, ( s, 3H), 3.67 (s, 3H). 3.57, (a.,

2H), 2.54, (t, 2H, J = 7.41 Hz), 0.90, (t, 3H, J = 7.33 Hz).

Grade O

Preparation of 5- / 3- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) thenyl) -2,4-thiazolidinedione

An analogous procedure to that described in Example 1 above, Step 0), using methyl 3- (4- (2-propyl-4- (4-methoxyphenoxy) phenoxy) butoxy) phenylation, was obtained (obtained in the previous step). of Step B), as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, CDCl ₃ ):

δ, 8.14, (bs, 1H), 7.30, (m, 1H), 6.98-6.69, (m, 10H), 5.31, (s. , 1H,), 4.00, (m, 4H), 3.77, (s, 3H),

2.53, (t, 2H, J = 7.52 Hz), 2.03, (m, 4H), 1.59, (m,

2H), 0.90, (t, 3H, J = 7.32 Hz).

Example 52) ♦ Φ «·

44 4

13ο

Preparation of 5- / 3- (4- (2-propyl-4- (4-chlorophenoxy) phenoxy) butoxy) phenyl / 2,4-thiazolidinedione

44

4 4 1 • ♦ 45

Stage A)

Preparation of 4-14-bromobutoxy) -3-propylphenyl-4-chlorophenyl ether

An analogous procedure to that described in Example 150 above, Step A), using 2-propyl-4- (4-chlorophenoxy) -phenol (prepared as described above in Example 23), Step A) using 4- chlorophenol), as a starting material, the desired title compound.

Grade B;

Preparation of methyl-3- (4- (2-propyl-4- (4-chlorophenoxy) phenoxy) butoxy) phenylation

In an analogous manner to that described in Example 15 above, Step B), using 4- (4-bromobutoxy) -3-propylphenyl-4-chlorophenyl ether, (obtained in the foregoing, above), was 44 44 44. 4 4 4 4 444 4 4 4

4 44 44 444

443 44 443 44

44 4444 444

4444 44 44 44 44

of Step A) and methyl 3-hydroxyphenylacetate as starting materials, the title compound is prepared.

¹ H-NMR (400 MHz, ODCl 3):?

dplta, 7.23-7.19, (m, 2H), 6.86-6.78, (ar., 9H), 4.04, (m, 4Hm), 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 O

Preparation of 5- [3- (4- (2-propyl-4- (4-chlorophenoxy) phenoxy) butoxy) phenyl]

2,4-thiazolidinedione

In an analogous manner to that described in Example 1 (Step C) above, using methyl 3- (4- (2-propyl-4- (4-chlorophenoxy) phenoxy) butoxy) phenylacetate (obtained in the foregoing) The above-described title compound was prepared as described in Step E) above as a starting material.

^] Η-Μ (400 MHz, ΟΠΟΙΟΙ):

delta, 8.22, (bs, 1H), 7.32-7.20, (m, 2H), 6.99-6.77 (m, 9H), 5.31, (s 1 H, 4.00, (m, 4H), 2.54, (t, 2H,

J = 7.32 Hz), 2.00, (m, 4H), 1.59, (m, 2H), 0.90, (δ, 3H, J = 7.33 Hz).

Example 53)

032> 4,444 * »* * 4,444 44,444,444 4,444 444 4444

444 44 444 44 4 ·· 4444 4444

444444 44 44 44 44

Preparation of 5- / 3- (3- (2-propyl-4- (4-methylaulfonylphenoxy) phenoxypropoxy) phenyl) -2,4-thiazolidinedione

Stage A)

Preparation of methyl 3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) -phenoxypropoxy) -mandelate

In an analogous manner to that described in Example 22 above, Step (6), the title compound, ¹ H-NMR, was prepared using methyl 3- (3-bromopropoxy) -mandelate as the starting material. 400 MHz, CDC

delta,. 7.80- (m, 2H-); 7.00-6.84, (ar., 9H), 5.13, (d.

1H, "J = 5.58 Hz), 4.19 to 4.13 (m. _R 4H), 3.74 (s., 3H) ,.

3.41 (a, 1H, 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 8β-chloro-3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) propoxy) phenylacetate

In an analogous manner to that described in Example 22 above,

Step D), using methyl 3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) propoxy) mandelate. (obtained under the preceding "Step A" above) as the default ms-.

The title compound is obtained.

’Η-ΙΜ, (400 MHz, GDS1 ^):

δ, 7.86, (m, 2H), 7.27 - 6.85, (ar., 9H), 5.30, (a,

1H), 4.20-4.13, (m, 4H), 3.75, (s, 3H), 3.02, (s, 3H),

2.56, (t, 2H, 7.49), 0.90, (t, 3H, J = 7.32 Hz).

9 ··· «9 99 99 99

9 9 · 9 9 999 «

9 99 99 9994

999 99 999 99

99,999,999

9999 99 9999

G)

Preparation of 5- [3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

An analogous procedure to that described in Example 22), Step E, above was using ethyl-alpha-chloro-3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) propoxy). of phenylacetate (obtained under Step B above) as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 8.20, (bs, 1H), 7.84, (m, 2H), 7.30-6.83, (ar., 9H), 5.35, (s, 1H) 4.16, (t, 2H, J = 6.71 Hz), 4.06, (t, 2H, J = 6.43 Hz), 3.02, (s, 3H), 2 56 (t, 2H, 6.80)

Hz), 2.28, (quint., 2H, J = 6.02 Hz), 1.55, (m, 2H,), 0.90, (t, 3H, J = 7.32 Hz) .

43½

4444

4 «44 44 44 • · 4 4444 4444

4,9444,444 · * 449 ·· 4 ·····

44 4444 4444

4444 44 44 ·· ·· ··

1 k 1 δ d 54)

Preparation of 5- [3- (4- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) butoxy) phenyl] -2,4-thiazolidinedione

SO ₂ CH ₃

Stage A)

Preparation of methyl 3- (4- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) butoxy) manganate

Analogous to the procedure described above in Example 22). Step C), using methyl 3- (4-bromobutoxy) -mandelate as the starting material, provided the title compound.

¹ H-NMR (400 MHz, CDO ₃ ):

.delta., 7.82, (m, 2H), 7.26-6.83, (ar., 9H), 5.13, (d, 1H, J = 5.58 Hz), 4 07-4.02 (m, 4H). 3.74 (s, 3H),

3.41, (d, 1H, 5.62 Hz), 3.02, (s, 3H), 2.57, (t, 3H, J = 7.24 Hz); , (m, 4H), 0.90, (t, 3H, J = 7.33 Hz).

··················· · 4 · 4

443 44 443 44 4

T3T »4 44 ··

4 · * · 44 44 44 44 44

Grade);)

Preparation of methyl-alpha-chloro-3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) butoxy) phenylacetate

In an analogous manner to that described in Example 22 above, Step D), using methyl 3- (4- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) butoxy) Mendelate (obtained in the foregoing, supra) of Step A), as a starting material, the desired title compound.

¹ H-NMR, (400 MHz, GDG 1 →):

.delta., 7.86, (m, 2H), 7.27 - 6.85, (ar., 9H), 5.30, (a,

1H), 4.07-4.02, (m, 4H), 3.75, (s, 3H), 3.02, (s, 3H),

2.57, (t, 2H, J = 7.24 Hz), 0.90, (t, 3H, J = 7.32 Hz).

G e G)

Preparation of 5- [3- (4- (2-propyl-4- (4-methylsulfohylphenoxy) phenoxy) butoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 22 above, Step E), using ethyl-alpha-chloro-3- (3- (2-propyl-4- (4-methylsulfonylphenoxy) phenoxy) butoxy) phenylacetate (obtained in within the previous step B) described above. as a starting material, the title compound is obtained.

¹ H-NMR (400 MHz, GDCl 3):

delta, 8.20 ,. (bs, 1H), 7.84, (m, 2H), 7.30-6.83, (ar., 9H), 5.35, (s, 1H), 4.16 (t, 2H, J = 6.71 Hz), 4.06, (t, 2H, J = 6.43 Hz), 3.02, (s, 3H), 2.56, ( t, 2H, 6.80 Hz),

000 * / 36 • 0

000 0 · · »89

9 9 9

9 81

0 · 0 0 8 8 8 9

8 8 8

0 0 ·

00

2,28 ,. (quint., 3Η, J = 7.32 Hz)

_2H,; J = 6.02 Hz), 2.00,

).

(m, 4H) 0.90 (t,

Example 55)

Preparation of 5- [4- (3- (2-propyl-5-phenoxy) phenoxy propoxy) phenyl] -2,4-thiazolidinedione

Stage A)

Preparation of 2-propyl-5-phenoxyphenol

The solution, prepared by dissolving 29.0 g of 1-phenoxy- (3-propenyloxy) -benzene in 200.0 ml of ortho-dichlorobenzene, was heated at reflux for 24.0 hours.

Thereafter, the reaction mixture was cooled to room temperature, and after subsequent chromatographic work-up, two intermediates, i.e. Intermediate 1), (3.33 g), with Intermediate 2), (2.81 g) were obtained.

Intermediate 1) was hydrogenated in methanol using 0.8 g of a catalyst (palladium on charcoal).

9494

99 99

4 9 9 4 4 9 4 9 4 5

4 4 4 99 4 9 4 5

4 4 4 4 4 9 9

4 9 4 ♦ ♦ · • • • «« «« <<<

The reaction mixture was then filtered through diatomaceous earth, and after removal of all volatiles from the filtrate, the title compound was obtained.

¹ H-NMR, (400 MHz, OBCl ₃ ):

δ, 7.16-7.01, (m, 6H), 6.54, (dd, 1H, J = 6.20 Hz, and J = 2.30 Hz), 6.45, (d. 1 H, J = 2.30 Hz), 4.72 (s, 1H),

2.56, (t, 2H, J = 7.50 Hz 1, 1.64, (m, 2H), 0.98, (t, 3H, J = 7.40 Hz).

S t p e B.)

Preparation of methyl 3- (3- (2-propyl-5-phenoxyphenoxy) propoxy) phenyl acetate

In an analogous manner to that described in Example 1), Step C), the title compound was prepared using 2-propyl-5-phenoxyphenol (obtained from Step A above) as the starting material.

¹ H-NMR, (400 MHz, GBCl ₃ ):

δ, 7.31 - 6.82, (m, 10H), 6.55, (d, 1H, J = 2.30 Hz), 6.52, (dd, 1H, J = 8.20 Hz) .delta. with J = 2.30 Hz), 4.13 (t, 2H,

J = 6.20 Hz), 4.05, (t, 2H, J = 6.00 Hz), 3.66, (s, 3H),

3.54, (s, 2H), 2.52, (t, 2H, J = 7.40 Hz), 2.23, (quint., 2H, J = 6.20 Hz), 1.54 δ (hex, 2H, J = 7.40 Hz), 0.90, (t, 3.H, J = 7.30 Hz)

432

Stage C)

Preparation of 5- [4- (3- (2-propyl-5-phenoxyphenoxy) propoxy) phenyl] -2,4-thiazolidinedione

In an analogous manner to that described in Example 1), Step C), using methyl 3- (3- (2-propyl-5-phenoxyphenoxy) propoxy) phenylacetate (obtained under Step B above), ,. as a starting material, the title compound is obtained.

¹ HvNMR ,. (400 MHz, CDCl 3):

delta,. 7.95 (bs, 1H), 7.31-6.87, (m, 10H), 6.55 (d, J = 2.30 Hz). 6,52 ,. (d.d., 1H, J = 8.20 Hz, and J = 2.30 Hz),

3H, J = 7.30 Hz).

Example 56)

Preparation of 5- / 4- (3- (2-propyl-3- (phenoxyphenoxy) propoxy) phenyl) -2,4-thiazolidinedione

O

H ···· «· • Cl Cl Cl Cl Cl Cl Cl • • • • • • Cl Cl • Cl Cl • Cl Cl Cl Cl · · ·

9 9 4

6 4 6

96

434

Stage A)

Preparation of 2-propyl-3-phenoxyphenol

Intermediate 2), (2.81 g), obtained as described above for Example 55), Step A), was hydrogenated in methanol using 0.61 g, a catalyst, i.e. palladium on charcoal.

After the reaction mixture was filtered through diatomaceous earth, all of the volatile constituents of the filtrate were removed to give the title compound.

¹ H-NMR (400 MHz, CDCl ₃ ):

delta 7.34 to 6.95 (m., 6H), 6,6O _r (d., 1H, J = 8.00 Hz), 6.48 (d., 1H, J = 8.00 Hz), 4.80, (s, 1H), 2.65, (t, 2H,

J = 7.60 Hz), 1.64, (m, 2H), 0.97, (t, 3H, J = 7.40 Hz).

Grade Bú

Preparation of methyl 3- (3- (2-propyl-3- (phenoxyphenoxy) propoxy) phenylation)

In an analogous manner to that described in Example 1, Step B) above, the title compound was prepared using 2-propyl-3-phenoxyphenol (obtained from Step A above) as starting material. . ¹ H-NMR, (400MHz, CDCl 3):

δ, 7.29-6.86, (m, 10H), 6.65 (d, 1H, J = 7.70 Hz), 6.49, (d, 1H, J = 8, 20 Hz), 4.17-4.13, (m, 4H), 3.66, (s, 3H), 3.54, (s, 2H), 2.60, (t, 2H) , J = 7.60 Hz),

······························

2 _r , 27 _r (quint., 2H, J = 6.10 Hz), 1.50, (hex, 2H, J = 7.60 Hz),

0.87, (t, 3H, J = 7.30 Hz).

S o p o n O

Preparation of 5- / 4- (3- (2-propyl-3- (phenoxyphenoxy) propoxy) phenyl) -2,4-thiazolidinedione

In an analogous manner to that described in Example 1, Step G. above, using methyl 3- (3- (2-propyl-3-phenoxyphenoxy) propoxy) phenylacetate (obtained as described in Step B above). The title compound was prepared as the starting material.

¹ H-NMR, (400 MHz, C.DG ₁₃ );

δ, 8.05, (bs, 1H), 7.32 * 6.88, (m, 10H), 6.64 (d, 1H, J = 7.40 Hz), 6, 49 (d, 1H, J = 7.30Hz), 5.32 (s,

1H), 4.20-4.13, (m, 4H), 2.60, (t, 2H, J = 7.30 Hz),. 2.28, (quint., 2H, J = 6.00 Hz), 1.49, (hex, 2H, J = 7.50 Hz), 0.86, (t, 3H, J = 7, 30 Hz).

Example 1 a d 57)

Preparation of 5- / 3- (4- (2-propyl-3- (phenoxyphenoxybutoxy) phenyl) -2,4-thiazolidinedione ·············· ······································································

In an analogous manner to that described in Example 22), Steps B) through E) above, using ethyl 3- (4-bromobutoxy) -mandelate and 2-propyl-3-phenoxyphenol (prepared as described above in Example 56), Step A), as a starting material, the title compound was prepared.

¹ H-NMR, (400 MHz, CDCl 3? Delta, 7.96, (bs, 1H), 7.36-6.93, (m, 10H), 6.80, (d, 1H, J = 8.20 Hz), 6.53 (d, 1H, J = 8.30), 5.35, (s, 1H), 4.08, (m, 4H), 2.66 (t, 2H, J = 7.60 Hz), 2.03, (m, 4H),

1.56, (m, 2H), 0.92, (t, 3H, J = 7.40 Hz).

Example 58)

Preparation of 5- / 3- (3- (2- (2-propenyl) -4- (phenoxyphenoxy) propoxyphenyl) -2,4-thaisolidin dione

Stage A)

Preparation of 2- (2-propenyl) -4-phenoxyphenol

A solution prepared by dissolving 11.00 g of 1-phenoxy- (4-propenvloxy) -benzene in 150.0 ml of ortho-dichlorobenzene was heated at reflux for 24 hours.

Thereafter, the reaction mixture was cooled to room temperature and then stirred. Chromatography on silica gel gave the title compound (10.3 g).

¹ H-NMR, (400 MHz, CDCl 3):?

δ, 5.70-4.76, (m, 8H), 6.06-5.96, (m, 1H), 5.21 5.15, (ddt, 2H), 4.86, ( s, 1H), 3.40, (d, 2H, J = 1.40 Hz ⁾

Stage S)

Preparation of 5- / 3- (3- (2- (2-propenyl) -4- (phenoxyphenoxy) propoxyphenyl) 2,4-thiazolidinedione

In an analogous manner to that described in Example 22 above,

Steps B) to E), using ethyl 3- (3-bromopropoxy) -mandelate, and 2- (2-propenyl) -4-phenoxyphenol, (obtained in the foregoing). The above-described compound (A) was prepared as the starting material.

¹ H-NMR (400 MHz, GDC1 _3):

δ, 8.25, (bd, 1H), 7.35 - 6.83, (m, 1H), 5.97, 5.88, (m, 1H), 5.32, ( s, 1H), 5.05-5.00, (m, 4H),

4.47, (dt, 4H), 2.28, (m, 2H).

Example, 59)

Preparation of 5- (3- (3- (1-fluoropropyl) -4-phenoxyphenoxy) propoxyphenyl)

2,4-thiazolidinedione

Stage A)

Preparation of 2- (1-fluoropropyl) -4-phenoxyphenol

To a solution prepared to dissolve 5.00 g of 2- (2-propenyl) 4-phenoxyphenol (prepared as described above in Example 58), Step A) in 40.0 mL of tetrahydrofuran was added. · ·

w was added at 0 ° C a solution (1.25 equivalents) of borane methyl sulfide in tetrahydrofuran, and the resulting reaction mixture was stirred for 3.0 hours, during which the temperature of the reaction mixture rose spontaneously to room temperature.

Then absolute ethanol (10.0 mL) was added to the reaction mixture, followed by 2.27 g of sodium hydroxide in 10.0 mL of water]. The reaction mixture was then cooled to 0 ° C, followed by the careful addition of 4.50 mL, 30% hydrogen peroxide. The reaction mixture was then partitioned between water and ether. After separation of the organic and aqueous phases, the ether extract was washed sequentially with water and brine, and dried over sodium sulfate, and concentrated under reduced pressure, the residue was chromatographed on silica gel, to give the desired intermediate, ¹ H-NMR, (400 MHz, GBCl ^):

delta, 7.33-6.90, (m, 8H), 4.12, (t, 2H, J = 5.20 Hz),

3.68, (t, 2H, J = 5.90 Hz), 2.77 _r . (t, 2H, J = 6.80Hz),

1.89 (hex, 2H, J = 5.90 Hz),

Grade A ·])

Preparation of 2- (1-fluoropropyl) -4-phenoxyphenol

The intermediate (2.20 g) obtained in the above step A) was dissolved in 30.0 ml of tetrahydrofuran, and the resulting solution was mixed at 0 ° C with 4.76 ml of diethylaminosulfurtrifluoride.

The reaction mixture was then stirred for 4.0 hours, and after the addition of aqueous sodium bicarbonate solution, washed with water, followed by drying with sodium sulfate, concentrated, and the residue bvl chromatographed on silica gel to give the desired title compound. said compound.

140 ¹ H-NMR, (400 MHz, CDGL1):

delta, 7.33 - 6.75 (m., 8H), 4.69 (s., 1H), 4.45 (dt, 2H, J - 47.30 Hz 5.90 H _z) 2.74 (t, 2H, J = 7.30 Hz), 2.05, (m, 2H).

Step B)

Preparation of 5- / 3- (3-O-fluoropropyl) -4- (phenoxyphenoxy) propoxyphenyl / 2,4-thiazolidinedione

In an analogous manner to that described in Example 22 above, Steps B through E), using ethyl 3- (3-bromopropoxy) -mandelate, and 2- (1-fluoropropyl) -4-phenoxyphenol (obtained in the preceding step). of Step A, above), as a starting material, the desired title compound.

¹ H-NMR (400 MHz, CHCl 3):

delta, 7.94 (bs, 1H), 7.40-6.80, (m, 12H), 5.35, (s,

1H), 4.44, (dt, 2H, J = 47.30 Hz and 5.90 Hz), 4.22, (t,

2H, J = 6.10 Hz), 4.17 (t, 2H, J = 6.10 Hz), 2.73, (t,

2H, J = 7.20 Hz), 2.30, (m, 2H), 1.95, (m, 2H).

Example 60)

Preparation of 5- / 3- (3- (2-propyl-4- (4-ethoxycarbonylphenoxy) phenoxypropoxy) phenyl) -2,4-thiazolidinedione.

ο '

cooc ₂ h ₅

Stage A)

Preparation of 2-propyl-4- (4-ethoxycarbonyl) phenoxyphenol

Stage A ₁ )

Preparation of 4- (4-ethoxycarbonylphenoxy) phenyl-allyl ether

A solution prepared by dissolving 10.00 g of 4-8-llyloxyphenol, further 12.33 g of 4-fluoroethylbenzoate, and 2.91 g of sodium hydride (60% dispersion in mineral oil) in 50.0 ml of dimethylsulfoxide, It was stirred at room temperature T50 (C L ^P _R for 24.0 hours.

The reaction mixture was then cooled, and the excess carefully quenched with water. After subsequent extraction of the reaction mixture and separation of the organic and aqueous phases, the organic layer was washed with water, and after drying with sodium sulfate, filtered, and evaporated.

The oily residue was chromatographed on silica gel to give the desired 4- (4-ethoxycarbonylphenoxy) phenyl allyl ether.

Grade A2)

199 9

4 4 · 99 9 99 99 4 9 4 4 · 4 9 4 4 9 4 4 4 9 4 4 4 9 4 4 4 4

999 9 99 4 4 4 9 9 4 4 4

Preparation of 2-propyl-4- (4-ethoxycarbonyl) -phenoxyphenol

A solution prepared by dissolving 3.90 g of 4- (4-ethoxycarbonylphenoxy) -phenyl-allyl ether (obtained as described above in Step A-1) in 50.0 ml of 1,2-dichlorobenzene was heated to reflux. under reflux for 30.0 hours.

After cooling to room temperature, the mixture was chromatographed on silica gel. and 3.46 g of intermediate was obtained, which was hydrogenated in 130.0 ml of ethanol in the presence.

0.30 g, palladium on activated carbon. The reaction mixture was then filtered through diatomaceous earth, and concentrated in vacuo.

The title compound was obtained.

¹ H-NMR (400 MHz, CDCl 3):

delta, 7.99, (d, 2H, J = 9.00 Hz), 6.93, (d, 2H, J = 9.00 Hz) 6.87, (s, 1H), 6, 80, (dd, 2H), 4.36, (c, 2H, J = 7.00 Hz) ,. 2.59, (t, 2H, J = 7.40 Hz), 1.68-1.60, (m, 2H), 0.98, (t, 3H, J = 7.20 Hz) .

Step B)

Preparation of 5- / 3- (3- (2-propyl-4- (4-ethoxycarbonylphenoxy) -phenoxypropoxy) -phenyl) -2,4-thiazolidinedione

In an analogous manner to that described in Example 22), Steps B) through E) above, 2-propyl-4- (4-ethoxycarbonyl) -phenoxyphenol (obtained from ethyl 3- (3-bromopropoxy) -mandelate) was obtained. within the previous step A) described above, respectively. As the starting materials, the title compound was obtained.

@ ¹ H-NMR (400 MHz, CDCl3): .delta.

δ, 8.00, (d, bs, 3H), 7.40-6.80, (m, 9H), 5.35, (s, 1H), 4.36, (k 2H, J = 7.00 Hz), 4.22 (t, 2H, J)

6.10 Hz) ,. 4.18, (t, 2H, J = 6.00 Hz), 2.59, (t, 2H, J =

7.40 Hz), 2.32, (hex, 2H, J = 6.00 Hz), 1.60, (m, 2H), 1.39, (t, 3H, J = 7.30) Hz), 0.93, (t, 3H, J = 7.20 Hz).

Example 61)

Preparation of 5- / 4- (3- (4- (1,2-benzisoxazol-3-yl) -2-propylphenoxy) propoxy) -phenyl 1 -2,4-thiazolidinedione

In an analogous manner to that described in Example 22), Steps B) through E) above, using ethyl 4- (3-bromopropoxy) -mendelate, and 4- (1,2-benzisoxazol-3-yl) -2- propylphenol, (International Patent Application-WO-97 / 28,115), as a starting material, the desired title compound was prepared.

4 4

4

1 H-NMR. (400 MHz ,. (M1)} ::

Example. 62)

Preparation -5- / 3- (4 - ((1,2-benzisoxazol-3-yl) -2-propylphenoxy) butoxy) feny1 / _r -2 4-thia one zolidindi

An analogous procedure to that described in Example 22 above was using ethyl 3- (4-bromobutoxy) -mallate, and 4-0,2-benzisoxazol-3-yl) -2-propylphenol. (International Patent Application-WO-97 / 28.115), as a starting material, prepared the desired compound and the title compound.

@ ¹ H-NMR .delta _. (400 MHz, GEC1):

• »

(m, 2Η), 0.96, (t, 3H, J = 7.30 Hz).

Example 1 a d 63)

Preparation of 5- / 4- {3- (3- (2-phenylethyl) -7-propyl-benzothiophen-6-yl) oxy) -1-propoxy / phenyl-2,4,4-thiazolidinedione

H

0 '

Stage A)

Preparation of 1-diaz-4-phenyl-2-butanone

Solution prepared by dissolving 10,00 g of hydrocinemoyl chloride = 3-phenylpropionyl chloride; in 100.0 ml of dried diethyl ether was carefully added to a freshly prepared ether solution of diazomethane (85.60 g, Diszalde = N-methyl-N-nitroso) 9 99 99 99 9999 94 9 99 99 4 «« · ♦ · 9 99 «* · * w

p-toluenesulfonamide in 100.0 mL, dried ethyl ether) at 0 ° C.

The resulting reaction mixture was then held at ΟθΟ until degassing was complete (15.0 minutes) and then allowed to warm to room temperature over 15.0 minutes. Then 5.0 mL of acetic acid was added to the reaction mixture, and the mixture was shaken between. phthalate buffer pH 4.0, 8 methyl tert-butyl ether. After separating the organic and aqueous phases, the organic layer was washed with water, and after drying with magnesium sulfate, filtered and evaporated.

The title compound was obtained as an oily consistency which was used as the crude product without further purification or delay.

¹ H-NMR, (400 MHz, CHCl ₃ ):

.delta., 7.32-7.18, (mult, 5H), 5.19, bs, 1H), 3.04 2.92, (mult, 4H).

Grade B.)

Preparation of 1-bromo-4-phenyl-2-butanone

A solution prepared by dissolving 12.89 g of the crude product ie 1-diaz-4-phenyl-2-butanone in 150.0 ml of dried dichloromethane (obtained under the above-described Step A) and cooled to 0 ° C, was added dropwise with 36.0 mL of a 48% hydrobromic acid solution.

After gas evolution ceased in the reaction mixture, the mixture was partitioned between isopropyl acetate and water, and after separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with magnesium sulfate, filtered and evaporated.

The title compound was obtained in the form

4444 ♦ 4 4 44 44 4 * 4 #

444 44 4 4 4 44 4 4 4444

4444 «44 44 * 44 44 44

ΥΥΖ oily consistency, which when standing still crystalline mucous.

¹ H-NMR, (400 MHz, GD-Gl-1):

delta 7.30 to 7.16 (mult., 5H), 3.83 (s., 2H), 2.97 to 2.91 (mult., _4H).

Stage C)

Preparation of 1- (3-methoxyphenyl) -thio-4-phenyl-2-butanone

A solution prepared by dissolving 20.212 g of 1-bromo-4-phenyl-2-butanone (obtained as described in Step A above) in 225.0 ml of dried dimethylformamide was treated with added di-isopropvlethylamine, (16, 22 ml), followed by 11.424 grams of 3-methoxythiophenol, and the resulting reaction mixture was stirred at room temperature for 6.0 hours, and was then shaken between isopropyl acetate and phthalate buffer at pH 4.0.

After separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with magnesium sulfate, filtered, and concentrated.

The residue was chromatographed on silica gel, eluting with hexane / dichloromethane (5.0: 1.0) to give the title compound.

¹ H-NMR, (400 MHz, CUCl 2):

delta, 7.26-7.12, (mult., 6H). 6.83 (dd, 2H, J = 4.70,

2.20 Hz). 6.73 (dd, 1H, J = 8.30, 2.40 Hz), 3.76, (s,

3H), 3.63, (s, 2H), 2.88, (oct, 4H, J = 5.80 Hz).

9499 · * • 9

9 ·

9499 94

99

9 9 • 9 99

9 9 9

49

49

9 · ·

9 9 • 9 9 ·

9 9 9

9 «

Grade H)

Preparation of 3- (2-phenylethyl) -6-methoxybenzothiophene

A solution prepared by dissolving 495.0 g of 1- (3-methoxyphenyl) thio-4-phenyl-2-but-8-one (obtained as described in Step O above) in 85.0 ml of dried diehormethane was added. dropwise, at 0 ° C, to the solution obtained by mixing 17.0 ml of methanesulfonic acid with 34.0 ml of dichloromethane.

The resulting reaction mixture was then allowed to stir at 0 ° C for 20 / 0minutes and then allowed to warm to room temperature, then poured rapidly into an intensively stirred, cooled mixture of excess 5N sodium hydroxide solution and methyl tert. After separating the organic 8 aqueous phase, the organic layer was dried with magnesium sulfate, and after filtration was concentrated.

The residue was chromatographed on silica gel, eluting with hexane: dichloromethane (5.0: 1.0).

The title compound was obtained as a clear oil, oil-like, @ ¹ H-NMR (400 MHz, GDCl3):

.delta., 7.66, (d, 1H, J = 8.80 Hz), 7.37-7.20, (mult., 6H), 7.05. (dd, 1H, J = 8.80, 2.40 Hz), 6.91, (t, 1H, J = 0.90 Hz), 3.90, (s, 3H), 3.16- 3.02, (mult., 4H).

Step E)

Preparation of 3- (2-phenylethyl) -6-hydroxybenzothiophene

4444

Μ 44 44 · ♦ «4444 4 4 4 4 44 44 44 44 4444

446 44 446 «4 β

44 4444 4444

4444 44 44 44 44 44

W

The solution, prepared by dissolving 5.483 g of β 3- (2-phenylethyl) 6-methoxybenzothiophene (obtained as described above in Step D), in 60.0 mL of dried dichloromethane was stirred at minus 10 with stirring. 0 ° C, mixed with 1M bromide boron solution (20.81 mL, dichloromethane solution).

After 2.0 hours, the reaction mixture was quickly warmed to room temperature and then partitioned between isopropyl acetate and aqueous sodium bicarbonate. After separation of the organic and aqueous phases, the organic layer was washed once with water, and after drying with magnesium sulfate, filtered, and evaporated.

The residue, as a semi-solid, was chromatographed on silica gel, eluting with hexane: ethyl acetate (2.5: 1.0).

The title compound was obtained as a pale yellow solid.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 7.60, (d, 1H, J = 8.80 Hz), 7.35-7.23, (mult, 6H),

6.94 (dd, 1H, J = 8.70, 2.30 Hz), 6.88, (s, 1H), 5.40, (s, 1H), 3 ', 13-3, O 2 (mult., 4H).

Grade E?)

Preparation of 3- (2-phenylethyl) -6-allyloxybenzothophene

The solution prepared by dissolving 4,651 g of 3- (2-phenylethyl) 6-hydroxy-benzothiophene (obtained under the above-described Step E) in 40.0 ml of dried dimethylformamide was treated with added allyl bromide (1, 66 ml),

4 * • · 44 44 444 »4 <

44 4444 4444

4444 44 44 44 44> ♦ and then 6.26 grams of cesium carbonate.

After 2.50 hours at room temperature, the reaction mixture was shaken between isopropyl acetate and phthalate buffer pH 4.0.

After separation of the organic and aqueous phases, the organic layer was washed twice with water, and dried over magnesium sulfate, filtered. and evaporated.

The resulting residue was chromatographed on silica gel, using hexane: dichloromethane (3.0: 1.0) as eluant, to obtain the desired, title compound, as a clear _r substance oil.

¹ H-NMR, (400 MHz, COCl 2):

delta, 7.73 (d, 1H, J = 8.80 Hz), 7.47-7.34 (mult, 6H),

7.19, (dd, 1H, J = 8.80, 2.30 Hz), 6.99 (s, 1H), 6.22, (d-quint, 1H, J = 4.30) Hz), 5.62, (d-quart., 1H, J = 17.30,

1.60 Hz), 5.44 (d-quart, 1H, J = 10.50, 1.40 Hz), 4.69 (t, 1H, J = 1.50 Hz), 4.67 »(t, 1H, J = 1.50 Hz), 3.25-3.12, (mult., 4H).

G e G)

Preparation of 3- (2-phenylethyl) -6-hydroxy-7-allyl-benzothiophene

A solution prepared by dissolving 4.373 g of 3- (2-phenylethyl) -6-allyloxybenzothiophene (obtained as described in Step F above) in 45.0 ml. 1,2-dichlorobenzene, bvl heated at reflux under nitrogen atmosphere for 8.50 hours.

P _on the what the reaction mixture was cooled to about 50.0 ° C, the solvent of the mixture under high vacuum removed and to the residue solidified.

The solid residue was then dissolved in 100.0 mL of dichloromethane,

• · φ «* * · Φ

ΦΦ Φ · ·· ΦΦ

156 and after isolation 8 followed by evaporation, the residue was chromatographed on silica gel using dichloromethane as eluent.

Evaporation of the appropriate fractions collected afforded the title compound as a pale yellow solid.

¹ H-NMR, (400MHz, GEC ₁₃ ):

.delta., 7.53 (d, 1H, J = 8.50 Hz), 7.35-7.20 (mult, 5H),

6.95 (d, 1H, J = 8.50 Hz), 6.93, (d, 1H, J = 8.40 Hz), 6.06. (apparent d. pent. -), 1H, J = 7.10, 3.90 Hz), 5.23, (quart. 1H, J = 15.70, 1.70 Hz), 5, 77, (d.quart, 1H, J = 11.50, 1.80 Hz), 5.09, (s, 1H 3 _r 67, (dt, 2H, J = 6.30, 1.60 Hz) 1), 3 / 3-3.01, (mult, 4H), 1.27, (t, 3H, J = 7.20 Hz).

Grade H)

Preparation of 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene

Solutions; prepared by dissolving 3), 062 g of 3- (2-phenylethyl) 6-hydroxy-7-8-llyl-benzothiophene (obtained under the preceding G-step described above) in 60.0 µl of ethyl tert-butyl ether, was placed in a hydrogenation vessel, 8 after addition of 306.0 mg of 5% palladium on charcoal, the reaction mixture was hydrogenated in a Parr apparatus at 0.098 MPa for 1.0 hour.

After the reaction mixture was filtered through diatomaceous earth, it was evaporated to give the title compound as a yellow oil of oil consistency.

Upon standing at rest, a light yellow colored solid was obtained which required no further purification.

0 ♦ «« 0 • • • • • • • • •

0 0 0

0 0 0

0 0 · 0 0 0

¹ H-NMR (400 MHz, ODG 1):

δ, 7.45, (d., 1H, J = 8.50 Hz), 7.32-7.20, (mult.,

6H, 6.89 ,. (d, 1H, J = 8.40 Hz), 5.28, (s, 1H), 3.10, 3.01, (mult, 4H), 2.84, (dd, 2H, J = 7.70, 1.60 Hz), 1.74 (hex, 2H, J = 6.00 Hz), 1.02, (t, 3H, J = 7.40).

S t u p i n I)

Preparation of methyl 4- / 3- (3- (2-phenyl-ethyl) -7-propyl-benzothiophen-6-yloxy) -1-propoxy / -phenyl acetate

In an analogous manner to that described in Example 1), Step B) above, using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene (obtained under Step H above) as starting material, to obtain the title compound.

¹ H-NMR, (400 MHz, CDCl ₃ ):

delta, 7.50-7.42, (m, 4H 7.31, (d, 2H, J = 8.80 Hz)),

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83, (m, 3H),

6.46, (m, 1H), 4.21-4.16, (m, 4H), 3.67, (s, 3H),

3.54, (s, 2H), 2.95, (t, 2H, J = 7.40 Hz), 2.29, (quint., 2H, J = 6.30 Hz), 1.71 , (hex., 2H, J = 5.90 Hz), 1.01, (t, 3H, J = 7.30 Hz).

Grade J?)

Preparation of 5- / 4- (3- (3- (2-phenylethyl) -7-propylbenzothiophen-6.-yloxy) -1-propoxy) -1-phenyl-2,4-thiazolidinedione

99

9 9 9

9 9 9 9

99

9999

9 9

9 ·

9999 99

99

9 9 9

9 99

9 9 9

99

In an analogous manner to that described in Example 1), Step G), it was using methyl- [4- (3- (7-propyl-3- (2-phenylethyl) benzothiophen-6-yloxy)] - 1-propoxy) -phenylacetate (obtained as described above in Step I above) as a starting material, the title compound is obtained.

¹ H-NMR (400 MHz, CDCl 3):

delta, 9.46 (bs, 1H), 7.59 (d, 1H, J = 8.60 Hz), 7.38 7.24, (m, 4H), 7.09 , (d., 1H, J = 8.80 Hz), 6.98, (d., 2H,

J = 8.80 Hz), 6.92-6.83, (m, 3H), 6.46, (a, 1H), 5.30, (s, 1H), 4.26 , (b.O, quart., 4H, J = 5.503 Hz), 3.11, (v.

y v

š. kvint. 4H), 2.91, (ddd, 2H, J = 7.40, 1.40 Hz), 2.34, (quint., 2H, J = 6.00 Hz), 1.76, (hex ., 2H, J = 7.50 Hz),

1.03, (t, 3H, J = 7.30 Hz).

Example 1 64)

Preparation of 5- / 3- (4- (3- (2-phenylethyl) -7-propylbenzothiophen-1,1-dioxide-6-yloxy) -1-butoxy) -1-phenyl-2,4,4-thiszolidinedione

O

• 4 44 44 • · · 4 4 4444

4 44 44 444 »• 4 4 4 4 4 444 4

44 4444 4444

4444 44 44 44 44 44

Τ /

Stage A)

Preparation of 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene-1,1-dioxide

A solution prepared by dissolving 3.515 g of 3- (2-phenylethyl) 6-hydroxy-7-propylbenzothiophene (obtained as described in Example 63 above). Step H), in 40.0 mL of dichloromethane, was cooled to 0 ° C, and mixed while stirring with 5.457 g, 75% m-chloroperbenzoic acid (in solid form)

After 15.0 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for a further 1.0 hour. The reaction mixture was then partitioned between isopropyl acetate and aqueous sodium bicarbonate solution, and after separation of the organic and aqueous phases, the organic layer was washed with aqueous sodium bicarbonate solution and then with water and dried over magnesium sulfate, filtered and evaporated.

The residue, as a solid, was chromatographed on silica gel, eluting with hexane: ethyl acetate (5.0: 1.0).

The title compound was obtained as a white solid.

¹ H-NMR, (400 MHz, CEG 1 →):

.delta., 7.35-7.19, (m, 4H), 7.04 (s, 1H, J = 8.10 Hz),

6.89, (br, 1H, J = 8.20 Hz), 6.63 (broad b, 1H), 6.29, (t, 1H, d = 1.50 Hz) 2.97 £ 2.78, (m, 6H), 1.74, (d.sex., 2H,

J = 7.20, 2.90 Hz), 1.03, (t, 3H, J = 7.40 Hz).

Grade ffi)

9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

9 «9999 999«

9999 99 * 9 99 9

Preparation of methyl 1- (4- (7-propyl-3- (2-phenylethyl) benzothiophene, 1-dioxide-6-yloxy) -1-butoxy) phenylacetate

In an analogous manner to that described in Example 1), Step B), using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene-1,1-dioxide (obtained under Step A above), ), as a starting material, the title compound.

’Η-ΝΜΒ, (400 MHz, δ, 7.50 - 7.42, (m, 4H), 7.31, (d, 2H, J = 8.80 Hz),

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83, (m, 3H),

6.46, (a, 1H), 4.21-4.16, (m, 4H), 3.67, (s, 3H),

3.54, (s, 2H), 2.95, (t, 2H, J = 7.40 Hz), 2.29, (quint., 2H, J = 6.30 Hz), 1.71 , (hex., 2H, J = 5.90 Hz), 1.01, (t, 3H, J = 7.30 Hz) »

Stage C)

Preparation of 5- / 3- (4- (3- (2-phenylethyl) -7-propylbenzothiophen-1,1-dioxide-6-yloxy) -1-butoxy) -1-phenyl-1,4,4-thiazolidinedione

Following the process described in example 1) Step &), stalks, using methyl 3 - ((4- (7-propyl-3- (2-phenyl-ethyl) _{benzothiophen-1, t} 1-dioxide-6 yl) -oxy4-1-butoxy) phenylacetate (diethyl oxalate, as described above, step b), starting material is prepared, the title compound ^»1 H-NMR (400 MHz, CTC1 _3): :

delta, 8.42 (bs, 1H), 7.32-7.19, (m, 6H), 7.12, (d,

1 J (J = 8.30 Hz), 6.98 (d, J = 8.10 Hz), 6.91-6.85, (m, 4H) ,. 6.30, (s, 1H), 5.30, (s, 1H), 4.04, (quart.,

4H ,. J = 6.30 Hz), 2.94 to 2.88 (m., .. 4H), 2.02 to 1.98 (ur. _R

4H) 1.69, hex, 2H. J = 5.20 Hz), 0.99. (t, 3H, J = 7.30Hz).

4 99 99 99

9 4 4 4 · 4444

4 4 4 99 4444 444 44 444

44 44-4 4444

4444 44 44 44 44 44

Example; 65)

Preparation of 5- / 4- (3- (7-propyl-3- (2-phenylethyl) -benzothiophen-1,1-dioxide-6-yloxy) -1-propoxy) / phenyl-2,4-thiezolidinedione

Stage A)

Preparation of methyl 4- (3- (7-propyl-3- (2-phenylethyl) benzothiophen-1-dioxide-6-yloxy) -1-propoxy-4-phenylate)

ΦΦΦΦ

* ΦΦ ΦΦ ΦΦ • * Φ ΦΦΦΦ ΦΦΦΦ

Φ Φ · Φ · Φ φφφφ

ΦΦ ΦΦΦ ΦΦ «ΦΦ · Φ Φ

Φ ΦΦ Φ · Φ · φφφφ ΦΦΦΦ · · ·· Φφ φφ

462

In an analogous manner to that described in Example 1 above, Step B), using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene-1,1-dioxide (obtained as described in Example 64 above). Step A), as a starting material, the desired title compound.

¹ H-NMR, (400 MHz, CDCl 3): δ 7.50-7.42, (mr., 4H), 7.31, (d, 2H, J = 8.80 Hz),

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83, (ur., 3H),

6.46, (s, 1H), 4.21-4.16, (m, 4H), 3.67, (s, 3H),

3.54, (s, 2H), 2.95, (t, 2H, J = 7.40 Hz), 2.29, (quint., 2H, 6.30 Hz), 1.71, ( hex, 2H, J = 5.90 Hz), 1.01, (t,

3H, J = 7.30 Hz).

Stage n · Β;)

Preparation of 5- / 4- (3- (3- (2-phenylethyl) -7-propyl-benzothiophen-1,1-dioxide-6-yloxy) -1-propoxy) -1-phenyl-2,4,4-thiazolidinedi onu

An analogous procedure to that described in Example 1 above, Step C), using methyl 4- (3- (3- (2-phenylethyl) -7-propyl benzothiophen-1,1-dioxide-6-yloxy)) (1-propoxy) -phenylate (obtained under Step A above) as a starting material, the title compound of formula ( ¹ H-N1R '(400 MHz, CDCl 3)):

delta, 8.87 (bs, 1H), 7.32-7.24, (m, 6H), 7.21, (t, 2H, J = 7.10 Hz), 7, 12 (d, 1H, J = 8.10 Hz), 6.90 (d,

2H, J = 8.70 Hz), 6.89 (d, 1H, J = 8.20 Hz), 6.30, (s,

1H). 5.31 (s, 1H), 4.16 (quart., 4H, J = 5.90 Hz),

2.95-2.87, (m, 4H), 2.81, (t, 2H, J = 7.70 Hz), 2.29;

9999 99 99 49 94 • 4 9 4 9 9 4 4

9 4 4 4

4 4 4 4 4 9 9 4 4 4 · • · · 9 4 4 4 4 4

4444 94 49 44 44 49 (quint., 2Η, J = 6.00 Hz), 1.67 ,. (hex., 2H, J = 7.70 Hz), 0.98, (t, 3H, J = 7.40 Hz).

Example * 66)

Preparation of 5- / 3- (4- (3- (2-phenyl-ethyl) -7-propyl-benzothiophen-1-oxide-6-yloxy) -1-butoxy) -phenyl-2,4-thiazolidinedione

Stage A)

Preparation of 3- (2-phenylethyl-1-6-hydroxy-7-propyl-benzothiophene-1-oxide)

A solution prepared by dissolving 2.017 g of 3- (2-phenylethyl) 6-hydroxy-7-propyl-benzothiophene (obtained as described in Example 63 above), Step H) in 40.0 ml of dichloromethane,

999 · 99 99 99 99 • 9 · · 4 4 4 4 4 4 4 • 4 4 · ·· 4 4 4 4 • 444 4 444 44 4

44 4444 4444

4444 44 44 44 44 44 was brought to 0 ° C, and mixed while stirring with 1.567 g, 75% m-chloroperbenzoic acid, (in solid form) *

After 15.0 minutes, the reaction mixture was allowed to warm to room temperature and stirred at this temperature for an additional 1.50 hours. Then, the reaction mixture was shaken between isopropyl acetate, aqueous sodium bicarbonate solution, and after separation of the organic and aqueous phases, the organic layer was washed with aqueous sodium bicarbonate solution, then with water, and dried over magnesium sulfate, filtered, and evaporated.

The solid residue was chromatographed on silica gel, using a two-step gradient elution, with hexane: ethyl acetate. (5.0: 1.0) J hexane: ethyl acetate, (5.0 t 2.0) J and hexane: ethyl acetate methanol, (5.0: 2.0: 0.35).

The title compound was obtained as a white solid.

¹ H-NMR (400 MHz, GDC1 _3):

δ, 8.53, (bs, 1H,), 7.33-7.18, (mult., 5H), 7.01, (d, J = 8.20 Hz), 6 88 (d, 1H, J = 8.20 Hz), 6.50, (s, 1H), 2.99-2.77, (mult, 4H), 1.67, (hex. J, 2H

7.60 Hz) »0.95» (t, 3H, J = 6.70 Hz).

Step B)

Preparation of methyl 3- (4- (3- (2-phenylthyl) -7-propyl-benzothiophen-1-oxide-5-yloxy) -1-butoxy) -phenylacetate

In an analogous manner to that described in Example 1, Step B) above, using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzothiophene-1-oxide (obtained in the foregoing, supra) was used. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The desired title compound was prepared as described in Step A) as a starting material.

¹ H-NMR (400 MHz, CJM1):

gel, 7.50-7.42, (m, 4H), 7.31 (d, 2H, J = 8.80 Hz),

7.19-7.16, (d, 2H, J = 8.30 Hz), 6.92-6.83, (m, 3H), 6.46 * (a, 1H), 4, 21 - 4.16 * (m, 4H), 3.67 * (s, 3H), 3.54, (s, 2H), 2.95, (t, 2H / [beta] = 7.40 Hz) * 2.29 * (quint., 2H,

J χ 6.30 Hz), 1.71, (hex, 2H, J = 5.90 Hz), 1.01, (t, 3H,

J = 7 * 30Hz).

S o u u o O

Preparation of 5- / 3- (4- (33- (2-phenyl-ethyl) -7-propyl-benzothiophen-1-oxide-6-yloxy) -1-butoxy) -phenyl-2,4-thiazolidinedione

In an analogous manner to that described in Example 1 above, Step C), using methyl 3- (4- (3- (2-phenylethyl) -7-propyl-benzothiophen-1-oxide-6-yloxy)) was: 1-butoxy) -phenylacetate (obtained under Step B above) as a starting material, the title compound: 1 H-NMR * (400 MHz, CDCl 3) diastereoisomeric pair prepared as a starting material :

delta, 9.62-9.53 (broad b, 1H), 7.32-7.17, (m, 6H),

6.96 - 6.86, (m, 4H), 6.60, (s, 0.5H), 6.59, (s, 0.5H),

5.26, (s, 0.5H), 5.25, (s, 0.5H), 4.09-4.03, (m. * 4H), 3.01-2.84, ( m., 6H), 2.05-2.00, (m, 4H), 1.70, bs, 2H * J = 8.50 Hz), 0.98, (t, 1, 50 H, J = 7.40 Hz) 0.95 (t,

1.50 H * J = 7.30 Hz)

700

Example 67)

Preparation of 5- / 4- (3- (3- (2,2-dimethylpropyl) -7-propylbenzofuran-6-yloxy) -1-propoxy) -1-phenyl-2,4,4-thiazolidinedione

Stage A)

Preparation of 1-diaz-4,4-dimethyl-2-pentanone

A solution prepared by dissolving 1.136 g of tert-butyl acetyl chloride in 10.0 ml of dried ethyl ether was slowly added to a freshly prepared ether solution of diazomethane (obtained from 20.0 g of Diazald = N-methyl-N-). nitroso-p-toluenesulfonamide), cooled to 0 ° C.

After stirring for 30 minutes, the reaction mixture was allowed to warm to room temperature over a further 30 minutes. After the subsequent addition of 2.0 mL of acetic acid, the mixture was partitioned between methyl tert-butyl ether. and water. After separation of the organic and aqueous phases, the organic layer was washed once with water, and after drying with magnesium sulfate, filtered, and concentrated.

The title compound was obtained in the form

4β7a oil-like consistency which was used without further purification.

¹ H-NMR, (400 MHz, CD 1 O 4):

δ, 5.18, (bs, 1H), 2.15, (bs, 2H), 1.01, (s, 9H).

Step B)

Preparation of 1-bromo-4,4-dimethyl-2-pentanone

A solution prepared by dissolving 1,233'g of the crude product, i.e. 1-diaz-4,4-dimethyl-2-pentanone (obtained under Step A above) in 12.0 ml of dichloromethane and cooled to a temperature of minus 10.0 ° C, was mixed under stirring, dropwise, with stirring. 1.14 ml, 48% hydrobromic acid solution.

After gas evolution ceased in the reaction mixture, the mixture was stirred at room temperature for 15 minutes, and then water was partitioned between isopropyl acetate 8. After separating the organic 8 aqueous phase, the organic layer was washed once with water, and after drying with magnesium sulfate was filtered, and evaporated.

The title compound was obtained as an oily consistency which was used without further processing.

¹ H-NMR, (400 MHz, CDCl ₃ ):?

.delta., 3.85, (s, 2H), 2.50, (s, 2H), 1.01, (s, 9H).

Stage C)

Preparation of 1- (3-methoxyphenoxy) -4,4-dimethyl-1,2-pentanone

A solution prepared by dissolving 1.626 g of 1-bromo-4,4-dimethyl-2-pentanone. (obtained under Step B above) in 18.0 mL of dimethylformamide. was stirred with 1.225 g of 3-methoxyphenol, 8 3.292 g of cesium carbonate with stirring, and the resulting reaction mixture was stirred for 2.50 hours.

Then the reaction mixture was shaken between isopropyl acetate, and a phthalate buffer of pH 4.0. After separation of the organic and aqueous phases, the organic layer was washed twice with water and, after drying with magnesium sulfate, filtered and concentrated.

The residue as an oil was chromatographed on silica gel using hexane: ethyl acetate (4.0: 1.0). as eluent, and the title compound was obtained.

¹ H-NMR (400 MHz, CBCl 3):?

δ 7.18 (ddd, 1H, J = 7.70, 6.90, 0.70 Hz, 4.47, (s, 2H), 3.78, (s, 3H), 2.44, (s, 2H), 1.05, (s, 9 Hz).

Degree. (B)

Preparation of 3- (2,2-dimethylpropyl) -? - methoxybenzofuran

A solution prepared by dissolving 1.408 g of 1- (3-methoxyphenoxy) 4,4-dimethyl-2-pentanone (obtained as described above in Step C) in 15.0 ml of dried dichloromethane was added. to 30.0 ml of phosphorus oxychloride, and the resulting reaction mixture was stirred at 40.0 ° C for 2.0 hours. The reaction mixture was then diluted 2 x with 30.0 ml of xylenes each time and then under high vacuum. thickened.

The nonvolatile components were partitioned between isopropyl acetate, and aqueous sodium bicarbonate solution. After removal of the organic phase and the aqueous phase, the organic layer was washed with aqueous sodium bicarbonate solution, and dried over magnesium sulfate, filtered.

Removal of the solvents gave a residue which was chromatographed on silica gel using hexane: dichloromethane (3.0: 1.0) as eluent to give the title compound, ¹ H-NMR, ( 400 MHz, GDCl4:

delta,. 7.40, (d, 1H, J = 8.60 Hz), 7.31, (s, 1H), 7.00, (d, TH, J = 2.20 Hz), 6.88 , (dd, 1H, J = 8.60, 2.40 Hz),

3.85, (s, 3H), 2.52, (s, 2H), 0.98, (s, 9H).

Step E)

Preparation of 3- (2,2-dimethylpropyl) -6-hydroxybenzofuran

To a solution prepared by dissolving> 379 g of 3- (2,2-dimethylpropyl) -6-methoxybenzofuran (obtained as described above in Step D) in 35.0 ml of dried dichloromethane, cooled to minus 10.0 ° C, 3.70 mL was added. Of a 1M solution of bromide boron in dichloromethane, and after the reaction mixture was allowed to warm to room temperature, was stirred for 1.0 hour.

The reaction mixture was then partitioned between isopropyl acetate and aqueous sodium bicarbonate solution. After separating the organic and aqueous phases, the organic layer was washed twice with water, and after drying with magnesium sulfate, filtered and then the volatiles were removed.

The residue was chromatographed on silica gel using hexane: ethyl acetate (5.0 r 1.0) as eluent to give the title compound.

@ ¹ H-NMR (400 MHz, CDCl3): .delta.

delta, 7.34 (d, 1H, J = 8.4 Hz), 7.28, Os, 1H), 6.93 (d, 1H, J = 2.20 Hz), 6.76, (dd, 1H, J = 8.40, 2.20 Hz), 4.98, (s, 1H), 2.49, (a, 2H), 0.95, (a. , 9H).

Grade F)

Preparation 3> (2,2-Dimethylpropyl) -6-sllyloxybenzofurar

The solution prepared by dissolving 2,880 g of 3Ϊ- (2,2-dimethylpropyl) -6-hydroxy-benzofuran (obtained as described above in Step E) in 30) of 0, dried dimethylformamide, was mixed while stirring. stirring first with 1.282 g of allyl bromide and then with 4.828 g of cesium carbonate.

FG> 2.0 hours, the reaction mixture was shaken between. isopropyl acetate, and a phthalate buffer of pH 4.0. After separation of the organic and aqueous phases, the organic layer was washed twice with water, and dried over magnesium sulfate, filtered and concentrated.

The title compound was obtained which was sufficiently pure that further processing was not necessary. ¹ H-NME, (400 MHz, CB € ₁₃ ):

δ, 7.37, (d, 1H, d = 8.60 Hz), 7.28, (s, 1H), 6.99, (d, 1H, d = 2.20 Hz), 6.87 (dd, 1H, J = 8.60, 2.20 Hz), 6.07, (mult, 1H), 5.43, (quart., 1H, J = 17.30) 1.60 Hz), 5.29, (d; quart, 1H, J = 10.50, 1.60 Hz), 4.56, (t, 1H, J = 1.50 Hz);

1.50 Hz), 4.55, (t, 1H, J = 1.50 Hz), 2.49, (s, 2H), 0.95, (s, 9H).

• 4

4

777

Degree. G.)

Preparation of 3- (2,2-dimethylpropyl) -6-hydroxy-7-allyl-benzofuran

Solution prepared by dissolution; 3.226 g of 3- (2,2-dimethylpropyl) -6-8-llyloxybenzofuran (obtained under the previous IP step described above) in 1,2-dichlorobenzene was heated at reflux for 8 hours. 0 hodím.

After the reaction mixture was cooled to about 50.0 ° C, the solvent was distilled off under high vacuum, and the residue, as a solid, was dissolved in refluxing cyclohexane. Then the resulting solution was cooled to room temperature, and filtered.

The mother liquor was evaporated, and chromatographed; on silica gel, eluting with hexane-ethyl acetate (2.5: 1.0) to give an additional solid which was added to the previously prepared product to give all the desired solids. the title compound.

¹ H-NMR, (400 MHz, CECl 2):

delta 7.32 (s., 1H), 7.26 (d., 1H, d - 8.30 Hz), 6.80 (d., ₁ H, J - 8.40 Hz), 6.09, (quart., 1H, J = 13.30, 1.00)

Hz), 5.26 ,. (quart., 1H, J = 1.70 Hz) ,. 5.20 (hex., 1H, J =

2.50? Hz), 5.16, (quart., 1H, J = 1.50 Hz), 3.72, (t, 1Ή,

J = 1.50 Hz), 3.70, (t, 1H, J = 1.50 Hz), 2.51, (s, 2H),

0.98, (s, 9H).

S t u p e HO

Preparation of 3> (2,2-dimethylpropyl) -6-hydroxy-7-propylbenzofuran · ··· ·

The solution prepared by dissolving 1.912 g of 3- (2,2-dimethylpropyl) -6-hydroxy-7-allyl-benzofuran (obtained under the above-described Step G) was mixed in a hydrogenation vessel with the catalyst, i.e. 200.0 mg, 5% palladium and activated carbon.

The resulting reaction mixture was hydrogenated in a Parr apparatus, at a pressure of 0 ', 098 β, for 1.0 hour. After removal of the catalyst from the reaction mixture by filtration through diatomaceous earth, the filtrate was evaporated, and the resulting solid residue, i.e. the desired title compound, was used without further purification.

¹ H-NMR (400 MHz, CRCl 3):?

δ, 7.28, (s, 1H), 7.17, (d, 1H, J = 8.30 Hz), 6.72, (d, 1H, J = 8.40-Hz) ), 4.82, (s, 1H), 2.83 (t, 2H, J =

7.70 Hz) ,. 2.48, (s, 2H) &gt; 1.70, (hex, 2H, J = 9.20 Hz),

0.99, (t, 3H, J = 7.50 Hz), 0.95, (s, 9H).

S 'tupen (I)

Preparation of Methyl-4- (3 - (3- (2,2-dimethylpropyl) -7-propyl 1-benzofuran-6-yloxy) -1-propoxy) phenylacetate

In an analogous manner to that described in Example 1), Step Bi) above, using 3- (2,2-dimethyl-1-propyl) -6-hydroxy-7-propyl-benzofuran (obtained in the preceding step described above) H), as a starting material, the title compound.

¹ H-NMR, (400'MH 2, CECl 2) ::

delta, 7.50-7.42 (m, 4H), 7.31 (d, 2H, J = 8.80 Hz),

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83 (m, 3H),

6, .46, (s, 1H), 4.21 - 4.16, (m, 4H), 3.67, (s, 3H), 3.54, »· · ·

Δ3 (a., 2H), 2.95, (t, 2H, J = 7.40 Hz), 2.29, (quint., 2H,

J = 6.30: Hz), 1.71, (hex, 2H, J = 5.90 Hz), 1.0.1, (t, 3K, J = 7.30 Hz).

Degree <T)

Preparation 5- / 4- (3- (3- ( 2 , 2-dimethylpropyl) -7-propyl-benzofuran-6-yl _O xy) -1-propoxy) / - feny1-2,4-thiazolidinedione

An analogous procedure to that described in Example 1 above, Step O), using methyl 4- (3- (3- (2,2-dimethyl-1-propyl) -7-propyl 1-benzofursn-6-yl) (oxy) -1-propoxy) phenylaeetate (obtained under the preceding "Step I" above) as a starting material, the title compound is obtained.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 8.43, (bs, 1H), 7.32-7.23, (mr., 5H), 6.92, (d.

2H, J = 8.80 Hz), 6.84 (d, 1H, J = 8.60 Hz), 5.32 (s, 1H),

4.19 (apparent quart., 4H, J _gvg = 6.00 Hz), 2.82, (dd, 2H,

J = 7.60, 1.50 Hz), 2.27, (quint., 2H, J = 6.10 Hz), 1.64, (hex, 2H, J = 7.30 Hz), 0, 94, (a., 9H), 0.92, (t, 3H,

J and 7.40 Hz).

Example 6.8)

Preparation of 5- [3- (4- (3- (2,2-Dimethylpropyl) -7-propylbenzofursn-6-yloxy) -1-butoxy)] phenyl-2,4-thiazolidinedione

Τ '/

4 44 4 4 • ·· · ··

4 · * * * I I I I I I

4 4 4 4 4 4 4 4 44 44

£? t u fo A ')

Preparation of methyl-3- (4- (3- (2,2-dimethylaminosaccharin propyl) _{-7-propyl-benzofuran-RA-6-yloxy)} -1-butoxy) -phenyl acetate enylace

In an analogous manner to that described in Example 1, Step B) above, using 3- (2,2-dimethyl-1-propyl) -6-hydroxy-7-propyl-benzofuran (obtained as described above in of Example 67), Step H), as a starting material, the title compound was prepared.

@ ¹ H-NMR (400 MHz, CDCl3): .delta.

delta, 7.50'- 7.42, (m, 4H), 7.31, (di, 2H, J = 8.80 Hz),

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83, (nr., 3H),

6.46, (s, 1H), 4.21-4.16, (m, 4H), 3.67, (s, 3H,),

3.54, (s, 2H), 2.95, (t, 2H, J = 7.40-phiz), 2.29, (quint., 2H, J = 6.30.} Hz), 1.71, <hex, 2H, J = 5.90 Hz), 1.01, (t, 3H, J = 7.30 Hz).

Stupe® B) 444

Preparation of 5- [3- (4- (3- (2,2-dimethylpropyl) -7-propylbenzofuran-6-yloxy) -1-butoxy)] - phenyl-2,4,4-thiazolidinedione

An analogous procedure to that described in Example 1 above, Step C), using methyl 3- (4- (7-propyl-3- (2,2-dimethyl-1-propyl) -benzofuran-6-yl)), (oxy) -1-butoxy) -phenylacetate (obtained under Step A above), as a starting material, the desired title compound.

¹ H-NMR, (400'MHz, CDCl 3) _?

Example 6.9)

Preparation of 5- (3- (4- (3- (2-phenylethyl) -7-propyl-benzofuran-6-yloxy) -1-butoxy)) - phenyl-1-24-thiazolidinedione

O,

HN

• 99 * * 9 9 • • 9 9 9 v v

Stage A)

Preparation of 1- (3-methoxyphenoxy) -4-phenyl-2-butanone

The solution, prepared by dissolving 5.519 g of 1-bromo-4-phenyl-2-butanone (prepared as described in Example 63 above), Step E, in the form of dry-dried dimethylformamide, was first mixed with 3.608 g of 3-bromobutanone. of methoxyphenol, and then

9.481 g, cesium carbonate.

After the resulting reaction mixture was stirred at room temperature for 2.0 hours, it was shaken between isopropyl acetate and phthalate buffer at pH 4.0. After separation of the organic and aqueous phases, the organic layer was washed twice with water, and and dried over magnesium sulfate, and filtered, and concentrated.

The residue was chromatographed on ηβ silica gel, using hexane? ethyl acetate (5.0: 1.0) as eluent.

The title compound was obtained as a yellow solid.

¹ H-NMR, (400 MHz, CEC ₁₃ ):

δ, 7.29-7.14, (mult., 6H), 6.54, (d.d., 1H, J = 8.30,

2.30 Hz), 6.42, (t, 1H, J = 2.40 Hz), 6.39, (dd, 1H, J = 8.10, 2.50 Hz), 4.49, ( s, 2H 1, 3.76, (s, 3H), 2.93, (s, 2H, overlapping dt, 1H), 2.70, (dt, 1H, J = 7.90, 10 , 50Hz)

Grade Bó)

Preparation of 3- (2-phenylethyl) -6-methoxybenzofuran

To the solution prepared by mixing? 10.0 mL of dichloromethane, with 5.68 mL of methanesulfonic acid, and cooled to minus 1.0 ° C, was added dropwise to the solution obtained.

a tt tt9 *

»♦ ·« · _t by dissolving 2,368 g of 1- (3-methoxyphenoxy) -4-phenyl-2-butsnonu (obtained under the foregoing, the above-described Steps AU in 25.0 url dry dichloromethane, and the resulting reaction mixture The reaction mixture was poured rapidly into a vigorously stirred, and cooled mixture, prepared from a mixture of an excess of 5N sodium hydroxide solution and methyl tert-butyl ether. aqueous phase, the organic layer was dried with magnesium sulfate, filtered, and concentrated.

The residue was chromatographed over silica gel, using a gradient elution, with hexane: dichloromethane (4.0: 1.0) to hexane: dichloromethane (1.0: 1.0),

The title compound is obtained in the form of a clear oil.

¹ H-NMR (400 MHz, GDCl 3):

δ, 7.36, (d., 1H, J = 8.50 Hz), 7.31-7.19, (mult., 6H), 7.00, (d., 1H, J = 2.20) Hz), 6.87 (dd, 1H, J = 8,50,2,20 Hz), 3.84 (s., _3H), 3.02 to 2.91 (mult., 4H) .

Grade 0)

Preparation 3 :-( 2-Phenylethyl) -6-hydroxybenzofuran

A solution prepared by dissolving 2.066 g of 3- (2-phenylethyl) 6-methoxybenzofuran (obtained as described in Step E above). in 20.0 mL of dried dichloromethane, cooled to minus 10.0 ° C, was mixed with the solution obtained by dissolving bromine boron in dichloromethane (total 8.40 mL, 1 M bromide boron solution) with stirring.

After 15 minutes, the resulting reaction mixture was allowed to warm to room temperature and stirred for 15.0 minutes. After shaking between isopropyl acetate and pH 7.0 phosphate buffer, the organic and aqueous phases were separated, and the organic layer was washed twice with pH 7.0 buffer, and then dried with magnesium sulfate, filtered, and evaporated.

The residue, as an oily substance, was chromatographed on silica gel using a gradient elution with dichloromethane (100%) to dichloromethane: ethyl acetate (40.0: 1.0).

The title compound was obtained as a pale yellow solid.

@ ¹ H-NMR (400 MHz, CO2):

δ, 7.32, (d, 1H, J = 8.40 Hz), 7.30 - 7.19, (mult., 6H), 6.93, (d, 1H, J = 2.20) Hz), 6.76, (dd, 1H, J = 8.40, 2.20; Hz), 4.88, (bs, 1H;), 3.01-2.90, ( mult., 4H).

Step D)

Preparation of 3- (2-phenylethyl) -6-a-11-yloxybenzene of uranium

To a solution prepared by dissolving 1.128 g of 3- (2-phenylethyl) -6-hydroxybenzofuran (obtained as described above in Step C) in 15.0 ml of dried dimethylformamide was added, with stirring, to 0. 43 ml of allyl bromide and then 1.620 g of cesium carbonate.

After the resulting reaction mixture was stirred at room temperature overnight, the mixture was partitioned between isopropyl acetate, and a phthalate buffer of pH 4.0. After separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with magnesium sulfate, filtered and evaporated.

The title compound was obtained and required no further purification.

· * »« »· · 4444 4 9 4« • * 44 44 4444 • 444 44 444 44 4

4444 44 44 »4 44 4

¹ H-NMR (400 MHz, CDCl 3):

delta, 7.36, (d, 1H, J = 8.60 Hz), 7.30-7.18, (mult., 6ffi), 7in,; (d, 1H, J = 2) 20 Hz), 6.89 (dd, 1H, J = 8.60,

2.30 Hz), 6.13-6.03, (mult., 1H), 5.43. (d, quart., 1H,

J = 17.30, 1.60 Hz), 5.30, (quart. 1H, J = 10.50, 1.40 Hz),

4.57, (t, 1H _: J = 1.50 Hz), 4.56, (tr, 1H, J = 1.50 Hz), 35.01-2.91, (mult. ,, 4H).

Stupem E)

Preparation of 35- (2-phenylethyl) -6-hydroxy-7-allyl-benzofuran

A solution prepared by dissolving 1,245 g of 3- (2-phenylethyl) 6-allyloxybenzofuran (obtained as described above in Step D) in 20.0 ml of 1,2-dichlorobenzene was heated to reflux. under reflux in a nitrogen atmosphere for 11 hours.

After cooling the solution to a temperature of about 50.0 ° C, the solvent was removed under high vacuum until a solid residue was obtained which was dissolved in 100.0 ml of dichloromethane and after subsequent isolation and evaporation it was chromatographed on silica gel. using hexane: ethyl acetate (5.0: 1.0) as eluent.

Evaporation of the appropriate fractions gave the title compound as a pale yellow solid.

¹ H-NMR, (400 MHz, CDCl 3) δ 7.35-7.19, (mult, 7H), 6.82 (d, 1H, J = 8.20 Hz),

6, 12 ,. (mult., 1H), 5.25 - 5.14, (overlapping d.quart., 2H, downward field J% 17.20, 1.70 HzJ in growing field mix <1 4.0-, 19 , 21.60 Hz), ^3.73: (t., IH, J = 1.60 Hz) ♦ 4 · 49 4

9 · 4 4 4 9 9 9 4

4,9444 4 9 4 4

4 4 4 4 4 4 4 4 4 4

4 9 4 4 4 4 9 4 4 5

4444 99 44 44 49 44

770

3.70, (t, 1H, J = 1.60 Hz), 3.06 -2.92, (mult., 4H).

Stupem F)

Preparation of 3- (2-phenylethyl) -6-hydroxy-7-propylbenzofurene

A solution prepared by dissolving 1.116 g of 3- (2-phenylethyl) 6-hydroxy-7-sllyl-benzofurne (obtained as described above in Step E) in 12.0 ml of methyl tert-butyl ether was The reaction mixture was hydrogenated in a Parr apparatus, under a hydrogen pressure of 0.098 MPa, for 0.50 hours.

Thereafter, the reaction mixture was filtered through diatomaceous earth, and the filtrate was evaporated to give the title compound as a yellow oil, which solidified to a slightly yellow, solid, requiring no further purification.

¹ H-NMR, (400 MHz, CUClyl) δ delta, 7.36-7.22, (mult., 7H), 6.78, (d, 1H, J = 8.30 Hz),

5.17, (s, 1H), 3.06-2.95, (mult, 4H), 2.91, (t, 2H,

J = 7.60 Hz), 1.79, (hex, 2H, J = 6.00 Hz), 1.04, (t, 3H,

J = 7.30 Hz).

G)

Preparation of Methyl 1-3- (4- (3- (2-Phenylethyl) -7-propyl-benzofuran-6-yloxy) -1-butoxy) -phenylacetate ♦ * * φ φ φ φ φ φ · · · ♦ ♦ ♦ ♦ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

In an analogous manner to that described in Example 1), Step A) above. using 3- (2-phenylethyl) -6-hydroxy-7-propylbenzofuran (obtained as described above in Step F) as a starting material, the title compound was obtained.

^ H NMR (400 MHz, CBC1 ₃₎ delta 7.50 to 7.42 (m., 4H), 7.31 (d., 2H, J = 8.80 Hz \

7.19-7.16 (d, 2H, J = 8.30 Hz), 6.92-6.83, (m, 3H),

6.46, (s, 1H). 4.21 - 4.16, (m, 4H), 3.67, (s, 3H),

3.54, (s, 2H), 2.95, (t, 2H, J = 7.40 Hz), 2.29, (quint., 2H, J = 6.30 Hz), 1.71 , (hex., 2H, J = 5.90 Hz), 1.01, (t, 3H, J = 7.30 Hz).

S h e p H)

Preparation of 5- [3- (4- (1- (2-phenylethyl) -7-propyl-benzofuran-6-yloxy) -1-hutoxy)] - phenyl-2,4-thiazolidinedione

An analogous procedure to that described in Example T), Step C), using methyl 4- (4- (3- (2-phenylethyl) -7-propylbenzofuran-6-yloxy) -1-butoxy) 1-Phenylacetate (obtained under Step G above) as a starting material, the title compound is obtained. ¹ H-NMR, (400 MHz, CBO 1 -):

delta, 8.67, (bs, 1H), 7.32-7.18, (m, 4H), 6.90, (d.d.,

1H, J = 8.30, 2.50. ¹ Hz), 6.85 (dj, 1H, J = 8.50 Hz), 5.29,

Cs., 1H), 4.14-4.04, (m, 4H), 2.96, (m, 4H), 2.85, (t, 2H, J = 7.60 Hz), 2.00, (broad b, 4H), 1.67, (hex., 2H,

J = 5.60 Hz), 0.94, (t, 3H, J = 7.40 Hz).

4 «····

Example 1 8 d 70)

Preparation of 5- [3- (4- (3- (2-Phenylethyl) -7-propyl-benzothiophen-6-yloxy) -1-butoxy)] -phenyl-2,4-1hi-azole d ind i onu

Stage A)

Preparation of methyl 1-3- (4- (3- (2-phenyl-ethyl) -7-propyl-benzothiophen-6-yloxy) -1-butoxy) -phenylacetate

In an analogous manner to that described in Example 1), Step B), using 3- (2-phenyl-ethyl) -6-hydpoxy-7-propylbenzothiophene (obtained as described in Example 63 above), Step H). ,. as a starting material, the title compound is obtained.

(400 MHz, GDO1):

δ, 7.57, (d, 1H, J = 8.70 Hz), 7.34, (t, 2H, J = 7.30

Hz), 7.28-7.24, (mult., 4H), 7.06, (d, 1H, J = 8.70 Hz).

6.92 - 6.84, (mult, 4H), 4.14, (bd, 2H, J = 5.20 Hz), 4.08, (bd, 2H, J = 5.50 Hz), 3.71, (s, 3H), 3.62, (s, 2H),

3.13-3.06, (mult, 4H), 2.91, (dd, 2H, J = 9.20, 7.60 Hz).

sr; v- ·:

* ♦ · * · * • * · • * 0 0 0 0 0 00 ··>

• ♦ 9 • 000 00 ♦ * · 0 0 0 • 0 * 0 00 00

ZY2

2.05. (B.p., > 4H, .delta. = 2.70 Hz), 1.77, (hex., 2H, J = 7.50 Hz), 1.04, (t, 3H, J = 7.40 (Hz).

Step B)

Preparation of 5- [3- (4- (3- (2-Phenylethyl) -7-propyl-benzothiophen-6-yloxy) -1-butoxy)] - phenyl-2,4,4-thiazolidinedione

An analogous procedure to that described in Example 1), Step O, above was using methyl 3- (4- (3- (2-phenylethyl) -7-propylbenzothiophen-6-yloxy) - 1-Butoxy) -phenylate (obtained under Step A above) as a starting material, the desired title compound is prepared. ¹ H-NMR, (400 MHz, CDCl 3 δ delta, 9.41, (bs, 1H), 7.56 (d, 1H, J = S, 80 Hz), 7.35 7, 20, (mult., 6H), 7.05, (d, 1H, J = 8.80 Hz), 6.99 - 6.85, (mult., 4H), 5.26, (bs. , 1H), 4.1 2 (bs, 2H), 4.07, (bs, 2H), 3.08, (bs, 4H), 2.90, ( bw, 2H, J = 7.50 Hz), 2.04, (bs, 4H), 1.76, (bs, 2H, J = 7.60 Hz);

1.02, (t, 3H, J = 7.30 Hz).

Example; 71)

Preparation of 5- / 4- (3- (3- (2-phenylethyl) -7-propylbenzothiophen-1-oxide 6-yloxy) -1-propoxy) -phenyl 1-2,4- thiazolidinedione

4 W44 · 4

An analogous procedure to that described in Example 66 (Step A) above was using 5- / 3- (4- (3- (2-phenylethyl) -7-propylbenzothiophen-S-yloxy) -1-butoxy) of tert-phenyl-2,4-thiazolidinedione, as a starting material, the title compound.

H-WR ,. (400 MHz, CEC.1 ^ ;; diastereoisomeric pair):

delta, 8.83 (br s, 1H, 7.36 - 7.32 (mult., 4H), 7.28 - 7.20 _(mult.,, 4H) ,. 6.99 - 6.93, (mult., 3H), 6.64, (d., 1H, J =

1.40 Hz), 5.34 (s, 1H), 4.21 (broad t, 4H, J = 5.90 Hz),

3.07-2.92 (mult, 4H), 2.87 (b.p., 2H, J = 7.60 Hz),

2.33, (pent, 2H, J = 5.80 Hz) ,. 1.70, (bs, 2H, J = 7.8Q):

Hz), 1.01, (dt, 3H, J = 7.30, 1.70 Hz).

Priklaď 72)

Preparation of 5- / 4- (3- (2-propyl-4- (4-fluorophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione.

4 • * 9 • 9 • 999 «4

99 99 »· • 9 9 9 9 99 4

49,944 44 ·

49 9 9 44 4 ·· ··

S- t u fo A ')

Preparation of 5- / 4- (3- (2-propyl-4- (4-fluorophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

The title compound was prepared in an analogous manner to that described in Example 22 above, Step G), using 2-propyl-4- (4-fluorophenoxy) -phenol (obtained as described in Example 22 above). 23), Step A) using 4-fluorophenol as starting material), and then following an analogous procedure to that described in Example 23) Step D), ¹ H-NMR, (400 MHz, CDCl 3):

delta, 7.98, (bs, 1H), 7.32, (d, 2H, J = 8.66 Hz), 6.90, (m, 6H), 6.76, (m 3H), 5.37 (a, 1H), 4.17 (t, 2H, J = 4.14 Hz), 4.09, (t, 2H, J = 5.94 Hz) ), 2.52, (k., 2H,

7.50 Hz), 2.26 ,. (t, 2H, J = 0.02 Hz), 1.54 * (m, 2H, 7.50 Hz), 0.88, (t, 3H, J = 7.32 Hz).

Example 733) • 4 • 4444 • 4 * 4444

44 44 44 4 4 4 4

443 44 <44 44 4

44 4444 4444

4444 «44 44 44 44 44

Preparation of 5- [4- (3- (2-propyl-4- (4-tolylsulfonamidophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

Stage A)

Preparation of 2-propyl-4- (4-tolylsulfonamidophenoxy) phenol

A solution prepared by dissolving 5.0 g (33.30 mmol) of 4allyloxyphenol (prepared as described in Example 22 above), Step Aβ. 5.17 g, (36.60 mmol) of 4-fluoro-1-nitrobenzene; 6.90 g, (49.90 mmol) of potassium carbonate, and 20.0 mL of dimethylacetamide were heated to reflux exceeds.

The reaction mixture was then partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and concentrated. The resulting residue was chromatographed on silica gel using dichloromethane and hexane (20% to 50%) as eluent.

Syro obtained 7.30 g, intermediate (i.e., Compound A1), as an yellowish oil, of an oily consistency.

► 9 »·» 9

9999 ·· 9 • • 9. 9

9 * 9 • 9 99

9 9 9

9 9 9 • 9 9

9 9 9 9 9 99 / η

The intermediate, i.e. the compound designated A _1, as a yellow colored solid of oily consistency (7.30 g) obtained in the foregoing context, the operations described above, was pýevedena to 30.0 ml of dichlorobenzene, and the solution was heated under reflux under reflux overnight.

The reaction mixture was then concentrated to a black oil of oily consistency which was chromatographed on silica gel using 1% acetone in hexane as eluent.

4.90 g of intermediate (Compound A1) were obtained as an orange-colored oil.

In the above operation, the compound (A1) obtained in the form of an orange-colored oily consistency (£0.0 g, 3.68 mmol) was dissolved in 5.0 ml of dimethylformamide containing 626.0 mg, ( 9.20 mmol), imidazole.

After addition of 468.0 mg, (4.42 mmol) of t-butyldimethylchlorosiline, the reaction mixture was stirred for 4.0 hours and then partitioned between ethyl acetate and water.

After separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and concentrated to give about 1.50 g of an oily colored oil which was dissolved in 10.0 mL of ethyl acetate. To the resulting solution was added 250.0 mg of palladium on activated carbon, and the reaction mixture was stirred under a hydrogen atmosphere for 45.0 minutes.

The reaction mixture was then filtered through diatomaceous earth, and the filtrate was concentrated,

1.42 of another intermediate, designated Compound (A), was obtained as an orange-orange, oily consistency.

In the previous operation described above, it is obtained »9» 99 ♦ 9 9 · * 9

9 »• 9

9999 99

9,999,93 chen (A ' ₃ ), (700.0 mg, 1.96 mmol), in the form of an orange-colored oily consistency, was dissolved in 5.0 ml of dichloromethane and 0.40 ml, (4.90 mmol), pyridine, and 448.0 mg, (2.35 mmol), tosyl chloride, ieptoluenesulfonyl chloride, and 10.0 mg, a, dim-dimethylaminopyridine, were added, and the resulting reaction mixture was stirred over night.

Then the reaction mixture was partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and concentrated.

800.0 mg of another intermediate, designated Compound (A), was obtained as an orange-colored substance, oily in consistency.

In the above-described operation, compound (A), prepared as described above, was prepared. After dissolution in 5.0 mL of tetrahydrofuran, cooled to 0 ° C, t-butylammonium fluoride was added to the resulting solution, and the resulting reaction mixture was stirred for 2.0 hours.

Then, the reaction mixture was partitioned between ethyl acetate, and water, and after separation of the organic and aqueous phases, the organic layer was dried with sodium sulfate, and concentrated.

440.0 mg of the title compound are obtained in the form of an orange-colored substance, having an oily consistency, i.e. 2-propyl-4- (4-tolylsulfonamidophenoxy) phenol.

¹ H-NME, (400 MHz, CDCl 3): δ, 7.37, (d, 2H), 6.92, (d, 2H), 6.85, (m, 3H), 6, 79, (bs, 2H), 7.41, (bs, 1H), 3.04, (s, 3H), 2.57, (t, 2H). 1.65, (m, 2H), 0.97, (t, 3H).

φφ φφφφ

429 • «φφφφ

ΦΦ «9 • Φ · ΦΦ φφ • φ · φ · · • φ φ

«• φφφφ φ * φφ

Stage Β)

Preparation of ethyl 1-4- (3- (2-propyl-4- (4-tolylsulfonamidophenoxy) phenoxy) propoxy) manganese

In an analogous manner to that described in Example 22 above, Step G), using 2-propyl-4- (4-tolylsulfonamidophenoxy) phenol, (19.0 g, 62.00 mmol), (obtained in the foregoing, above) as described in Step A), and ethyl 4- (3-bromopropoxy) -mandelate (19.50 g, 58.90 mmol) (prepared as described in Example 22 above), Step B) as starting materials, Prepared title compound® »

Stage C)

Preparation of ethyl-alpha-chloro-4- (3- (2-propyl-4- (4-tolylsulfonemidophenoxy) phenoxy) propoxy) phenylacetate

In an analogous manner to that described in Example 22, Step G, above, ethyl 1-4- (3- (2-propyl-4- (4-tolylsulfonamido-phenoxy) phenoxy) propoxy) -mandelate was ( 16.80 g (20.18 mmol) obtained as described above in Step B) as a starting material, the title compound is obtained.

¹ H-NMR, (400MHz, CDCl 3):

δ, 7.37, (d, 2H), 7.23, (m, 6H), 6.91, (d, 2H),

6.82 (m, 3H), 6.73 (bs, 2H), 5.27 (bs, 1H), 4.73 (bs, 1H), 4.20, (m, 2H), 3.93, (t, 2H), 3.84, (t,

2H), 2.85, (s, 3H), 2.57, (t, 2H), 1.93, (m, 2H),

1.05, (t, 3H), 0.95, (t, 3H).

// 0

9 9

9

9999 ·· ·· ·· • 9 9 9 9

9 9

Μ

99

Degree Π)

Preparation of 5- [4- (3- (2-propyl-4- (4-tolylsulfonamidophenoxy) phenoxy) propoxy) phenyl] -2,4-thiazolidinedione

An analogous procedure to that described in Example 1) (Step C), second paragraph) was using ethyl-alpha-chloro-4- (3- (2-propyl-4- (4-tolylsulfonimidophenoxy) phenoxy) propoxy). Phenylacetate, obtained as described above in Step C), as a starting material, to obtain the title compound.

¹ H-NMR , (400 Mffiz, , cnci ₃ ): delta, 8.0b, (s.s. ,, 1H) »» 7.29, (d. , 2H) r 7.23 T (m., 6H), 6,89, (m, 2H) 6,85, ( m, 3H) _; 6,72, ( š.s. r 2H:), 5.30, (3., 1H), 4.67, (š.s. > 1H), 4.01 ,. (i.e. »» 2H) r 3.84, (t, 2H), 2.88, (p., 3H), 2, 57, (i.e. 2H) ,. b »98, ( m, 2H). 1 (m., 2H), 0.97, (i.e., 3H ').

Example) 74)

Preparation of 5- / 4- (3- (2-propyl-4-pyrazinyloxyphenoxy) propoxy) phenyl / 2,4-thiazolidinedione

S t u p e A)

Preparation of 2-propyl-4-pyrazinyloxyphenol

The title compound was prepared using an analogous procedure to that described above in Example 73) "Step A), except that chlorpyrazine was used as the starting material in place of 4-fluoronitrobenzene.

¹ H-NMR, (400 MHz, CDCl 3):

δ, 8.36, (s, 1H), 8.21, (s, 1H), 8.10, (d, 1H),

6.90, (d, 1H), 6.82, (m, 1H), 6.74, (d, 1H), 5.67, (bs, 1H), 2.55, (t, 2H), 1.59, (m, 2H), 0.95, (t, 3H).

Step B)

Preparation of ethyl 4- (3- (2-propyl-4-pyrazinyloxyphenoxy) propoxy) mandelate

In an analogous manner to that described in Example 22), Step O), 2-propyl-4-pyrimidinyloxyphenol (19.0 g, 62.0 mmol) was obtained as described in Step A) above. and 19.50 g, (58.90 mmol) of ethyl 4- (3-bromopropoxy) mandelate (prepared in an analogous manner to that described in Example 22 above), Step O), as starting materials, in the desired form, the title compound.

Stage C) · · · · · · · · · · · · · · · · · · · · · · · · · ·

/ AZ.

Preparation of ethyl alpha-chloro-4- (3- (2-propyl-4-pyrazinoyloxyphenoxy) propoxy) phenylacetate

An analogous procedure to that described in Example 22 above, Step D), using 16.80 g, (30.18 mmol), ethyl 4- (3- (2-propyl-4-pyrazinyloxy-phenoxy) propoxy) mandelate (obtained under Step B above) as a starting material, the title compound is obtained.

Grade: ^Ώ ·)

Preparation of 5- / 4- (3- (2-propyl-4-pyrazinoyloxyphenyl) propoxy) phenyl / 2,4-thiazolidinedione

In an analogous manner to that described in Example 1) (Step O), second paragraph), using ethyl-alpha-chloro-4- (3- (2-propyl-4-pyrazinyloxyphenoxy) propoxy) phenylate as the starting material , the title compound is obtained.

¹ H-NMR, (400 MHz, GDG 1 →):

delta, 8.35 ,. (s, 1H), 8.20, (s, 1H), 8.07, (d, 1H),

7.95 (bs, 1H), 7.32. (D., 2H), 6.93 (m., 3H), 6.85 (m.,. 2H), 5.32 _row (s., 1H), 4 .17 "(m., 4H), 2.55 (t,

2H), 2.26, (m, 2H), 1.57, (m, 2H), 0.90, (t, 3H).

Example 75)

Preparation of 5- / 3- (3- (2-cyclopropylmethyl-4-phenoxy) propoxy) phenyl / 2,4-thiazolidinedione

Stage A)

Preparation of 2-O-cyclopropylmethyl-4-phenoxyphenol

To a solution prepared by dissolving 1.00 g (4.45 mmol) of 2-allyloxy-4-phenoxyphenol (International Patent Application WO87 / 28.115) in ethyl ether, and cooled to 0 ° C, was under nitrogen atmosphere. 20.0 ml of a diszomethane solution, 0.70 M solution in ethyl ether) were added, and palladium acetate (catal. 2.0 mg) was added to the resulting reaction mixture bvlc after stirring for five minutes. diazomethane (6.0 mL, 0.70M solution in ether) and the reaction mixture was stirred at room temperature for 30.0 minutes.

Then, the reaction mixture was filtered through a pad of diatomaceous earth, and ether was removed from the filtrate in vacuo. The residue was purified on a silica gel flash column using 10% ethyl acetate in hexane. After evaporation of the purified fractions, the solvent was removed in vacuo to give the title compound.

¹ H-NMR, (400 MHz, CDCl 3):?

δ, 7.32-6.77, (ar., 8H), 4.82, (s, 1H), 2.53, (d, 2H, J = 6.65 Hz), 0.55, (m, 2H).

Grade®)

Preparation of 5- / 3- (3- (2-cyclopropylmethyl-4-phenoxy) propoxy) phenyl) 2,4-thiazolidinedione

An analogous procedure to that described in Example 2 (2) (Stages B) through D) above was using methyl 3- (3-bromopropoxy) Mendelate, and 2-cyclopropylmethyl-4-phenoxyphenol, ( prepared as described above in Step A) as a starting material, to obtain the title compound.

¹ H-NMR, (400 MHz, CDCl 3):?

δ, 7.35 - 6.83, (ar., 12H), 5.33, (s, 1H), 4.16, (m, 4H), 2.52, (d, 2H, J = 6.87 H), 2.27, (quint., 2H, J = 6.04 Hz), 0.47, (m, 2H), 0.12, (m, 2H).

Claims (27)

PATENT CLAIMS Arylthiazolidinedione derivatives of the general formula I HN ^ / AH-Y-CH = CHsVcHrX -Ar ² wherein Ar ¹ is a 1. Arylene or 2. a heteroarylene group, these groups being optionally substituted by 1 to 4 groups of substituents R ^a , Ar ² is 1. ortho-substituted aryl or 2. an ortho-substituted heteroaryl wherein the ortho substituents are selected from R and the aryl and heteroaryl groups are optionally further substituted with 1 to 4 groups independently selected from the group of substituents R ^a , X and Y independently represent O, S, NR ^b , or CH 2, Z is an oxygen or sulfur atom, n is an integer of 0 to 3, R is (C 1 -C 10) alkyl optionally substituted with (C 1 -C 4) halogen and (C 3 -C 6) cycloalkyl; 2. C 3 -C 10 alkenyl; or 3. C 3 to C 8 cycloalkyl; R ^a represents 1. alkanoyl of 1 to 5 carbon atoms, 2. alkyl of 1 to 15 carbon atoms, 3. alkenyl of 2 to 15 carbon atoms, · · alk alk 2 2 enyl enyl enyl enyl enyl enyl enyl alk alk alk alk · · · · · · · · · · · · · · · · · · · · · · · · JK 4. C 2 to C 15 alkynyl; 5. halogen atom, 6. OR ^b , 7. aryl, or 8. heteroaryl, wherein the alkyl, alkenyl, alkynyl and alkanoyl groups are optionally substituted with 1 to 5 R ^c groups and the aryl and heteroaryl groups are optionally substituted with 1 to 5 R ^d groups; R ^b is 1. a hydrogen atom, 2. alkyl of 1 to 10 carbon atoms, 3. alkenyl of 2 to 10 carbon atoms; 4. C 2 to C 10 alkynyl; 5. aryl, 6. heteroaryl, 7. arylalkyl of 1 to 15 carbon atoms in the alkyl moiety; 8. heteroaryl having 1 to 15 carbon atoms in the alkyl moiety; 9. C 1 -C 15 alkanoyl; 10. C 3 -C 8 -cycloalkyl, wherein the alkyl, alkenyl, alkynyl radicals are optionally substituted; substituted with 1 to 4 R ^c substituents and the cycloalkyl, aryl and heteroaryl radicals are optionally substituted. substituted with 1 to 4 substituents independently selected from R ^d , R ^c is 1. halogen, 2. aryl, 3. heteroaryl, 4. cyano, 5. nitro, 6. OR ^f , 7. S (O) _m R ^f , where m = 0, 1 or 2, provided that when m is 1 or 2, R ^{f has a} meaning other than H, 8. NR ^f R ^f , • · ··· · ♦ · 9. NR ^f COR ^f 10. NR ^f CO ₂ R ^f 11. NR ^f CON (R ^f ) ₂ , 12. NR ^f SO ₂ R ^f , provided that R ^{f is} not H, 13. COR ^f , 14. CO ₂ R ^f 15. CON (R ^f ) ₂ 16. SO ₂ N (R ^f ) ₂ 17. OCON (R ^f ) ₂ , or 18th cycloalkyl of 3-8 carbon atoms, said cycloalkyl, aryl and heteroaryl are optionally substituted by 1 to 3 halogen atoms or alkyl groups of 1-6 0 carbon atoms, R ^d represents a first group R ^c, 2. alkyl of 1 to 10 carbon atoms, 3. alkenyl of 2 to 10 carbon atoms; 4. C 2 to C 10 alkynyl; 5. arylalkyl of 1 to 10 carbon atoms in the alkyl moiety; 6. C 1 -C 10 heteroarylalkyl, wherein alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted with a group independently selected from R ^e ; R ^e represents 1. halogen atom, 2. amino, 3. a carboxyl group, 4. alkyl of 1 to 4 carbon atoms, 5. C 1 -C 4 alkoxy; 6. hydroxy, 7. aryl, 8. arylalkyl of 1 to 4 carbon atoms; 9. aryloxy, R ^f is 1. a hydrogen atom, 2. alkyl of 1 to 10 carbon atoms; 3. alkenyl of 2 to 10 carbon atoms; 4. C 2 to C 10 alkynyl; 5. aryl, 6. heteroaryl, 7. arylalkyl of 1 to 15 carbon atoms in the alkyl moiety. 8. heteroarylalkyl of 1 to 15 carbon atoms in the alkyl moiety 9. C 1 -C 15 alkanoyl; 10. C 3 -C 8 cycloalkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with 1 to 4 substituents R ^e as well as pharmaceutically acceptable salts thereof. Arylthiazolidinedione derivatives of the general formula I according to claim 1, in which Z represents a sulfur atom. Arylthiazolidindionové third derivatives of the formula I according to claim 1, wherein Ar ¹ is arylene optionally substituted with 1-4 groups of R ^a. Arylthiazolidinedione derivatives of the general formula I according to claim 3, in which Ar ¹ represents a phenylene group, optionally substituted with 1 to 2 groups selected from halogen and 1 to 4 carbon atoms. Arylthiazolidinedione derivatives of the general formula I according to claim 1, in which X and Y are independently CH ₂ , O or S. Arylthiazolidinedione derivatives of the general formula I according to claim 5, in which X and Y are oxygen atoms. 44 4444 Arylthiazolidinedione derivatives of the general formula I according to claim 1, in which Ar ² represents a group (R ^a ') o wherein R ^a represents R ^a or forms 2 R groups ^and on adjacent carbon atoms with these atoms a 5- or 6-membered aromatic ring containing 0-2 heteroatoms selected from N, O and S (O) _m wherein m is 0-2, the ring being optionally substituted with 1-2 groups of R ^a. Arylthiazolidinedione derivatives of the general formula I according to claim 7, in which R represents alkyl of 3 to 4 carbon atoms. 9th Arylthiazolidindionové derivatives of formula I according to claim 7, wherein Ra ^'is OR ^b, aryl optionally substituted with 1-5 substituents independently selected from R ^d and alkyl of 1 to 15 carbon atoms, optionally substituted with 1 to 5 groups, independently selected from R ^c . 10th Arylthiazolidindionové derivatives of formula I according to claim 7, wherein the two R groups ^and adjacent carbon atoms form with these atoms a 5- or 6-membered aromatic ring containing 1-2 heteroatoms selected from N, O and S (O) _m wherein m is 0-2, the ring being optionally substituted with 1-2 groups of R ^a. Arylthiazolidinedione derivatives of the general formula I according to claim 7, in which R ^a represents O-phenyl, wherein the phenyl is optionally substituted by 1 to 4 groups from R ^d , phenyl optionally substituted by 1 to 2 halogen atoms or alkyl of 1 to 5 atoms. carbon, eventually φφ φφφφ Φ Φ Φ Φ 2θο φφ φφ> 4 4>> Φ ·· substituted by 1 to 5 groups independently selected from halogen, phenyl and cycloalkyl of 3 to 8 carbon atoms. Arylthiazolidinedione derivatives of the general formula I according to claim 7, in which the two R groups ^and on adjacent carbon atoms form, with these atoms, a 5- or 6-membered aromatic ring selected from isoxazole, thiophene, S-oxide and S-dioxide or furan. wherein the rings are optionally substituted with one to two R groups ^and Arylthiazolidinedione derivatives of the general formula I according to claim 1, in which n is 1 or 2. Arylthiazolidinedione derivatives of the general formula Ia according to claim 1, ^and represents R ^a or forms two R groups ^and on adjacent carbon atoms with these atoms a 5- or 6-membered aromatic ring containing 0-2 heteroatoms from N, O and S ( O) _m , wherein m is 0 to 2, said ring being optionally substituted with 1 to 2 substituents from group j , Y, Z, n, ^and R and R are as defined in claim 1. Arylthiazolidinedione derivatives of the general formula Ia according to claim 14, in which Z represents a sulfur atom. 99,999 • 9 · 9,999 * 9 · 9,9 9 99 9999 201 .............. Arylthiazolidinedione derivatives of the general formula Ia according to claim 14, wherein Y represents a sulfur atom or an oxygen atom and X represents an oxygen atom. 17. Arylthiazolidinedione derivatives of the general formula Ia according to claim 14, in which R represents alkyl of 3 to 4 carbon atoms. Arylthiazolidinedione derivatives of the general formula Ia according to claim 14, wherein n is 1 or 2. Arylthiazolidinedione derivatives of the general formula Ia according to claim 14, in which Z is a sulfur atom, X is an oxygen atom, Y represents 1. oxygen atom or 2. sulfur atom, R is alkyl of 3 to 4 carbon atoms, R ^a represents 1 halogen atom or 2. alkyl of 1 to 5 carbon atoms, R ^a is 1. O-aryl, optionally substituted with 1 to 3 groups independently selected from R ^d , 2. aryl, optionally substituted with 1 to 3 R ^d groups, 3rd alkyl of 1-5 carbon atoms, substituted with 1-5 R ^C groups, or is the group R 2 ^and on adjacent carbon atoms together with those atoms A 5- or 6-membered aromatic ring containing 0 to 2 heteroatoms from N, O and S (O) _m , wherein m is 0 to 2, which ring is optionally substituted with 1 to 2 R ^d groups. ·· · ♦ · · 2. & L Arylthiazolidinedione derivatives of the general formula I according to claim 1 1 from the group of Tables 1, 2 and 3 below Table 1. 4 4 4 4 4 4 4 3 4 4 • • t t t t t t t »» »» »· · · · · · · · · · · ············ Y-L-X A / B Ra O (CH 2) 3 O O / CH Ph O (CH 2) 3 O 0 / CH CH 2 C (CH 3) 3 O (CH 2) 40 O / CH CH 2 C (CH 3) 3 O (CH 2) 40 0 / CH (CH2) 2Ph O (CH 2) 3 O HE Ph O (CH 2) 3 O O / N ' CH 2 C (CH 3) 3 O (CH 2) 3 O HE CF3 O (CH 2) 3 O HE (CH2) 2Pk O (CH 2) 3 O HE (CH2) 4Ph O (CH 2) 3 O HE CH2-c-Hex ** O (CH 2) 3 O HE CH 2 C (CH 3) 2 Ph O (CH 2) 40 HE CF3 O (CH 2) 3 O S / CH (CH2) 2Ph O (CH 2) 40 S / CH (CH2) 2Ph O (CH 2) 40 SO / CH (CH2) 2Ph O (CH 2) 3 O SO / CH (CH 2) 2? H O (CH 2) 3 O SO2 / CH Ph O (CH 2) 40 SO2 / CH (CH2) 2Ph O (CH 2) 3 O SO2 / CH (CH2) 2Ph 9 9 9. 99 49 «9 99 90 99 9 · 4 · 9409 4 4 44 94 4949 • * 90 90 99 2,0 $ .............. * instead of attaching the group Y to the phenyl ring, ** c-Hex means cyclohexyl Table 2 OF Ra * Y-L-X R ** Rd with H 4 O (CH 2) 3 O propyl 4 ’ H with 3-C1 4 O (CH 2) 3 O propyl 4 ’ H with 3-F 4 O (CH ₂ ) 3 O propyl 4 ’ H with 3-propyl 4 O (CH 2) 3 O propyl 4 ’ H with 3-C1 4 S (CH 2) 3 O propyl 4 ’ H with 3-C1 4 O (CH 2) 40 propyl 4 ’ H with 3-propyl 4 O (CH 2) 40 propyl 4 ’ H with H 4 O (CH 2) 40 propyl 4 ’ H with H 3 O (CH 2) 3 O propyl 4 ’ H with H 3 O (CH 2) 40 propyl 4 ’ H 0 H 3 O (CH 2) 3 O propyl 4 ’ H 0 H 4 O (CH 2) 3 O propyl 4 ’ H with H 4 O (CH 2) 3 O propyl 4 ’ 4-SO2CH3 with H 4 O (CH 2) 3 O propyl 4 ’ 4-CH3 with H 4 O (CH 2) 3 O propyl 4 ’ 4-C1 with H 4 O (CH ₂ ) 3 O propyl 4 ’ 4-Ph with H 3 O (CH 2) 3 O propyl 4 ’ 4-OCH3 with H 3 O (CH 2) 3 O propyl 4 ’ 4-F with H 3 (CH ₂ ) 40 propyl 4 ’ H 99 ············ 44 4 4 4 ·· 443 · 4 44 44 ·· 4444 4,444 4 · 444 4 · 44 4444 4 ··· 4444 44 ·· 44 4 · ·· ζ Ra * Y-L-X WITH Η 4 (CH ₂ ) 40 WITH Η 4 (CH 2) 40 WITH Η 3 (CH 2) 40 WITH Η 3 (CH2) 50 WITH Η 3 (CH2) 50 WITH Η 3 (CH2) 50 WITH Η 3 O (CH 2) 5 WITH Η 4 O (CH 2) 4 WITH Η 3 O (CH ₂ ) 4 WITH Η 3 O (CH 2) 5 WITH Η 3 O (CH 2) 3 O WITH Η 4 O (CH 2) 3 O WITH Η 3 O (CH 2) 3 O WITH Η 3 O (CH 2) 3 O WITH 3-propyl 4 O (CH 2) 3 O WITH Η 4 O (CH 2) 40 WITH Η 4 O (CH 2) 40 WITH Η 3 O (CH 2) 40 WITH Η 3 O (CH ₂ ) 40 WITH Η 3 O (CH 2) 3 O WITH Η 3 O (CH 2) 40 WITH Η 4 O (CH 2) 3 O WITH Η 4 O (CH 2) 3 O WITH Η 3 O (CH 2) 40 WITH Η 3 O (CH 2) 3 O WITH Η 3 O (CH 2) 3 O WITH Η 3 O (CH 2) 3 O WITH Η 4 O (CH 2) 3 O WITH Η 4 O (CH 2) 3 O WITH Η 3 O (CH 2) 3 O R propyl ** 4 ’ Rd 4-OCH3 propyl 4 ’ 4-C1 propyl 4 ’ 4-C1 propyl 4 ’ H propyl 4 ’ 4-OCH3 propyl 4 ’ 4-F propyl 4 ’ 4-Ph propyl 4 ’ 4-OCH3 propyl 4 ’ 4-F propyl 4 ’ 4-C1 propyl 4 ’ 3-CH3-4-C1 propyl 4 ’ 4-CH 2 CH (CH 3) 2 propyl 4 ’ 4-C-pentyl propyl 4 ’ 4-CH (CH 3) 2 propyl 4 ’ 4-OCH3 propyl 4 ’ 4-OCH3 propyl 4 ’ 4-F propyl 4 ’ 4-OCH3 propyl 4 ’ 4-C1 propyl 4 ’ 4-SO2CH3 propyl 4 ’ 4-SO2CH3 propyl 5 ’ H propyl 3 ’ H propyl 3 ’ H allyl 4 ’  H 3-F-propyl 4 ' H propyl 4 ’ 4-CO 2 CH 2 CH 3 propyl 4 ’ 4-F propyl 4 ’ 4- (4´-tolylsulfone · amide) c-pr-CH2t 4 ’ H In »00« 0 2ί> $ 00 00 00 00 0 «0 0000 000« 0 · 00 00 000 «• 000 00 000 00 0 0 00 0000 0000 0000 00 00 00 00 phenyl ring, + c-pr represents cyclopropyl, Table 3. * n Ra (l) Ra (2) 4 3 4-F-Ph H. 3 3 2-naphthyloxy H 3 3 2- dib enz ofuranyl H 3 3 phenoxy propyl 4 3 3-isoxazolyl H 3 4 3-isoxazolyl H 4 3 pyrazinyloxy H * instead of attaching an oxygen atom to the phenyl ring. 21. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) according to claim 1 together with a pharmaceutically acceptable carrier. 22. A method of treating, ameliorating or preventing diabetes in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I). 23. A method of treating, ameliorating, or preventing hyperglycemia in a mammal, comprising administering to the mammal an effective amount of a compound of Formula I. «· ··« · 99 • 4 ·· 49 99 4 4 4 4 4 4 4 9 4 »4 4 4 4 4 44 4 9 4 4 9 4 9 4 4 · 4 · 4 9 4 9 4 444 44 44 44 94 24. A method of treating, ameliorating or preventing hyperlipidemia in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I). 25. A method of treating, ameliorating or preventing obesity in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I). 26. A method of treating, ameliorating or preventing hypercholesterolemia in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I). 27. A method of treating, ameliorating or preventing hypertriglyceridemia in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I).