CZ20002286A3 - Arylthiazolidinedione derivatives - Google Patents

Abstract

Arylthiazolidinedione derivatives of general formula I, in which individual symbols have specific meanings, are effective agonists of the PPAR receptor and can therefore be used in the form of a pharmaceutical composition, which also forms part of a solution, for the treatment, alleviation or prevention of diabetes, hyperglycemia, hyperlipidemia including hypercholesterolemia and hypertriglyceridemia, atherosclerosis, obesity, vascular restenosis and similar diseases, disorders and conditions in the development of which PPAR is involved.

Description

Technical area

Arylthiazolidinedione derivatives and their pharmaceutically acceptable salts. These substances are particularly effective as PPAR agonists. The invention also provides a method for producing these substances and a pharmaceutical composition containing them.

State of the art

Diabetes is a disease that is caused by a variety of causes and is manifested mainly by an increased concentration of glucose in the blood plasma, hyperglycemia. If this condition is not treated, the disease progresses and there is an increased and premature mortality of patients due to the increased risk of damage to small and large vessels, resulting in nephropathy, neuropathy, hypertension, retinopathy, stroke and heart disease. For this reason, controlling the concentration of glucose 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, the patient produces little or no insulin. In type II diabetes, which is not insulin-dependent, NIDDM, patients often have insulin concentrations in the blood that correspond to healthy individuals and in some cases are even higher. However, in these patients, tissues that are normally sensitive to insulin have developed resistance to its action, so that glucose and lipid metabolism in muscles, liver and adipose tissue in particular is affected, and normal plasma insulin concentrations are insufficient to overcome tissue resistance.

• · · · * ·

Insulin resistance is not primarily caused by a reduction in the number of insulin receptors, but rather by a defect in postinsulin receptor binding, which is not yet satisfactorily explained. The resulting insulin resistance results in insufficient activation of glucose after its intake, insufficient oxidation and storage in muscle, and also insufficient suppression of lipolysis in adipose tissue and glucose production and secretion in liver tissue.

The current treatment for NIDDM has not changed much in recent years and has its limitations. Exercise and a reduced food intake dramatically improve this type of diabetes, but patients are usually unwilling to change their lifestyle. This type of diabetes usually develops in people with sedentary jobs and increased body weight, especially in the case of a high-fat diet. Increasing the concentration of insulin in the plasma, by administering sulfonylurea derivatives such as tolbutamide or glipizide, which stimulate the beta cells of the pancreas to secrete more insulin, or by injecting insulin, can ensure sufficient concentration of this substance to stimulate resistant tissues. However, this treatment method can lead to a dangerous decrease in the concentration of glucose in the blood plasma and usually also further increases insulin resistance, so that even its increased concentrations are insufficient. Biguanide derivatives increase the sensitivity of tissues to insulin and may have a beneficial effect. These substances, especially phenformin and metformin, can cause acidosis due to the presence of lactic acid, as well as vomiting and diarrhea.

Glitazones, such as 5-benzylthiazolidine-2,4-diones, are a newer class of agents with a somewhat different mode of improving the symptoms of NIDDM. These agents substantially increase the sensitivity of muscle, liver, and adipose tissue to insulin in an animal model of the disease and can completely correct elevated glucose, triglyceride, and nonesterified fatty acid concentrations without the risk of hypoglycemia.

Hyperlipidemia is a condition characterized by an abnormal increase in the concentration of lipids in the blood serum. These are mainly cholesterol, triglycerides and phospholipids. These lipids are not in solution in the blood plasma, but are bound to proteins and transported as macromolecular complexes, referred to as lipoproteins. These phenomena have been described in the Merck Manual, 16th edition 1992, e.g. 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 treatment for this condition, a diet is often adjusted to a low intake of fat and cholesterol, and physical exercise is recommended. If these measures are not sufficient, medications are administered. LDL is commonly referred to as the “bad” cholesterol, while HDL has a beneficial effect. Although it is desirable to reduce the increased concentration of LDL cholesterol, it is also desirable to increase the concentration of HDL cholesterol. It has been shown that an increased concentration of HDL is associated with a lower risk of coronary artery disease, as described in 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 a substance that increases HDL is nicotinic acid, but the amount of this acid needed for this purpose is associated with adverse effects, e.g., the development of fleeting rashes.

Peroxisome proliferation-enhancing agents are substances with various structures that, when administered to rodents, cause a dramatic increase in • φ • · φ φ

φ • ΦΦΦ

The number of peroxisomes in the liver and kidneys and their enlargement are increased, and at the same time the capacity of peroxisomes to metabolize fatty acids is also increased through increased expression of beta-oxidation cycle enzymes. Compounds from this group include fibrates, which also reduce the concentration of fats in the blood serum, herbicides and some phthalates. Peroxisome proliferation can also be induced by dietary and physiological factors, such as a diet rich in fats and exposure to cold.

Three subtypes of receptors have been identified so far that are activated by peroxisome proliferator-activated receptors. These receptors are called PPARs. They are the alpha receptor, PPARalpha, the gamma receptor, PPARgamma, and the delta receptor, PPARdelta. The identification of the PPARalpha receptor, which belongs to the nuclear hormone receptor activated by peroxisome proliferator-activated receptors, has facilitated the analysis of the mechanism of the proliferation-promoting agents. The PPARalpha receptor is activated by a number of medium- and long-chain fatty acids and is involved in the stimulation of fatty acid beta-oxidation. This receptor is also involved in the activity of fibrates and fatty acids in rodents and humans. Derivatives of these substances, such as clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate, and etofibrate, as well as gemfibrozil, produce a significant reduction in plasma triglyceride concentrations and a modest reduction in LDL cholesterol and are used in particular for the treatment of hypertriglyceridemia.

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

An example of a gene that responds to PPARgamma2 is the tissue-specific adipocyte P2 gene. Although peroxisome proliferator-activated receptors, including fibrates and fatty acids, also activate PPAR transcriptional activity, only prostaglandin _J2 derivatives have been identified as natural ligands for the PPARgamma subtype, and these derivatives can also bind thiazolidinedione antidiabetic agents with high affinity.

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

International patent application WO 96/01430 describes a subtype of human PPAR, hNUCIB. The amino acid sequence of this substance is different from human PPARdelta, referred to as hNUC1, differing by a single amino acid residue, namely an alamin at position 292. Based on in vivo experiments, the authors believe that the hNUCIB protein suppresses the activity of hPPARα and the activity of thyroid hormone receptors.

International patent application WO 97/28149 states that a group of PPARdelta agonists can increase plasma HDL concentration. According to patent applications WO 97/27857, 97/28115, 97/28137 and 97/27847, some groups of substances can be used as antidiabetic ·· ΒΒΒΒΒ ·· · ΒΒΒΒΒ Β • · · · · Β • · · · Β Β Β ΒΒΒΒΒ

6· · · ΒΒΒΒΒ Β • ΒΒΒ ΒΒΒ Β· ·Β substances, substances promoting weight loss, antisclerotic substances and antihyperlipidemic substances, all of which may act via PPAR activation.

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

All glitazones that have progressed to human clinical trials, and almost all glitazones described in the literature, have an aryl group at the 5-position of the thiazolidinedione linked through one carbon atom. Although several compounds have been prepared in which the 4-(oxy)phenyl group is linked directly to the 5-position of the thiazolidinedione, these compounds have not shown hypoglycemic activity.

Thus, it was shown that 5-/5-/2-(2-benzoxazolylmethylamino)ethoxy/phenyl/-2,4-thiazolidinedione of formula 1 has no antihyperglycemic activity in ob/ob mice, and it was shown that relatively high PPARgamma activation is required for this substance according to 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

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

Another compound, 5-/4-(phenylethoxy)phenyl/-2,4-thiazolidinedione of formula 2, had no antihyperglycemic effect in a mouse model of diabetes, although it reduced the activity of aldose reductase. According to Sohda et al., Chem. Pharm. Bull, 1982, 30, 3580-3600, and Sohda et al. Chem. Pharm. Bull. 1982, 30, 3601-3616. As an example of other aldose reductase inhibitors from the phenylthiazolidinedione group, 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 Sohda et al., Chem. Pharm. Bull., 1982, 30, 3601-3616 may be mentioned.

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

( _CH2 ) _n

O

X.

Ri

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

4 4 4 4444

4 44 44 44

It has now been found, quite unexpectedly, that some substituted

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

The essence of the invention

The invention consists of arylthiazolidinedione derivatives of the general formula I

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

Ar ¹ represents 1. an arylene group or

2. a heteroarylene group, wherein these groups are optionally substituted with 1 to 4 groups from the group of substituents R ^a ,

Ar ² represents 1. ortho-substituted aryl or

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

9 4 99 • 9 4 4

94

4 9

4 4

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

Z represents an oxygen or sulfur atom, n represents an integer from 0 to 3,

R represents 1. alkyl of 3 to 10 carbon atoms, optionally substituted with 1 to 4 groups from the group of halogen atom and cycloalkyl of 3 to 6 carbon atoms,

2. alkenyl of 3 to 10 carbon atoms or

3. cycloalkyl of 3 to 8 carbon atoms,

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. alkynyl of 2 to 15 carbon atoms,

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 represents 1. a hydrogen atom,

2. alkyl of 1 to 10 carbon atoms,

3. alkenyl of 2 to 10 carbon atoms,

4. alkynyl of 2 to 10 carbon atoms,

5. aryl,

6. heteroaryl,

7. arylalkyl with 1 to 15 carbon atoms in the alkyl part,

8. heteroaryl with 1 to 15 carbon atoms in the alkyl part,

9. alkanoyl of 1 to 15 carbon atoms,

10. cycloalkyl of 3 to 8 carbon atoms, wherein the alkyl, alkenyl, alkynyl residues are optionally substituted with 1 to 4 substituents ^{R c and} the cycloalkyl, aryl and ·· ·· • ·

R ^c represents 1. a halogen atom,

2. aryl,

3. heteroaryl,

4. cyano group,

5. nitro group,

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 does not represent 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 with 1 to 3 halogen atoms or alkyl groups of 1 to 6 carbon atoms, R ^d represents 1. the group R ^c ,

2. alkyl of 1 to 10 carbon atoms,

3. alkenyl of 2 to 10 carbon atoms,

4. alkynyl of 2 to 10 carbon atoms,

5. arylalkyl with 1 to 10 carbon atoms in the alkyl part,

6. heteroarylalkyl of 1 to 10 carbon atoms in the alkyl portion, wherein the alkyl, alkenyl, alkynyl, aryl and heteroaryl are optionally substituted with a group independently selected from R ^e , ♦ · ···· ·· ·· • · · ·

9 99 • · · · • 9 8 9

88 ·* 98 • · · I • · · (

9 8 1

9 9 4 ·· ··

R ^e means 1. halogen atom,

2. amino group,

3. carboxyl group,

4. alkyl of 1 to 4 carbon atoms,

5. an alkoxy group of 1 to 4 carbon atoms,

6. hydroxy group,

7. aryl,

8. arylalkyl of 1 to 4 carbon atoms,

9. aryloxy group,

R ^f represents 1. a hydrogen atom,

2. alkyl of 1 to 10 carbon atoms,

3. alkenyl of 2 to 10 carbon atoms,

4. alkynyl of 2 to 10 carbon atoms,

5. aryl,

6. heteroaryl,

7. arylalkyl having 1 to 15 carbon atoms in the alkyl portion.

8. heteroarylalkyl with 1 to 15 carbon atoms in the alkyl part

9. alkanoyl of 1 to 15 carbon atoms,

10. cycloalkyl of 3 to 8 carbon atoms, 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.

In one subgroup of compounds of general formula I, Z represents a sulfur atom.

In another subgroup of compounds of general formula I, Ar ¹ represents an arylene group, optionally substituted with 1 to 4 groups R ^a . A preferred group is a phenylene group, optionally substituted with 1 to 2 groups from the group consisting of halogen atoms and alkyl of 1 to 4 carbon atoms. A preferred meaning for the arylene group is a phenylene group.

·· ·««·

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

In another subgroup of compounds of general formula I, X and Y represent CH2, O or S groups. Preferably, X and Y represent an oxygen atom.

In another subgroup of compounds of general formula I, Ar ² represents a group of general formula

where

R represents alkyl of 3 to 4 carbon atoms, optionally substituted with 1 to 4 groups from the group consisting of halogen and cycloalkyl of 3 to 6 carbon atoms, and

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

In a preferred subgroup of compounds, R ^a is selected from the groups OR ^b , and may also be aryl, optionally substituted with 1 to 5 groups R ^d and alkyl of up to 15 carbon atoms, optionally substituted with 1 to 5 groups R ^c . In another preferred subgroup of compounds, two groups R ^a on adjacent carbon atoms together form a 5- or 6-membered aromatic ring containing 1 to 2 heteroatoms from the group N, O and S(0) _m , where m is O to 2, this ring is optionally substituted with 1 to 2 groups R ^a . In another very preferred embodiment, R ^a represents an O-phenyl group, in which the phenyl radical is optionally substituted with 1 to 4 groups R ^d , and may also represent phenyl, optionally substituted with 1 to 2 halogen atoms and alkyl of 1 to 5 carbon atoms, optionally substituted with substituted with 1 to 5 substituents from the group consisting of halogen atom, phenyl and cycloalkyl of 3 to 8 carbon atoms.

• · · »» * d Ό ····»·····«

Ιο »··· ·· *« ** «» _<a

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

In another group of compounds of general formula I, n represents the integer 1 or 2.

A preferred embodiment of the compounds of general formula I can be expressed by general formula la

where

R ^a is selected from the groups R ^a , or 2 groups R ^a on adjacent carbon atoms together with these atoms form a 5- or 6-membered aromatic ring containing 0 to 2 heteroatoms from the group N, O and S(O) _m , where m is 0 to 2, this ring is optionally substituted with 1 to 2 groups as defined by R ^a ,

X, Y, Z, n, R and R ^a have the meaning given in formula I.

•· »4*4 • 4 4 • 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 4 4

Another subgroup of compounds of general formula I ^and consists of compounds of general formula I ^and (i)

Another subgroup of compounds of general formula la consists of compounds of general formula la(ii)

A preferred embodiment of the invention is the compounds of general formula Ia, in which Z represents a sulfur atom.

Another preferred embodiment of the invention is the compounds of general formula Ia, in which Y represents a sulfur or oxygen atom and X represents an oxygen atom.

··*·

Another very preferred embodiment of the invention is the compounds of general formula Ia, in which R represents alkyl of 3 to 4 carbon atoms.

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

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

X represents an oxygen atom,

Y represents 1. oxygen atom or

2. sulfur atom,

R represents alkyl of 3 to 4 carbon atoms,

R ^a represents 1. a halogen atom or

2. alkyl of 1 to 5 carbon atoms,

R ^a represents 1. O-aryl, optionally substituted with 1 to 3 R ^d groups,

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

3. alkyl of 1 to 5 carbon atoms, optionally substituted with 1 to 5 R ^c groups, or forms two R a groups ^together with adjacent carbon atoms to which 5- or

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

Representative compounds of the invention are listed in • 9 9999

9999 99

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

9··· 9999

99 49 99

following tables 1 up to 3. Table 1. R ^and 3 •in ^%4 B -YLX—Κ/ ¹ - _And ^from 0=/ ( ηνΆ- 0 Y-L-X A/B Ra 4 O(CH2)3O O/CH Ph 4 O(CH2)3O O/CH CH2C(CH3)3 3 O(CH2)4O O/CH CH2C(CH3)3 3 O(CH2)4O O/CH (CH2)2Ph 4 O( _CH2 )3O Y/N Ph 4 O(CH2)3O Y/N CH2C(CH3)3 4 O( _CH2 )3O Y/N cf ₃ 4 O(CH2)3O Y/N ' (CH ₂ ) 2Ph 4 O( _CH2 )3O Y/N (CH2)4Ph 4 O(CH2)3O Y/N CH2-c-Hex** 4 O(CH2)3O Y/N CH2C(CH3)2Ph 3 O(CH2)4O Y/N cf ₃ 4 O( _CH2 )3O S/CH (CH2)2Ph 3 O(CH2)4O S/CH (CH2)2Ph 3 O(CH2)4O SO/CH (CH2)2Ph 4 O( _CH2 )3O SO/CH (CH2)2Ph 4 O( _CH2 )3O SO2/CH Ph 3 O(CH2)4O SO2/CH (CH2)2Ph 4 O(CH2)3O SO2/CH (CH2)2Ph Y group connection point on phenyl circle,

**c-Hex means cyclohexyl • · ·

Table 2.

From Ra * Y-L-X with H 4 O( _CH2 ) _3O with 3-Cl 4 O( _CH2 ) _3O with 3-F 4 O( _CH2 ) _3O with 3-propyl 4 O( _CH2 ) _3O with 3-Cl 4 S( _CH2 ) _3O with 3-Cl 4 O(CH ₂ ) ₄ O with 3-propyl 4 O(CH ₂ ) ₄ O with H 4 O( _CH2 ) ₄₀ with H 3 O( _CH2 ) _3O with H 3 O(CH ₂ ) ₄ O 0 H 3 O( _CH2 ) _3O 0 H 4 O( _CH2 ) _3O with H 4 O( _CH2 ) _3O with H 4 O( _CH2 ) _3O with H 4 O( _CH2 ) _3O with H 4 O( _CH2 ) _3O with H O O O( _CH2 ) _3O with H 3 O( _CH2 ) _3O with H 3 ( _CH2 ) _4O with H 4 ( _CH2 )4O with H 4 ( _CH2 ) _4O with H 3 ( _CH2 )4O with H 3 ( _CH2 ) _5O with H 3 ( _CH2 )5O with H 3 ( _CH2 ) _5O

R 4' —0— -See R ** Red 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 - _SO2CH3 Propyl 4’ 4-CH ₃ 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

From Ra •i·· Y-L-X R Red sh H 3 O( _CH2 )5 propyl 4’ 4-Ph with H 4 O( _CH2 )4 propyl 4’ 4-OCH3 with H 3 O(CH2)4 propyl 4’ 4-F with H 3 O( _CH2 )5 propyl 4’ 4-CI with H 3 O( _CH2 )3O propyl 4’ 3-CH3-4-C1 with H 4 O(CH2)3O propyl 4’ 4- _CH2CH (CH3)2 with H 3 O(CH2)3O propyl 4’ 4-c-pentyl with H 3 O( _CH2 )3O propyl 4’ 4-CH(CH3)2 with 3-propyl 4 O( _CH2 )3O propyl 4’ 4-OCH3 with H 4 O( _CH2 )4O propyl 4’ 4-OCH3 with H 4 O(CH2)4O propyl 4’ 4-F with H 3 O( _CH2 )4O propyl 4’ 4-OCH3 with H 3 O(CH2)4O propyl 4’ 4-CI with H 3 O( _CH2 )3O propyl 4’ 4-SO2CH3 with H 3 O(CH2)4O propyl 4’ 4-SO2CH3 with H 4 O( _CH2 )3O propyl 5’ H with H 4 O( _CH2 )3O propyl 3’ H with H 3 O( _CH2 )4O propyl 3’ H with H 3 O( _CH2 )3O allyl 4’ H with H 3 O( _CH2 )3O 3-F-propyl 4’ H with H 3 O( _CH2 )3O propyl 4’ 4-CO2CH2CH3 with H 4 O( _CH2 )3O Propyl 4’ 4-F with H 4 O( _CH2 )3O propyl 4’ 4-(4’-tolylsulfone~ amide) with H 3 O( _CH2 )3O c-pr-CH ₂ T 4’ H place connection group Y on phenyl circle,

the place of attachment of the phenoxy group to the phenyl ring, I* c-pr means cyclopropyl,

Table 3.

Oh

• · · · · · • · ·· · · * · · ···· • · · · · · · · · · ·

. _Λ · · · η g ······ • · · · · · · · · · · · * n Ra(l) Ra(2) 4 3 4-F-Ph H 3 3 2-n.apnthyloxy H 3 3 2 - dibenzofuranyl H 3 3 phenoxy propyl 4 3 3-isoxazolyl H 3 4 3-isoxazolyl H 4 3 pyrazineoxy H *connect instead atom oxygen to phenyl circle.

The term "alkyl" and other groups derived from this group, such as alkoxyl or alkanoyl, refers to carbon chains, linear or branched or combined. Examples include methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, pentyl, hexyl, heptyl, octyl, nonyl, etc.

Alkenyl is a carbon chain containing at least one intercarbon 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, etc.

Alkynyl is a carbon chain containing at least one intercarbon triple bond and which is linear, branched, or combined. Examples include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, etc.

Cycloalkyl is a mono- or bicyclic saturated carbon ring system, each ring having from 3 to 10 carbon atoms. This term also includes cycloalkyl fused to an aryl group, in which the condensation occurs at the non-aromatic portion. For example

4 4 4 4 4

4

4444 44 cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

Aryl and also arylene means a mono- or bicyclic aromatic ring system containing only carbon atoms in the ring. This term also includes aryl groups fused to a monocyclic cycloalkyl radical or to a monocyclic heterocyclic radical when the point of condensation is in the aromatic moiety.

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

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

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

φ φ ···· ·· φφ ·· ·· • · φ ΦΦ·· ···· • φ φ φ φ φ φ · · · • φφφ Φ· ΦΦ· · · ·

·.···..· ·..··..·

The term "ortho-substituted" means that the substituent attached to an atom in the ring is attached to an atom adjacent to the point of attachment to the rest of the molecule.

A pharmaceutical composition containing the active ingredients according to the invention also forms part of the essence of the invention. This composition may, in addition to the active ingredients, also contain inert ingredients, i.e. carrier and other excipients. As an active ingredient, such a composition may also contain a combination of active ingredients, their complexes and substances resulting from the dissociation of the ingredients or their mutual reaction 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 occur 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 described substances contain olefinic double bonds and thus include both E and Z geometric isomers.

Some of the described substances may exist with different hydrogen bonding sites, i.e., they are tautomers. An example of such substances is a ketone and its enol. The invention includes individual tautomers and mixtures thereof of general formula I.

Compounds of general formula I can be separated into diastereoisomeric pairs, pairs of enantiomers, e.g. 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

...... **·* *«·* *·”* *··* be separated into individual stereoisomers in the usual manner, e.g. using an optically active acid as a resolving agent.

The enantiomer of a compound of formula I or Ia can also be prepared directly 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. 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. These include, for example, salts with arginine, betaine, caffeine, choline, Ν,Ν’-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

In the case where the derivative of the invention is basic in nature, salts can be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. From these acids it is possible to •4 4444 » 4 4 · I

4 4

4

4444 44 mention acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucilaginous, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, etc. Particularly preferred acids are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

It is clear that in the event that derivatives of general formula I are mentioned in the course of the application, this term always also includes pharmaceutically acceptable salts of these substances.

Use

The derivatives of the invention are effective antagonists of various activators of receptor subtypes that can be activated by peroxisome proliferators, in particular PPARalpha, PPARgamma and/or PPARdelta. The derivatives of the invention may be effective agonists of one subtype of these receptors, e.g. PPARgamma, or may be antagonists of more than one subtype, e.g. they may have dual effects on PPARalpha/gamma. The derivatives of the invention may be used to treat or prevent diseases, disorders or conditions mediated through activation of individual subtypes or combinations of subtypes of PPAR receptors. It is particularly concerned with the treatment of these diseases, disorders or conditions in mammals, including humans, by administering an effective amount of derivatives of general formula I. These disease states may be 1. diabetes, 2. hyperglycemia, 3. obesity, 4. hyperlipidemia, 5. hypertriglyceridemia, 6. hypercholesterolemia, including increased HDL concentration, 7. atherosclerosis, 8. vascular restenosis, 9. irritable bowel syndrome, 10. pancreatitis, 11. abdominal obesity, 12. fat cell tumors, 13. malignant tumors

9999

9 9 9 · φ 9 9 ♦ * Φ · · Φ · » * · • · Φ Φ φ φ « 9 Φ · • ·»· φφ · 9 9 9 9 9

9 9 9 9 9 9 9 9 9

9 99 φφ φφ φ φ · φ fat cells, such as liposarcoma and 14. other disorders in which the causative component is insulin resistance, including syndrome X and ovarian hyperandrogenism, which results in the formation of multiple ovarian cysts.

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

Administration and dose range

For administration to mammals, especially humans, any suitable route of administration may be chosen. The compounds of the invention may be administered, for example, orally, rectally, topically, parenterally, to the eye, to the lungs, via the nasal mucosa, etc. Dosage forms include tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. The preferred route of administration of the compounds is oral administration.

The effective dose for a particular compound may vary widely depending on the route of administration, the condition being treated, and its severity. The appropriate dose will always be determined by the attending physician.

In the treatment or prevention of diabetes and/or hyperglycemia or hypertriglyceridemia or other disease in which the compounds of general formula I are effective, the desired results can usually be achieved if the active ingredients are administered in a daily dose of 0.1 to 100 mg/kg of body weight, the derivatives are preferably administered all at once or divided into two to 6 partial doses in •9 9999

OC 999 9999 9999 *··· ·* ·· ·* 9. 99 throughout the day or in a form with prolonged release of the active substance. For most large mammals, the total daily dose ranges from 1.0 to 1000 mg, preferably 1 to 50 mg. In the case of a 70 kg human, the total daily dose will therefore usually range from 7 to 350 mg. The doses can be adjusted to achieve the optimal result.

Pharmaceutical agent

The invention also provides a pharmaceutical composition comprising the active compounds of formula I together with a pharmaceutically acceptable carrier. The pharmaceutical composition of the invention may comprise the active compound in free form or in the form of a pharmaceutically acceptable salt thereof and may comprise other commonly used additives together with a conventional carrier. 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 intended for oral, rectal or topical administration, for parenteral administration including subcutaneous, intramuscular and intravenous administration, for administration to the eye, to the lungs, e.g. by inhalation through the nose or mouth or for administration through the nasal mucosa, the most preferred route of administration in a given case will depend on the nature and severity of the disease being treated and on the nature of the active substance. The derivatives of the invention may be processed into dosage forms containing a single dose of the active substance.

For practical use, the derivatives of general formula I can be mixed as the active ingredient with a pharmaceutical carrier in a conventional manner.

The carrier will vary according to the dosage form being prepared. For the production of oral formulations, the carrier may include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, etc. in the case of liquid formulations such as suspensions, elixirs, and solutions, or solid carriers such as starches, sugars, microcrystalline cellulose, granulating agents, lubricants, binders, disintegrants, etc. in the case of solid formulations such as powders, hard and soft gelatin capsules, or tablets. A solid pharmaceutical formulation for oral administration is a very preferred form of the formulation of the invention.

Due to the ease of administration, tablets and capsules are the most preferred oral dosage form for the administration of active ingredients. If necessary, the tablets can be provided with conventional coatings from aqueous or non-aqueous solutions. The pharmaceutical composition according to the invention should contain the active ingredient in an amount of at least 0.1% by weight. The amount of active ingredient can 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 dose is achieved. Another suitable dosage form is, for example, nasal drops or sprays for administration into the nose.

Tablets, pills, capsules, etc. may contain binders such as gum tragacanth, gum acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch or alginic acid, lubricants such as magnesium stearate and sweeteners such as sucrose, lactose or saccharin. In the case of a capsule, the composition may also contain a liquid carrier such as an oil.

A variety of other materials may be used to form a coating or to modify the physical form of the compositions. For example, tablets may be coated with shellac, sugar, or both. Syrups or elixirs may contain sucrose in addition to the active ingredient as φφ φφφφ φ φ φ · φφ φφ • Φ φφ φ « φ · φ φφφ

φ · φ φ φ φ «φ φφφ «φφφ φφ sweetener, methylparaben and propylparaben as preservatives, and in addition, coloring and flavoring agents, such as cherry or orange flavoring.

The derivatives of general formula 1 can also be administered parenterally. Solutions and suspensions of the active derivatives can be prepared in water, optionally with the addition of a wetting agent such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures of these with oils. Under ordinary 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 and also sterile powders intended for the preparation of sterile solutions or dispersions immediately before use. In all cases, such a dosage form must be sterile and must be sufficiently fluid to be easily administered by syringe. Furthermore, this dosage form must be stable under the conditions of manufacture and storage and must be protected from contamination by microorganisms, such as bacteria or fungi. As a carrier, a solvent or dispersion medium can be used, which contains, for example, water, ethanol, a polyol, such as glycerol, propylene glycol and liquid polyethylene glycol, mixtures of these substances and vegetable oils can also be used.

Use of a combination of active ingredients

The derivatives of formula I can be used in combination with other active ingredients which can also be useful in the treatment, prevention or at least amelioration of the disease states for which the derivatives of formula I are used. These other ingredients can be administered in a conventional manner and in conventional amounts simultaneously with the derivatives of formula I, before or after their administration.

4 4·«4 *4 4 • · • 4

4 4 •••4 44 ♦ » 44

4 4 4 • 4 44

4 4 4

4* * · 4 4 • 4 4 4 » · 4 4

4 4 4 «4

In the case where the compound of formula I is administered simultaneously with one or more other substances, it is advantageous to administer all the active substances in the form of a pharmaceutical composition containing the derivatives of formula I and the other active substances. In some cases, it is possible to use all the active substances in lower doses compared to the doses when using these substances individually.

As examples of other active ingredients that can be combined with derivatives of general formula I and administered separately or in a common pharmaceutical composition, the following substances can be mentioned:

a) insulin sensitizers including (i) PPARgamma agonists such as glitazones, e.g. troglitazone, pioglitazone, englitazone, MCC555, BRL49653, etc. and compounds described in international applications 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, coestipol and dialkylaminoalkyl derivatives of cross-linked dextran, (iii) nicotinyl alcohol, nicotinic acid or its salts, (iv) PPARalpha agonists, such as fenofibric acid derivatives, e.g. gemfibrozil, clofibrate, fenofibrate and benzafibrate, (v) cholesterol absorption inhibitors, such as beta-sitosterol and acylCoA and cholesterol acyltransferase inhibitors, such as melinamide and (vi) probucol,

f) substances from the group of PPARdelta agonists, described e.g. in WO 97/28149 ·· ·»»«

g) anti-obesity agents such as fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide X5 inhibitors and substances from the group of beta ₃ adrenergic receptor agonists,

h) inhibitor of bile acid transport in the small intestine.

Biological tests

A. In vitro test on white adipose tissue

This test measures the efficacy of the derivatives of the invention in increasing the incorporation of ¹⁴ C-glucose into WAT glycogen after insulin activation for 5 hours in an in vitro system. All tests 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). Epididymal fat pads are cut into small fragments with a diameter of approximately 1 mm using scissors.

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 the test substance in a tissue culture incubator at 37 °C in an atmosphere of 5% carbon dioxide with shaking for 3 hours. ¹⁴ C-labeled glucose is then added and the mixture is incubated for a further 2 hours. The tubes are then centrifuged at low speed, the supernatant is removed and 1 M sodium hydroxide solution is added. After addition of alkali, the mixture is incubated for a further 10 minutes at 60 °C to dissolve the tissue. The resulting tissue hydrolysate 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 the labelled bound glycogen. The dried filter papers are then incubated in amyloglucosidase solution to break down glycogen to glucose. Scintillation fluid is added and the activity of the labeled carbon is determined in a scintillation counter. Test substances that increase the activity significantly above that obtained by incubation with insulin alone 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 potentiating the action of insulin. The active substances were titrated and the concentration at which 50% of the maximum potentiation or activation of insulin could be achieved was determined, this value was designated EC50.

B. Gal-4 hPPAR transactivation

a) Plasmids

The constructs for expression of the chimeric receptors, pcDNA3-hPPARgamma/GAL4, pcDNA3-hPPARdelta/GAL4 and pcDNA3-HPPARalpha/GAL4, were prepared by inserting the yeast GAL4 transcription factor DBD into the ligand binding domain region, LBD, of hPPARgamma, hPPARdelta and hPPARalpha. The reporter construct pUAS(5X)-tk-luc was generated by inserting five copies of the GAL4 element upstream of the herpes virus thymidine kinase promoter and the luciferase reporter gene. The 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 ¹⁰³ cells/well in 96-well tissue culture plates containing Dulbecco's modified Eagle's medium, high glucose DMEM with 10% charcoal-treated fetal calf serum (Gemini BioProducts, Calabasas, CA), medium containing 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, transfection was performed using Lipofectamine (GIBCO BRL, Gaithersburg, MD) according to the manufacturer's instructions. The procedure was performed so that the transfection mixtures for each well contained 0.48 microliters of Lipofectamine, 0.00075 micrograms of pcDNA3-PPAR/GAL4 as the expression vector, 0.045 micrograms of pUAS(5X)-tk-luc as the

99

9 9 9

9 99 • 9 4999 * · 9 • 9

9

9 9 •999 99

9 9 9

99 • 9 99

4 9 4

9 9 9

9 9 9

9 9 reporter vector and 0.0002 micrograms of pCMV-lacZ for internal control of transactivation efficiency. Cells were incubated in the transfection mixture for 5 hours at 37°C in an atmosphere containing 10% carbon dioxide. Cells were then incubated for approximately 48 hours in fresh high-glucose DMEM containing 5% charcoal-treated fetal calf serum, non-essential amino acids, 100 units/ml penicillin G, and 100 mg/ml streptomycin sulfate ± increasing concentrations of test substance. Since test substances were dissolved in DMSO, control cells were incubated in an equivalent concentration of DMSO, the final DMSO concentration was greater than or equal to 0.1%, a concentration that has no effect on transactivation. Disrupted cells were then recovered 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 tests

Male db/db mice, 10 to 11 weeks old, C57B1/KFJ (Jackson Labs, Bar Harbor, ME) were housed in cages of five and were given food (Purina) and water ad libitum. The animals and their food were weighed every two days, and the animals were given a daily gavage of vehicle medium, i.e. 0.5% carboxymethylcellulose ± test substance at the indicated dose. Suspensions of active substance were freshly prepared each day. Blood was collected from the tail vein throughout the test at intervals of 3 to 5 days, and plasma glucose and triglyceride concentrations were determined. A Boehringer Mannheim Hitachi 911 automatic analyzer was used for the determination.

9»

Φ φ φφφφ φφ • Φ φφφ φφ φφ» φ φφφφ φ • φ φ * φ • Φφφφ φ • φ φ φ φ φφ φφ

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

Derivatives of general formula I can be prepared by the procedures shown in the following schemes. The general symbols shown in the schemes have the same meaning as in general formula I, unless explicitly stated otherwise.

Scheme 1

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

a. LiHMDS, THF, TMSCI, NBS

b. where Z=S, thionoate, methoxyethanol

HCl, reflux

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

Alpha-bromination of the aryl acetate intermediate A1 with a halogenating agent such as N-bromosuccinimide in the presence of a base produces a halogenated intermediate which can be ring-closed with thiourea, in which Z is sulfur, in the presence of a strong aqueous acid solution, or with sodium acetate in an alcohol such as 2-methoxyethanol at elevated temperature. In this way, the resulting aryl thiazolidinones of formula I, in which Z is sulfur, are obtained.

4444

4 4

4 «4 * • * • 4 • 44

4444 44 ·· • 4 4 4

4 4'4

4« 44 • 4 4 4

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^-CH^X-Ar ² (B2) (Cl)

_Cs2CO3 , _DMF

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

_Cs2CO3 , _DMF

H ₃ COOC-CH ₂ -Ar ^t -Y-CH ₂ -(CH ₂ ) _n -CH ₂ -L ⁺ HX—Ar (C2) (Bl)

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 9 · ·

Scheme 2 shows the synthesis of intermediate A1, which contains the Ar ¹ and Ar ² groups linked by a bridge of up to 4 atoms. Intermediate A1 can be prepared by first linking a bridge T with two terminal leaving groups to the Ar ¹ or Ar ² group, in which bridge L and L' independently represent a conventional leaving group, such as a halide, preferably a bromide, or a sulfonyloxy group, such as a mesylate or tosylate. A further aryl group is then coupled in the presence of an inorganic base, e.g. cesium carbonate in DMF, thereby obtaining the aryl acetate ester containing said bridge as intermediate A1. The starting material for the bridge and the two further starting materials B1 and B2 are commercially available or can be prepared by known methods. Compounds of formula B2 can be obtained, for example, 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 zX Ar ²

_Cs2CO3 , _DMF

OH

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

a. thionyl chloride, pyridine, 'toluene

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

Scheme 4

HX-Ar ₂ (X=O)

El

1) (Tf) ₂ O, Pyridine

2) HY-CH ₂ (CH ₂ ) nC^CH (Y=O)

Pd(PPh ₃ ) ₄ , piperidine,

HY-CH — (-C=CAr ₂ (y=O) p9 ^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 ^CH2 - ⁾ⁿ (X=CH ₂ )

Bl (Y=O) Cl

_Cs2CO3 , _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 · Φ • · · · ·· • ····«· • · · Φ · · ·

9999 99 99 99 ·· 9999

9 9 · • Φ ··

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

1) H ₂ , Pd/C, Ethanol

2) (Ms) ₂ O, Pyr, CH ₂ Cl ₂

HoCOOC-CH ₂ -Αη-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 —LE2

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

Scheme 4 shows the synthesis of intermediate A1, in which the groups Ar ¹ and Ar ² are connected by a bridge of at most 4 atoms, in which one of the symbols X or Y is oxygen. Then, a palladium-catalyzed addition of the alkyne to the aryl bromide E1 or triflate E2 is carried out to give compounds D1 or D2. Their hydrogenation at atmospheric pressure gives saturated compounds C1 or C2, which are combined with B1 or B2 in the presence of an inorganic base, such as cesium carbonate in dimethylformamide, to give the aryl acetate intermediate A1. The starting materials for the synthesis according to Scheme 4 are commonly available or can be prepared by known methods.

»4 4**4 < 4 4 4 4 • 4 4 4

4 ••*4 44

JŠLÍ-S-SLZ____2_S_2_Y_S_^_S_5LÍ____Z_Z_E_É_1_?_5_3

The following Examples, described below, are provided for demonstration of the invention only, and are not to be construed as limiting the scope of the invention in any way.

Example)

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

Grade A)

Preparation of methyl-4-(3-bromopropoxy)-phenylacetate

A solution, prepared by dissolving 20.0 g (0.12 mol) of methyl 4-hydroxyphenylacetate, 97.20 g (0.48 mol) of 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.

*· ··>· with

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. 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 desired title compound was obtained.

¹ H-NMR, (400 MHz, CDCl^): (nuclear magnetic resonance spectra) delta, 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).

Grade 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)-phenylacetate, obtained in the previous, above-described Step A), 8.0 g (35.07 mmol) of 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 stirred overnight at a temperature of 40.0°C.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid solution, and after separating 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, 99% of the product was obtained.

9 ·

9

9

9 9

9999 99 »9 ·· • 9 9 * 9 99

9 «

99 • 9 99 « 9 9 9 • · 9 ·

9 9 9

9 9 9

99 an oily substance which was chromatographed over silica gel, using a mixture of 10% ethyl acetate in hexane as eluent, to give the desired 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 ).

Grade C)

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

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

Then, a solution prepared by dissolving 10.80 g (24.87 mmol) of methyl 4-(3-(2-propyl-4-phenoxy-phenoxy)-propoxy)-phenylacetate, obtained in the previous, above-described Step B), in 15.0 ml of tetrahydrofuran was added dropwise to the reaction mixture, and the reaction mixture was stirred at a temperature of minus 78.0°C for 2.0 hours.

Then, after adding 4.65 g, (26.12 mmol), of N-bromosuccinimide, the reaction mixture was allowed to warm to room temperature overnight. Then, the tetrahydrofuran was evaporated, and the resulting residue was partitioned between ethyl acetate and water. After separating the organic and aqueous phases, the organic layer was washed once with water, ·· ···· φ · · • · • · φφφ φφφφ »>·

Φ· • φ · φ φ φ

·· ·» him • · · φ φ* φφ φφ * · φ • · · φ φ φ

Φ· ·» ·Φ and was then dried over sodium sulfate, filtered, and evaporated.

Methyl-alpha-bromo-4-(3-(2-propyl-4-phenoxy-phenoxy)-propoxy)-phenylacetate was obtained in the form of an oily substance.

The resulting, above-mentioned substance in the form of an oily residue was dissolved in 100.0 ml of methoxyethanol, and to the resulting solution, 2.84 g (37.31 mmol) of thiourea and 2.14 g (26.12 mmol) of sodium acetate were added, and the resulting reaction mixture was heated at 115.0°C for 5.0 hours.

Then, after adding 19.43 ml of 6N hydrochloric acid solution, the reaction mixture was heated at 115.0°C for a further 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, dried over sodium sulfate, and after filtration, evaporated to an oily substance, which was chromatographed over silica gel, using a mixture of 1% methanol in dichloromethane as eluent.

The desired 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, ( p., 3H ),. 4.17, ( i.e., 2H, J = 6.30 Hz), 4 ,11, ( t., 2H, J = 6.00 Hz ) , 2.53, ( i.e. , 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]-isoxazolyloxy]propoxy)-phenyl]-2,4-thiazolidinedione

Grade A)

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

By the analogous procedure described above in Example 1), Step Efc), using 7-propyl-3-phenyl-6-hydroxy-benz[4,5]-[30X8Zol] (International Patent Application, WO-97/28.137) as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCl^:

delta,.. 7.92, ( d.d., 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&, ( d.d., 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 · ·

Degree ()

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

By an analogous procedure to that described above in Example 1), Step C), but using methyl-4-(3-(7-propyl-3-phenyl-6-benzo[4,5]-oxazolyloxy)-propoxy)-phenylacetate, obtained in the previous, above-described Step A'), as starting material, the title compound was prepared. ¹ H-NMR, (400 MHz, C10H11):

delta,. , 6.98, ( d., 2H, J = 8.80 Hz ), 6.92, ( d.d., 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,, í quint., 2H, J =

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

J = 7.30 Hz).

Mass spectrometry-chemical ionization (GI-MS):

m/e = 503.0, (M+1);

Example 3)

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

Grade A)

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

By an analogous procedure to that described above in Example 1), Step 8), using 7-propyl-3-neopentyl-6-hydroxy-benz[4,5]-oxazole, (International Patent Application, WO-97/

28.137) as starting material, the desired title compound was prepared.

¹ H-NMHy (400 MHz, CDfilj):

delta, 7.34, ( d.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 _f J = 7.20 Hz ), 2.78, ( a., 2H ), 2.28, ( quint., 2H, J =

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

Grade H) · · · 9 ·· 9 you

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

By an analogous procedure to that described above in Example 1), Step C), using methyl-4-(3-(7-propyl-3-neopentyl-6-benz-(4,5)-isoxazolyloxy)-propoxy)-phenylacetate obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared. ¹ H-.mR _r (400 Wíz,.. CHCl ₃ ):

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

Example 4)

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

H

O

• · · • · 4 Φ · · · · * • · • · • · ·

Grade A)

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

By an analogous procedure to that 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 starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, SLOCl-j):

delta, 7.53, ( d.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, ( d.d., 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 ).

Grade B)

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

By an analogous procedure to that described above in Example 1), Step G), using methyl 4-(3-(7-propyl-3-trifluoromethyl-6-benz-(4,5)-isoxazolyloxy)propoxy)phenylacetate obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared.

9 ···/··· « >

• 9

9999 • 9 9

9 9 ·· 99 • · 9 fl *· ·*· 99 • * · 9 • 9 9 9 • 9 9 9 9 • 9 9 9

99 ¹ H-NMfi, ( 400 MHz, CDCl·^:

delta, ( d.d.

6.92., ( t., ( t»,

1.66..

8.05,, I ( s.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, ( p., 1H ), 4.27 , 2H, J = 6.tO Hz ), 4.18, ( t.·, 2H, J = 6.10 Hz ), 2.85 , 2H, J = 7.50Hz ), 2.28, ( quint., 2H, J = 6.30 Hz ( hex. 2H, J = 5.90 Hz ), 0.92, ( i.e., 3H, J = 7.30 Hz ).

m/z, 512.30, (M+NH 2 ) y

Mass spectrometry-Cl:

Example 5)

Preparation of 5-[4-(3-(7-propyl-3-phenethyl-6-benz-(4,5)-isoxazolyloxy)-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-benz-[4,5]-thiazoxazolyloxy)-propoxy)-phenylacetate

By an analogous procedure to that described above in Example 1), Step B), using 7-propyl-3-phenethyl-6-hydroxy-benz[4,5]-isoxazole, (International Patent Application, WO-97/28*137), as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCl^:

delta, 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 ).

G e l e a d B)

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

By an analogous procedure to that described above in Example 1), Step C), but using methyl 4-(3-(7-propyl-3-trifluoromethyl-6-benz-(4,5)-isoxazolyloxy)propoxy)phenylacetate as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, ODC1 ₃ ):

delta, 8.10, ( w.s., 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).

Mass Spectrometry-CI: m/z, 531.50, (M+1)J

Example 6)

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

Grade A)

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

By an analogous procedure to that described above in Example 1), Step B), using 7-propyl-3-phenylbutyl-6-hydroxy-benz[4,5]-isoxazole as starting material, the desired title compound was prepared.

♦ · ·♦>· >44···· ·

• · • 44 • <

• 4 • · ·· 44

I • · I

4

4 • · · • · 44

4

4

4 • 4 ¹ Η-NMR, (400 MHz, CDGl-j):

delta. 7.31* ( d., 1H. J = 8.60 Hz ). 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,

Grade B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl-(3-(7-propyl-3-phenylbutyl) 6-benz-(4,5)-isoxazolyloxy-propoxy)-phenylacetate, obtained in the previous, above-described Step A), as starting material, the desired title compound was prepared, ¹ H-NMR, (400 MHz, CDCl-j):

delta, 8.10, ( w.a., 1H ), 7.32 - 7.-29, ( m., 3H ), 7.26 - 7.20 ( m., 2H ),. 7.17 - 7.11, ( Μ., 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 · • * <

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

SO

Example 7)

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

Grade A)

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

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

¹ H-NMR, < 400 MHz, ODCl 2 :

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

1H, J = 8.50 Hz ), 7.45 - 7.13¼ ( 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 φ · « * · ·· ;

··#· φφ·· ·«· ,ι· • · > · · <

φ · · · · · •··· ·· ·· ··

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

7.30 Hz).

Grade B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(3-(7-propyl-3-phenylbenzofuran-6-yl)propoxy)phenylacetate obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCl3):

delta, 8.18, ( w.s., 1H ), 7.69, ( s., 1H ), 7.63 - 7.59, ( m., 2H ), 7.55, ( d., IH, J = 8.50 Hz ), 7.45 - 7.40, ( m., 2H ), 7.36 - 7.27, ( ra., 2H ), 6.90 - 6.55 _r ( ra., 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,. ( i.e., 3H,, J = 7.30 Hz ).

Example 8)

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

• ·· 9 4 9 4

F2.

Grade A)

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

By an analogous procedure to that described above in Example 1), Step B), using 6-hydroxy-7-propyl-3-phenylbenzothiophene-1,1-dioxide as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, ODC12):

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, ( 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-benzothiophene-1,1-dioxide-6-yl)-propoxy)-phenyl]-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(3-(7-propyl-3-phenylbenzothiophen-1,1-dioxide-6-yl)-propoxy)-phenylacetate, obtained in the previous, above-described Step A), as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC.1^):

delta, 8.05, ( w.s., 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., ÍH ), 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 ).

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

Example 9)

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

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

Grade A)

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

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

delta,. 7.36,, ( d.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

G e l e a d B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(3-(7-propyl-3-cyclohexylmethyl-6-benz-(4,5)-isoxazolyloxy)-propoxy)-phenylacetate, obtained in the previous, above-described Step A), as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, ORGl^::

delta,, 8.25, ( s., 1H ), 7.36, ( d., IH, 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

Situations A)

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

By an analogous procedure to that described above in Example 1), Step B), using 2-propyl-4-(4-fluorophenyl)-phenol as starting material, the desired title compound was prepared.

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, ( 400 MHz, 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 ).

Grade B)

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

By an analogous procedure to that described above in Example V), Step C), using methyl 4-(3-(2-propyl-(4-fluorobiphenyloxy)-propoxy)-phenylacetate, obtained in the previous, above-described Step A), as starting material, the desired title compound was prepared^ ’η-Μ, ( 400 MHz, GDC1 ):

delta, 8.01, ( w.a., 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 ).

Case 11)

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

Grade A)

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

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

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

The desired title compound was obtained.

Grade B)

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

*

/ ·

8 9 98 88

£5

A solution prepared by dissolving 2.50 g, (7.18 mmol), of 4(3-bromopropoxy)-3-propylphenyl 1-phenyl ether, obtained in the previous, above-described Step A), further 1.42 g, (7.11 mmol), of methyl 3-chloro-4-hydroxyphenylacetate, and 2.43 g, (7.45 mmol), of cesium carbonate, was stirred overnight at a temperature of 40.0°C:..

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

The desired title compound was obtained.

¹ H-NMR, (400 MHz, GDE1^):

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

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

6H ) ( quint., 2H, J = 6.30 Hz ), 1.55, ( hex., 2H„ 5.60. Hz ), 0.89, ( t., 3H, J = 7.30 Hz ).

Grade G)

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

By an analogous procedure described above in Example 1),

Step G) was carried out using methyl 4-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-3-chlorophenylacetate, obtained in the previous, above-described Step B), as the starting material,

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

The desired title compound was prepared.

¹ H-NMR, (400 MHz, GTUGI):

delta, 8.46, ( w.s., 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

Grade A)

Preparation of methyl-4-(3-(2-propyl-4-phenoxyphenoxy)-propoxy)-3r fluorophenylacetate , , —,—<—«— ♦ ί*· ♦♦ ·

• · · 4 » 4 4 4 9 9 • 4« »♦· 4 4 4 · » .t « ,» » » . t* . 4 4 • 4 44 4 4 4 4 4444 44 44 44 4 * 4»

€0

By an analogous procedure to that described above in Example 11), Step B), using methyl 3-fluoro-4-hydroxyphenylacetate as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, ODCX^):

delta, 7.23 - 7.28„ ( m., 3H ), 7.11, ( d.d., 1H, J - 8.40,

2.10 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 _ø ( 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 ).

Grade B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl-4-(3-(2-propyl-4-phenoxyphenoxy)-propoxy)-3-fluorophenylacetate, obtained in the previous, above-described Step A), as the starting material, the desired title compound was prepared.

¹ H-NMR (400 MHz, CM):

delta. 6.10; Hz ), 4.15, ( t.,. 2H„ J = 6.00 Hz ), 3.67,, ( s., 2H ), 2.53, ( t.,. 2H _r 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* r* « t* · • · · ·

Gl • · < ·· ··

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

Grade A)

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

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

¹ H-NMR, (400 MHz, CDO1 ₃ ):

delta, 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 9

9 9 9

9 9 9

Step Β)

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

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

¹ H-NMR, (400 MHz, CDCl-j):

delta, 8.04, (w.s., 1H ), 7.28 - 7.24, ( m., 2H ), 7.18, ( d.d,,

( m«, 6H ),

Example 14)

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

Cl ^w — · · Λ Λ ♦Μ* ♦♦·· 444 *»<

• · · Φ · ί ♦ • · 4 4 49

Φ

ΦΦΦΦΦ

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

S u r e n A)

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-dimethylcarbamoylthiophenylacetate, in 30.0 ml, of methanol, was added 7.0 ml, (0.034 mol), of a 25% solution of sodium methoxide in methanol, and the resulting reaction mixture was heated to reflux for 2.0 hours.

Analysis using thin layer chromatography (TLC) revealed residual carbamate used as starting material.

Then, another 1.0 mL of a solution of sodium methoxide in methanol was added to the reaction mixture, and the mixture was stirred under reflux for another 30.0 minutes. After subsequent cooling to room temperature, the thiolate solution was added dropwise to a solution obtained by dissolving 12.0 mL (0.12 mol) of

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

After the reaction mixture was allowed to stand overnight, the reaction was quenched 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 as an aqueous solution first with 0.20 liters and then twice with 1.0 liters of ethyl acetate.

The combined organic layers were washed successively with water and brine, and after drying with anhydrous magnesium sulfate, they were filtered and concentrated.

The resulting residue was chromatographed on silica gel, using a mixture of 10% ethyl acetate in hexane as eluent.

The desired 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 99 « 99 9 9 9 9

9 9 9 9 4 4 9

9 4 9 4 4 4

44 44 49

6'Y

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),

EL degree)

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

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

The resulting reaction mixture was then partitioned between ethyl acetate and 2N hydrochloric acid. After separating the organic and aqueous phases, the organic layer was washed twice with water, dried over sodium sulfate, filtered, and evaporated to an oily substance, which was chromatographed on silica gel using a mixture of 10% ethyl acetate in hexane as eluent.

The desired title compound was obtained.

¹ H-NMR, (400 MHz, CDCl-j):

delta, 7.24 - 7.29, < m, , 3H ), 7.10, ( d.d., 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 ).

Grade G)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(3-(2-propyl-4-phenoxyphenoxy)-propylthio)-3-chlorophenylacetate obtained in the previous, above-described Step B) as starting material, the desired title compound was prepared.

12-NMR (400 MHz, CDCl3):

delta, 8.60,, ( w.s.,, 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

*

Λ * Σ * · * 4 4 4 Α Λ * ♦··· Μ·· ···

9 4 9 9 4 4

9 9 99

9 9 9 9 9 9

9 9 9 9 9 9

9999 99 99 99 • 9 9 4

9 9 «

9 9 9

49

GG

Grade A)

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

A solution prepared by dissolving 25.0 g (0.11 mol) of 4-phenoxy-2-propylphenyl _, 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 solution. After separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with sodium sulfate, it was filtered and evaporated.

The resulting residue, in the form of an oily substance, was chromatographed on ηε silica gel, using a mixture of dichloromethane:hexane, (1.0:1.0), as eluent.

The desired title compound was obtained.

G e l e a d B)

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

A solution, prepared by dissolving 5.70 _g (15.75 mmol) of 4(4-bromobutoxy)-3-propylphenyl-phenyl ether, obtained in the previous, above-described Step A), further 3.0 g (15.00 mmol) of methyl-3-chloro-4-hydroxyphenylacetate, and 5.38 g (16.50 mmol) of cesium carbonate, in 50.0 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 separating 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, an oily substance, was chromatographed on silica gel using a mixture of 10% ethyl acetate in hexane as eluent.

The desired title compound was obtained.

¹ H-NMR, (400 MHz, GQG1^):

delta, 7.28 -7.24, ( m., 3H ), 7.10, ( d.d., 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 r g e s (G)

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

2,4-thiazolidinedione

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

¹ H-NMR, (400 MHz, CDCl 3 ):

delta, 8.12, ( w.s., 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-thiazolidinedione

Grade A)

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

By an analogous procedure to that described above in Example 15), Step A), using methyl 3-propyl-4-hydroxyphenylacetate as the starting material, the desired title compound was prepared.

H-NMR, ( 400 MHz, delta, 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).

Grade B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(4-(2-propyl-4-phenoxyphenoxy)butoxy)-3-propylphenylacetate obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, ODC12):

delta, 8.14, ( S.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-thiezolidindione

-O ··

T-D • · • · • · ···· • · · · ·« *· » · · * • t ··

Grade A')

Preparation of methyl 1-4-(4-(2-propyl-4-phenoxyphenoxy)-butoxy)-phenylacetate

By an analogous procedure to that described above in Example 15), Step A), using methyl 4-hydroxyphenylacetate as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, ODG1 ₃ ):

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).

G e l e a d B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(4-(2-propyl-4-phenoxyphenoxy)buroxy)phenylacetate obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, QDG1^:

delta, 8.01, ( w.s., 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, Ja 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 ).

Ρ ρ i k 1 β a 18)

Preparation of 5-[3-(3-(2-propyl-4-phenoxyphenoxy)-propoxy)-phenyl]-2,4-thiazolidinedione .0

Grade A)

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

By an analogous procedure to that described above in Example 11), Step B), using methyl 3-hydroxyphenylacetate as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, 03301^):

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-

Grade B)

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

By a similar procedure as described above in Example 1), Step G), using methyl 3-(3-(2-propyl-4-phenoxyphenoxy)propoxy)phenylacetate obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

^] H-NMR, (400 MHz, GDC12):

delta, 8.48, ( w.s., 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

···· · · · · · ·

Grade A)

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

By an analogous procedure to that described above in Example 15), Step A), using methyl 3-hydroxyphenylacetate as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC12):

delta, 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).

G e l e a d B)

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

By an analogous procedure to that described above in Example 1), Step G), using methyl 3-(4-(2-propyl-4-phenoxyphenoxy)-butoxy)-phenylacetate obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz _, CDCl-2):

delta, 7.93,. ( w.s., 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 with 6.70 Hz ), 0.91, ( t., 3H, J = 7.40 Hz ).

• · ··· · • · • · · · « · · φ • · · · · · · · · ·

Example 20)

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

Grade A)

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

A solution prepared by dissolving 253.0 mg, (1.39 mmol), methyl 3-hydroxymandelate, 500.0 mg, (1.44 mmol), 4(3-bromopropoxy)-3-propylphenyl-phenyl ether, and 475.0 mg, (1.46 mmol), 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 solution, and after separating the organic and aqueous phases, the organic layer was washed twice with water, and after being dried with sodium sulfate, it was filtered and evaporated.

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

The desired title compound was obtained.

¹ H-NMR, (400 MHz, CDCl):

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, 20Hz ) , °>96,, ( i.e., 3H, J = 7 ,30 Hz ).

Grade B)

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

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

The reaction mixture was then partitioned between ethyl acetate and water, and after separating the organic and aqueous phases, the organic layer was washed twice with water, and after drying with sodium sulfate, it was filtered and evaporated.

The residue, in the form of an oily substance, was chromatographed on silica gel using a mixture of 3% methanol in dichloromethane as eluent.

The desired title compound was obtained, ¹ H-NMR, (400 MHz, OPC1 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 =

6.20 Hz ), 4.13, ( t. _r 2H, 0 = b.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 ).

• · ··· · • « · · · · · · • · 9 9 9 9 ·

999 99 999 99 9

99 · · · · 999· •999 99 99 ·· ·· ··

H

Example; 21 )

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

Grade A)

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

By an analogous procedure to that described above in Example 20), Step A), using ethyl 4-hydroxymandelate as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GBC1 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 _r 18 _ř ( t. _r 2H„ 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 *· 444

4444 44

4 9 4 4 4 ·· «4

Grade B)

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

By an analogous procedure to that described above in Example 20), Step B), using ethyl 4-(3-(2-propyl-4-phenoxyphenoxy)propoxy)mandelate obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CD12):

delta, 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-thiszolidinione

^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 9 4

9 4 9 4 9 4 9 9 4 9 ·

4 4 9 9 9 4 9 4 9 4

49 4 94 9 9 99 4 9 9 4

Grade A)

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

A’P grade

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 dium carbonate, in 250.0 ml, of dried dimethylformamide, and stirred at 40.0°C for 30.0 minutes, was subsequently added 5.20 ml, (0.06 mol), of allyl bromide, and the resulting reaction mixture was stirred overnight.

The reaction mixture was then partitioned between ethyl acetate and 0.2N hydrochloric acid solution, and after separating the organic and aqueous phases, the organic layer was washed with water, and after drying with sodium sulfate, it was 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^:

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

Level 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 previous, above-described Step A^), further 5.00 g, (28.70 mmol), 4-fluorophenylmethylsulfone, and 4.80 g, (34.45 mmol), potassium carbonate, in 50.0 ml, dried N,N-dimethylacetamide, was heated under 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, in the form of an oily substance, was chromatographed on silica gel using a mixture of hexane:ethyl acetate, (5.0:1.0), as the eluent.

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

¹ H-NMR, (400 MHz, GDC12):

delta, 7.84, ( d., 2H, J = 8.90 Hz ), 7.00, ( m., 6H ), 6.08, ( m., 1H ), 5.44, ( d.d., 1H, J = 1.50 Hz, 15.50 Hz ), 5.31 , ( d.d., IH, 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 in the previous, above-described Step A^), in dried 1,2-dichlorobenzene, was heated overnight at 180.0°C, • · • ·· ···♦ »4·· 44

Sat

Then, after evaporation of the solvent from the reaction mixture under vacuum, the resulting residue was chromatographed on silica gel, using a mixture of hexane:ethyl acetate, (4.0:1.0), as eluent.

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

delta, 7.84, ( d., 2H, J = 8.90 Hz ), 7.34, ( s., IH ), 7.01, ( d.d., 2H, J - 9.80 Hz, 2.00 Hz ), 6.84,. (d., 2H, J = 2.20

Hz ), 5.97,, ( m., 1H ), 5.18, ( d., 1H, J = 1.40 Hz ),. 5.15, ( d.d., 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 2-allyl-4-(4-methylsulfonyl)-phenoxyphenol, obtained in the previous, above-described Step A^), and 5% palladium on activated carbon, (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 passing through a short pad of silica gel, it was concentrated under vacuum.

The desired 2-propyl-4-(4-methylsulfonyl)-phenoxyphenol was obtained in the form of an oily substance, which was used further without further purification.

¹ H-NMR, (400 MHz, GDC1):

delta, 7.86, ( d., 2H, J = 8.90 Hz ), 7.02, ( d., 2H, J - 9.90

Hz ), 6.84, ( s., 1Η ), 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).

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

Grade B)

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

A solution prepared by dissolving 19.60 g (0.10 mol) of ethyl 4-hydroxymandelate, 60.75 g (0.30 mol) of 1,3-dibromopropane, and 35.75 g (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 1.0N hydrochloric acid. After separation of the organic and aqueous phases, the organic layer was washed twice with water, once with brine, and after subsequent drying with sodium sulfate, it was filtered, and the solvent was removed in vacuo.

The resulting residue, an oily substance, was chromatographed on silica gel using a gradient elution from 100% hexane to dichloromethane:hexane (2.0:1.0) to afford the desired title product.

¹ H-NMR, (400 MHz, CDCl^:

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 ).

«· ···· • · · · · · » • · · · ·· • ·»···* • · · · · · » ···· ·« ·· ·· tt

99

β.

Grade 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 in 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 hour.

Then, ethyl 4-(3-bromopropoxy) mandelate (obtained in the previous, above-described Step B) (19.50 g _{of Î} -?58.90.-<methanol) was added to the reaction mixture, and the reaction mixture was stirred overnight. Then, the reaction mixture was partitioned between ethyl acetate and 1.0N hydrochloric acid solution, 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, it was filtered and the solvent was removed in vacuo.

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

The desired title compound was obtained, ¹ H-NMR, (400 MHz, CDCl^:

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 _r 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.,20 Hz ).

Degree H) φ > φ φφ ·

ΦΦΦ· ·· 99 Φ* ·Φ

Φ ΦΦ Φ Φ Φφ φ • ΦΦΦ Φ φφ φ

99 999 99 ·

9Φ9 9 Φ φ « »

ΦΦΦ «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), ethyl-4-(3-(2-propyl-4-(4-methylsulfonyl)-phenoxy-phenoxypropoxy)-mendelate, (obtained in the previous, above-described Step C), further 2.95 ml, (36.51 mmol), pyridine, and 160.0 ml, toluene, was 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 separating the organic and aqueous phases, the organic layer was washed twice with water, once with brine, and after drying with sodium sulfate, it was filtered.

After removal of the solvent from the filtrate under vacuum, an oily residue was obtained, which was filtered through a pad of silica gel using acetone:hexane (1.0:4.0) as eluent.

The desired title compound was obtained.

¹ H-NMR, (400 MHz, CDCl^:

delta, 7.86, ( m., 2H ), 7.35, ( m., 2H 5, 7.03, ( m., 2H ),

6.92, ( m. , 2H ), 6.87, ( w.s., 3H ), 5.12, ( w.s., 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 ).

Grade E)

Preparation of 5-/4-(3-(2-propy1-4-(4-methylsulfonyl)-phenoxy)phenoxy)propoxy)-phenyl/-2,4-thiazolidinedione φφ φφφφ φ· ·* ·φ φ« φ φ φφφφφ φ φ · · • · φφφφ · « · * • φφφ » « « « φφ • · ♦ φφφφ · · · φ • φφφφφφφφφφ·· <fy

By an analogous procedure to that described above in Example 1), Step C, (second paragraph), using ethyl alpha-chloro4-(3-(2-propyl-4-(4-methylsulfonylphenoxy)-phenoxy)-propoxy)phenylacetate, obtained in the previous, above-described Step D), as starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC12):

delta , 8.18, _r ( s.s., 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, ( p., 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'

O ·· ·»*· ·* ·· 94 ·· • · * 9 9 9 9 9 4 4 4 • 9 · · 99 4 9 4 9 • 9 9 4 4 9 4 9 4 4 4 9

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

Grade A)

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

Grade Aj)

Preparation of 4v(4-methylphenoxy)-benzaldehyde

A solution prepared by dissolving 4.52 g, (40.29 mmol), 4-methylphenol, 5.00 g, (40.29 mmol), 4-fluorobenzaldehyde _r and 6.70 g, (48.35 mmol), potassium carbonate, in 40.0 ml, dimethylacetamide, was heated under 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, it was filtered and concentrated.

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

The desired title compound was obtained.

Grade A^)

Preparation of 4-(4-methylphenoxy)-phenol

A solution prepared by dissolving 9.00 g (41.63 mmol) of

4-(4-methylphenoxy)-benzaldehyde, (obtained in the previous, above-described Step Aj), 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 4 4 » 4 4 4 4

44 4 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% yield), and the resulting reaction mixture was stirred at room temperature for 3.0 hours.

Then, the reaction mixture was washed successively with saturated aqueous sodium bisulfite solution, saturated aqueous sodium bicarbonate solution, and water. After separating the organic and aqueous phases, the organic layer was concentrated, and the resulting residue, in the form of an oily substance, 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 1.0 hour.

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

The desired title compound was obtained.

Grade A^)

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

A solution prepared by dissolving 4.75 g (23.30 mmol) of

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

The reaction mixture was then cooled and, after neutralization,

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

• · · ·

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

The desired title compound was obtained.

§ t up e ň A^)

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

A solution prepared by dissolving 4.00 g, (16.37 mmol), of 4-(4-methylphenoxy)-phenyl-ethyl ether, in 50.0 ml, of 1,2-dichlorobenzene, was heated under reflux for 20.0 hours.

After cooling the solution, the solvent was removed in vacuo and the resulting residue, in the form of a crude oily substance, was chromatographed on silica gel using a mixture of 15% ethyl acetate in hexane as eluent.

The desired 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 previous Step A) and 5% palladium on carbon (0.90 g) in 30.0 mL of ethyl acetate was stirred at room temperature under a hydrogen atmosphere for 3.0 hours.

• ·

• · · · · · · · · ·

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

The desired title compound was obtained and used without further modification.

¹ H-NMR, (400 MHz, CDCl-3):

delta, 7.19, ( d., 2H )„ 6.86,. ( d., 1H ), 6.83, ( d.d., 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).

Grade B)

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

By an analogous procedure to that described above in Example 1), Step B), but using £9.0 g, (62.00 mmol), 2-propyl-4(4-methylphenoxy)-phenol, and 19.50 g, (58.90 mmol), methyl-4(3-bromopropoxy)-phenylacetate, (obtained in Example 1), Step A), and described above), as starting materials, the desired, title compound was prepared.

^] H-NMR, ( 400 MHz, CDCl^ ): ' delta, 7.18, ( d., 2H ), 7.07, ( d., 2H ), 6.85, ( m., 5B ),

6.76,. ( d., IH ), 6.70, ( d., 1H ), 5.33, ( s., IH ),, 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?

Grade C)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl-4-(3-(2-propyl-4-(4-methylphenoxy)-phenoxy)-propoxy)-phenylacetate, (19.50 g,/58.90 mmol/), (obtained in the previous, above-described Step B), as starting material, the desired title compound was prepared.

¹ H-NMR„ (400 MHz,, CUCl^):

Example 24)

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

By an analogous procedure to that described above in Example 23), using 4-chlorophenol, as opposed to 4-methyl phenol, in Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDG12):

delta, 8.-19, ( w.s., 1H ), 7.33, ( d., 2H ), 7.22, ( d., 2H ),

6.93, ( d., 2H ), 6.85, ( d., 1H ), 6.84, ( d., 2H ), 6.80, ( d.d., 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

By an analogous procedure to that described above in Example 23), using 4-phenylphenol, as opposed to 4-methyl phenol, in Step A), the desired title compound was prepared.

• ·

H-NMB, (400 MHz, GDC12):

delta. 8..01, ( w.s.. 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 ),. Qy 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-thiazolidinedione

By an analogous procedure to that described above in Example 23), using 4-methoxyphenol, as opposed to 4-methylphenol, in Step A), as the starting material, the desired title compound was prepared from methyl-(3-bromopropoxyphenylacetate, as opposed to methyl-4-(3-bromopropoxy)phenylacetate, in Step B).

•9 9999 ·· 99 • 9 9 9 · 9 9 9»9·

9 99 99 999·

999 99 999 · 9 9

99 9999 9·99

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

delta, 8.09 , ( s.s., 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, ( p., 1H ), 4.17, ( t., 2H ), 4.10, (t., 2H ), 3.77, ( with,, 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

By an analogous procedure to that described above in Example 26), the desired title compound was prepared using 4-fluorophenol, as opposed to 4-methoxy-phenol, as the starting material.

¹ H-NMR, (400 NHz, CDCl3:

delta, 8.01, ( w.s., IH ), 7.54, ( d., 2H ), 7.49, ( d., 2H \ • · ··· · • · • · · · • · ··· ···· φ · · · · · · « · ·

7.40, ( i.e., 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, ( i.e., 2H ), 2.56, ( i.e., 2H ), 2,; 29, ( quint., 2H ), 1.57, ( hex., 2H ), 0.90, ( i.e., 3H ).

Example 28)

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

Grade A)

Preparation of methyl 4-bromophenylacetate

A 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 under reflux overnight. The reaction mixture was then concentrated and partitioned between ethyl ether, and...saturated aqueous sodium bicarbonate solution.

•· 44··

• 4 44 4 4 44

4 4 4 4 4 4 ♦ · ·

4 44 44 4444

444 44 444 44 4

44 4··· 4444

4444 44 44 44 44 44

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

The desired title compound was obtained in the form of an oily substance.

¹ H-NMR,. ( 400 MHz, _:: GDC1 ₃ )::

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

Degree (fi)

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

A solution, prepared by dissolving 1.45 g, (6.35 mmol), methyl 4-bromophenylacetate, obtained in the previous, above-described Step A), further 0.89 g, (12.70 mmol), 1-hydroxy-3-butyne, 0.293 g, 4.0 mol%), tetrakis(triphenylphosphine)palladium(0), 0.109 g, (12.0 mol%), copper bromide, in 12.50 ml, triethylamine, was purged with nitrogen, and heated at reflux for 1.0 hour.

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 after drying with magnesium sulfate, it was filtered and evaporated.

The resulting residue in the form of an oily substance was chromatographed on silica gel using a mixture of chloroform:ethyl acetate (10.0::1.0) as eluent.

The desired title compound was obtained, ¹ H-NMR, (400 MHz, GDC12):

··· · ·· ·· 99 ·« ··

delta, 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)-phenylacetate

A solution prepared by dissolving 1.38 g (6.35 mmol) of methyl (4-(4-hydroxyl-1-butynyl)-phenylacetate, obtained in the previous, above-described Step B), in 25.0 ml of ethanol, was degassed and purged with nitrogen, and 10% palladium on activated carbon was added thereto.

The reaction mixture was then degassed and flushed with hydrogen, and subsequently stirred under a hydrogen atmosphere at room temperature for 2.0 hours, and then filtered through diatomaceous earth.

After evaporation of the filtrate, the desired title compound was obtained, ¹ H-NMR, (400 MHz, GBC1 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,. ( s.s., 1H).

Grade D)

Preparation of methyl-(4-(4-(2-propyl-4-phenoxy-phenoxy)-butyl-phenylacetate

99«·

9 9 999« 9*9«

9 99 99 9999

999 99 999 99 ·

99 9999 9999

9999 99 99 99 99 9 9

A solution prepared by dissolving 0.395 g, (1.80 mmol), methyl-(4-(4-hydroxybutyl)-phenylacetate, obtained in the previous, above-described 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.

The reaction mixture was then concentrated, diluted with ethyl acetate, washed twice with water, and brine. After separating the organic and aqueous phases, the organic layer was dried over sodium sulfate, filtered, and evaporated to give an oily residue.

AND

The oily substance obtained in the previous operation was added to the reaction mixture prepared by mixing 0.483 g, (2.12 mmol), 4-phenoxy-2-propylphenol, 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 (2-hydroxypropane-1,2,3-tricarboxylic acid) solution. After separation of the organic and aqueous phases, the organic layer was filtered and evaporated to an oily residue which was chromatographed on silica gel using toluene:hexane (1.0:1.0) as eluent.

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

·· ·♦··

S t u ρ e ň E)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl-(4-(4-(2-propyl-4-phenoxyphenoxy)-butyl)-phenylacetate, obtained in the previous, above-described Step D), as the starting material, the desired title compound was prepared.

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 4 9 4 9 9

4 9 4 9 9 4 4 4 9 9

9999 49 94 49 9 9 94

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

¹ H-NMR, (400 MHz, GOC1 ₃ ):

delta, 7.98, ( w.s., 1H ), 7.34, ( m., 2H ), 7.24, ( m., 3H ), 6.71 - 6.90, ( m., 6H ), 5.34, ( β., 1H ), 3.91, ( w.s., 2H ), 3.77, ( a., 3H ), 2.69, ( w.s., 2H )„ 2.52, ( t., 2H, =

7.30 Hz ), 1.81, (w.s., 4H ), 1.57, ( m., 2H ), 0.89, ( t.,

3H, J = 7.30 Hz).

Mass spectrometry-GI: m/e, 528.30, (M+Na)*

Example 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 0 000 00 0 ·0 ·0 · 0 00 0000 0000 0000 00 00 00 0· 00

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

¹ H-NMR, (400 MHz, GDC12):

delta, 7.98, ( w.a., 1H ), 7.32, ( m., 2H ), 7.19, ( m., 3H ), 6.75 - 6.84, ( m., 6H ), 5.35, ( s., 1H ), 3.93, ( w.a., 2H ), 2.69, ( w.s., 2® ), 2.54, ( t., 2H, J = 7.60 Hz ), 1.81, ( w.s., 4H ), 1.55, ( m., 2H ), 0.90, ( t., 3H, ď = 7.30 Hz ).

Mass spectrometry: m/e, 532.20, (M+Na)J

Example 31)

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

By an analogous procedure to that described above in Example 28), the desired title compound was prepared, with • 4 ···· • ♦ 9 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 9 9 9 9 9 9

9999 99 99 99 99 99 /00 with the difference that instead of methyl-(4-bromophenylacetate, in Step B), methyl-(3-bromo)-phenylacetate was used as the starting material, and in Step D) _instead of methyl-4-propyl-4,7phenoxyphenol, 2-propyl-4-(4-chlorophenoxy)phenol was used as the starting material.

¹ H-NMR,. ( 400 MHz, CDC1 ₃ ):

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

2H ),, 2,.54,. ( t., 2H, J = 7.60 Hz ), 1.81, ( w.s., 4H ), 1.55 , ( m.,, 2H )„ 0.90, ( t., 3H, J = 7.30 Hz ).

Mass spectrometry-CI:: m/e, 532.20.(M+Na)* _t

Example 3'2)

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

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 · « · · · · · 9 9 9 9

9999 99 99 99 99 99

The desired title compound was prepared by an analogous procedure to that described above in Example 28), with the difference that instead of methyl 4-bromophenylacetate,

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

¹ H-NMR, (400 MHz, CEIlGl^):

delta,. 8.11, ( w.s., 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 ).

Mass spectrometry-Cl: m/e, 490.30, (M+1)J

70,

Example 33)

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

O ·· «φφφ «· ♦ · φφ • · · · · φ Φ · Φ 9 · • Φ · ♦ · · 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9

9 9 9 9 9 9 9 9 9 9

ΦΦΦΦ 99 99 99 99 99 /02The desired title compound was prepared by an analogous procedure described above in Example 28), with the difference that instead of methyl-4-bromophenylacetate, methyl-3-bromophenylacetate was used as the starting material in Step B), and in the same Step B) instead of 3-butyn-1-ol, 4-pentyn-1-ol was used, and in Step D), instead of 2-propyl-4-phenoxyphenol, 2-propyl-4-(4-methoxyphenoxy)phenol was used as the starting material.

¹ H-NMR, (400 MHz, GBCl2):

delta, 8.19, ( w.s., 1H ), 7.34, ( m., 1H ), 7.21, ( te., 3H ),

6.90 - 6.71, ( ra., 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 ).

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

P r i k; 1. a d 34)

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

About «9

44 ·· *4 «4 9 9999 9949

9 99 99 9*99

49» 99 999 *9 9

99 9999 9999

9944 44 49 49 49 44

The desired title compound was prepared by an analogous procedure to that described above in Example 28), except that instead of methyl 1-4-bromophenylacetate, methyl 3-bromophenylacetate was used as the starting material in Step B), and in the same Step B), instead of 3-butyn-1-ol, 3-pentyn-1-yl was used, and in Step D), instead of 2-propyl-4-phenoxyphenol, 2-propyl-4-(4-fluorophenoxy)-phenol was used as the starting material.

¹ H-M5R, ( 400 MHz, COCl^:

delta, 8.33, ( w.s·., 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 ).

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

Example 35)

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

2,4-thiazolidinedione

About ····

4» ·* 44 «4 4 4444 4444

4 44 44 4444

444 44 444 44 4

44 4444 4444

4444 44 44 44 44 44 .455

Grade A)

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

A solution prepared by dissolving 1.0 g, (3.30 mmol), of 4(4-phenylphenoxy)-2-propylphenol, 0.832 ml, (4.95 mmol), of trifluoromethanesulfonic anhydride, and 0.400 ml, (4.95 mmol), of pyridine, in 3.0 ml, of dichloromethane, was stirred at temperatures ranging 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 separating the organic and aqueous phases, the organic layer was dried over sodium sulfate, filtered, and evaporated to an oily residue.

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

The reaction mixture was then 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 after subsequent drying with sodium sulfate, it was filtered and evaporated.

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

The desired title compound was obtained.

¹ H-NMR, (400 MHz, CDC1 ₃ ):

delta, 7.55, ( m., 5H ), 7.41, ( t., 2H, £ = 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 χ 7.60 Hz ), 2.55, ( t.,

4444 • · • 4 ·4 »4

4 444« 4444

4 44 «· 4444

444 44 444 4 t 4

44 444 4 4444

4444 44 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 Hz ).

Grade B)

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

By an analogous procedure to that described above in Example 28), Step C), the desired title compound was prepared using 5-(2-propyl-4-(4-phenylphenoxy)phenyl)pentyn-1-ol, obtained in the previous, above-described Step A), as the starting material.

¹ H-NMR, (400 MHz, CDCl 3 ):

- 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)-phenylacetate

By an analogous procedure to that described above in Example 28), Step D), the desired title compound was prepared using 5-(4-(4-phenylphenoxy)-2-propylphenyl)-1-pentanol and methyl 3-hydroxyphenylacetate as starting materials.

«9 99 β» 99 • 9 9 ·99· 9999

9 99 99 · 9 · 9

999 99 999 99 9

99 9999 9999 • 999 99 99 9 9 99 99 ¹ Η-NMR, (400 MHz, GDCl^):

delta, 7.55, ( m., 4H ), 7.42, ( t., 2H, J = 7.30 Hz ), 7.38, ( m. _r 1H ), 7.02 - 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-phenylphenoxy)-phenyl)pentoxy)phenyl/-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step O), the desired title compound was prepared, using methyl (3-(5-(2-propyl-4-(4-phenylphenoxy)phenyl)pentoxy)phenylacetate, obtained in the previous, above-described Step C), as the starting material.

1H-NMR, (400 MHz, GDC1):

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, (w.s., 2H ), 2.60 - 2.52, ( m.,

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

3H, 7.30 Hz).

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

Example 36)

9999 • 9 9 9 9 9 9

9 9 9 99

9 9 9 9 9 €

9 9 9 9 9 9 • •99 99 ·9 99 «9

9 9 9

9 9 9

9 9 9 • 9 9 9

9« 99

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

The desired title compound was prepared by an analogous procedure to that described above in Example 35), except that instead of 4-(4-phenylphenoxy)-2-propylphenol, 4-(4-methoxyphenoxy)-2-propylphenol was used as the starting material in Step A), and in the same Step 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^:

delta, 8.51, ( w.s., 1H ), 7.31, ( <3., 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 ).

Mass spectrometry-CI: m/e, 505.60, (M+)* • 9 ···· ·* ·· ···· • · « ·

• _ _ ·· ·· • · · · ·· «·

Example 37)

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

2,4-thiazolidinedione

The desired title compound was prepared by an analogous procedure to that described above in Example 35), except that instead of 4-(4-phenylphenoxy)-2-propylphenol, 4-(4-fluorophenoxy)-2-propylphenol was used as the starting material in Step A), and in the same Step A), (second part), instead of 4-pentyn-1-ol, 3-butyn-1-ol was used as the starting material.

1H-NMR, (400 MHz, CDCl):

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

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

¹ H-NMR, (400MHz, CDCl ₃ ):

delta, 8.07,,. ( s.s.,, 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 ).

Mass spectrometry-Cl: m/e, 546.20, (M+Na)J

Example 39) /770

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

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

¹ H-NMR, (400 MHz, GDC12):

delta,. 8.04,, ( w.s., 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 with 7.40 Hz ), 2.26, ( quint., 2H, J = 6.30 Hz ), 1.60, ( hex., 2H,. J = 5.60 Hz ),. 0.89, ( t.„ 3H _r J = 7.30 Hz ).

Mass spectrometry-GI: m/e, 544.0, (M+NH 2 ) J

Example 40) • · · · of// • · · · · ···

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

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

¹ H-NMR, (400 MHz, CDCl ₃ ):

delta, 7.89, ( w.s., 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, ( m., 2H ), 1.81, ( m., 1H ), 1.57, ( m., 4H ), 1.23, ( m.,

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

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

Example 41) • ·

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

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

¹ H-NMR, (400 MHz, GDC12):

delta, 9.79, ( w.s., 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, ( s.m., 2H ), 1.80 - 1.54, ( m., _; 8H ), 0.90, ( m., 3H,

7.30 Hz).

Mass spectrometry-01: m/e, 545.38, (M+);

Example 42) • · ··9 · • · • ·

» · · <

» · · « ·· ··

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

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

(400 MHz, CDG.l ₃ ):

delta, 8.23, ( w.s., 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, ( kwatt,, 1H ), 2.57, ( t., 2H, J = 7.80 Hz ), 2.30 ;

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

3H, J = 7.40 Hz).

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

Example. 43) ···· • · * · • ·

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

2,4-thiazolidinedione

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

(400 MHz, CDG1-j):

delta, 8.05,, ( s., 1H ), 7.83, ( d., 2H ), 7.66, ( d., 1H ), 7.46 - 7.39,, ( m.,, 2H ),. . 1.69,.. ( quart.,. 4H ), 0.99, ( t., 3H ).

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

Example 44)

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

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

’η-ΝΜΡ, (400 MHz, CDCl^):

delta, 7.99,- ( s.s., 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 ).

Mass spectrometry-CI: m/e, 567.30, (M+NH 2 ) J

Example. 45)

0/6 •4 '««· • 4 44 • · 4 4

4 44

4 4 4 4 • 4 4 4

44

44 • 4 4 4

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

Grade 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, potassium carbonate and silyl bromide were added, and the resulting reaction mixture was stirred at room temperature for 5.0 hours.

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

The resulting oily residue was chromatographed on silica gel using 15% ethyl acetate in hexanes as eluent to give 2-propyl 4-phenoxyphenyl allyl ether.

In the previous operation described above, the pure 2-propyl-4-phenoxy-allyl ether obtained was used for processing into • · 4 44 4

44 • 4 4 4

4 44

4 4 4

44 «4 44

4 4 4

4 4 4

4 4 4 • 4 4 4

44 the desired title compound by analogous procedures described above in Example 23), Steps A^), and A^).

¹ H-NMR, (400 MHz, ODC1 ₃ ):

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

4H„ J = 7.47 Jz ), 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/-2,4thiazolidinedione

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

¹ H-NMR, (400 MHz, CDCl-3):

delta, 7.36 - 6.69, ( ar. , 11H ), 5.35, ( p., 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) *· »··· from//

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

Grade A)

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

By an analogous procedure to that described above in Example 1), Step B), the desired title compound was prepared using 7-propyl-3-neophyll-6-hydroxy-benz-(4,5)-isoxazole, (International Patent Application, WO-97/28.137), as starting material.

¹ H-NMR, (400 MHz, CDCl-2):

delta, 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 4

9 4 4

9 4 4 • · 4 ·

4 4

4 4 4 4 4 4 4 4

4 49

Ml

Grade B)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(3-(7-propyl-3-neophyl-6-benz-(4,5)-isoxazolyloxy)propoxy)phenylacetate obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC12);

delta, 8.02, ( w.s., 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 = 7.45Ήζ ).

Example 47)

Preparation of 5-[3-(4-(7-propyl-3-trifluoromethyl-6-benz-(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 ·· 00

Grade A)

Preparation of ethyl-3-(4-(7-propyl-3-trifluoromethyl-6-benz-[4,5]isoxazolyloxy)butoxy)-mendelate, mendelate - 2-hydroxy-2-phenylethanoate)

By an analogous procedure to that described above in Example 22), Step C), using 7-propyl-3-trifluoromethyl-6-hydroxybenz-(4,5)-isoxazole, (International Patent Application No. WQ-97/

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

¹ H-NMR, (400 MHz, CDCl3):

delta, 7.50, ( d., 1H, J = 8.50 Hz ), 7.27 - 6.83, ( ar., 5H), 4.28 - 4.24,. ( m.,. 2H ), 4j .17 - 4.031, ( 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 ).

Grade B)

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

By an analogous procedure to that described above in Example 22), Step D), using ethyl 3-(4-(7-propyl-3-trifluoromethyl 6-benz-(4,5)-oxazolyloxy)butoxy)mendelate obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

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, ύ = 7.41 Hz )

4.17 - 4.031, ( m. _ø ( t., _; 3H, J = 7.16

Degree ¢)

Preparation of 5-[3-(4-(7-propyl-3-trifluoromethyl-6-benz-(4,5)-iso xezolyloxy)butoxy)phenyl]-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 22), Step E), using ethyl-alpha-chloro-3-(4-(7-propyl-3-trifluoromethyl-6-benz-(4,5)-isoxazolyloxy)butoxy-5-phenylacetate as the starting material obtained in the previous, above-described Step B), the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCO 3 ):

delta, 8.18, (w.s., 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 ň A)

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

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

S t e r g e n &)

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

By an analogous procedure described above in Example 11),

Step B) The desired title compound was prepared using methyl 4-hydroxy-3-propylphenylacetate and 4-(3-bromopropoxy)-3-propylphenylphenyl ether obtained in the previous, above-described Step A) as starting materials.

• 444

44

¹ H-NMR, (400 MHz, EDCI-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 = 6.70 Hz).

Grade O

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 1-4-(2-(2-propyl-4-(4-methoxyphenoxy)phenoxy)propoxy)-3-propylphenylacetate, obtained in the previous, above-described Step B), as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDO-j):

delta, 7.89, ( s.s., 1H ), 7.29 - 6.74, ( ar., 1OH ), 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-thisbslidindione t l c 1.

c c t t « · t t. r <, <- c <

t < t t c ' ' <

t, t ·. ·.

c c c <

t C ( i ic c c c

C l c

Grade A)

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

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

¹ H-NMR, (400 MHz, ORCl^:

delta, 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 ).

Grade B)

Preparation of ethyl-alpha-chloro-4-(4-(2-propyl-4-(4-methoxy-4-phenylphenoxy)butoxy)-phenylacetate • · · · · · · ·

424

By an analogous procedure to that described above in Example 22), Step D), using ethyl 4-(4-(2-propyl-4-(4-methoxyphenoxy)phenoxy)butoxy)mandelate (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC12):

delta, 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 ), 0.90, ( t. , 3H,. J = 7.36 Hz ).

Grade C)

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

By an analogous procedure to that described above in Example 22), Step E), using ethyl alpha-chloro-4-(4-(2-propyl-4(4-methoxy)phenoxy)phenoxy)butoxy)phenylacetate (obtained in the previous, above-described Step B) as starting material, the desired title compound was prepared. ¹ H-NMR, (400 MHz, _GDC13 ):

delta,, 8,18,. ( w.s., 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 ).

• · · · • ·

P ř ί k 1 a d 50)

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

Grade A)

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

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

¹ H-NMK.,, ( 400 MHz, CD.C1 ):

delta, 7.31, ( <3., 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 ).

::

Degree (ft)

Preparation of ethyl-alpha-chloro-4-14-(2-propyl-4-(4-fluorophenoxy)phenoxy)butoxy)phenylacetate

By an analogous procedure to that described above in Example 22), Step D), using ethyl 4-(4-(2-propyl-3-(4-fluorophenoxy)phenoxy)butoxy)mandelate (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC^):

delta, 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

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

¹ H-NMR,, ( 400 MHz, GHG1 ₃ ):

delta, 8.08, ( w.s., 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-2,4-thiazolidinedione

Grade A)

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

By an analogous procedure to that described above in Example 15), Step A), but using 2-propyl-4-(4-methoxyphenoxy)-phenol (prepared by the procedure described above in Example 23), Step A, using 4-methoxyphenol), as the starting material, the desired title compound was prepared.

Grade 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

M

By an analogous procedure to that described above in Example 15), Step B), using methyl 3-hydroxyphenylacetate and 4-(4-bromobutoxy)-3-propylphenyl-4-methoxyphenyl ether as starting materials, the desired title compound was prepared. 1 H-NMR (400 MHz, CDQ1 ):

delta,. 7.24 - 7.19, ( m., 2H ), 6.,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)phenyl]-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step 0), using methyl 3-(4-(2-propyl-4-(4-methoxyphenoxy)phenoxy)butoxy)phenylacetate (obtained in the previous, above-described Step B) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCl ₃ ):

delta, 8.14, (w.s., 1H,), 7.30, ( m., 1H ), 6.98 - 6.69, ( m., 10 H ), 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

13th

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

44

4 4 1 • ♦ 44

Grade A)

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

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

Grade B;

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

By an analogous procedure to that described above in Example 15), Step B), using 4-(4-bromobutoxy)-3-propylphenyl-4-chlorophenyl ether, (-obtained in the previous, above • 4 4*4« •4 44 44 4 «4 4 « 444 4 4 4

4 44 44 444

444 44 444 44

44 4444 444

4444 44 44 44 44 4

described in Step A), and methyl-3-hydroxyphenylacetate as starting materials, the desired title compound was prepared.

¹ H-NMR (400 MHz, ODG12):

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).

Grade O

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

2,4-thiazolidinedione

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

^] Η-Μ, ( 400 MHz, ΟΠΟΙΟΙ:

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

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

Example 53)

032>4 444* »* *4 44 44 «4 · 4444 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-methylsulfonylphenoxy)-phenoxypropoxy)phenyl/-2,4-thiazolidinedione

Grade A)

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

By an analogous procedure to that described above in Example 22), Step (C), using methyl 3-(3-bromopropoxy)-mandelate as the starting material, the desired title compound was prepared. ¹ H-NMR (400 MHz, CDCl3):

delta,. 7.-81 » ( m., 2H- ),, 7.00 - 6.84, ( ar., 9H ), 5.13, ( d.,

1H„ J = 5.58 Hz ), 4.19 - 4.13, ( m. _ø 4H ), 3.74, ( s., 3H ),.

3.41,, ( a.,, 1H, J = 5.62 Hz ),, 3.02,. ( p., 3H ),.. 2,,56, ( t.,

3H„ J = 7.52 Hz ), 0.90, ( t., 3H, J = 7.33 Hz ).

Grade B)

Preparation of methyl-81-chloro-3-(3-(2-propyl-4-(4-methylsulfonylphenoxy)phenoxy)propoxy)phenylacetate

By an analogous procedure described above in Example 22),

Step D) was carried out using methyl 3-(3-(2-propyl-4-(4-methylsulfonylphenoxy)phenoxy)propoxy)mandelate (obtained in the previous, above-described Step A) as the starting material.

material, the desired title compound was prepared.

’η-ΙΜ, (. 400 MHz, GDSl^):

delta, 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 9

99 9999 9999

9999 99 9999 9999

Grade G)

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

By an analogous procedure to that described above in Example 22), Step E), the desired title compound was prepared using ethyl alpha-chloro-3-(3-(2-propyl-4-(4-methylsulfonylphenoxy)phenoxy)propoxy)phenylacetate (obtained in the previous, above-described Step B) as the starting material.

¹ H-NMR, (400 MHz, CDCl-j):

delta. 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 4 444 4444

4 9444 444· * 449 ·· 4·····

44 4444 4444

4444 44 44 ·· ·· ··

P ř ί k 1 δ d 54)

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

_{SO2CH3 ​}

Grade A)

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

By an analogous procedure to that described above in Example 22), Step C, but using methyl 3-(4-bromobutoxy)-mandelate as the starting material, the desired title compound was prepared.

¹ H-NMR„ ( 400 MHz, CD01 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, ( p., 3H ) ,

3.41,, ( d., IH, 5.62 Hz ), 3.02, ( s., 3H ), 2.57, ( t.,3H, J = 7.24 Hz )„ 2.00,, ( m., 4H ), 0.90, ( t., 3H, J = 7.33 Hz ).

·· ·· 49 • · · · 4 · · · · « « • 4 4*·· 444«

444 44 444 44 4

T3T »4 44··

4·*· 44 44 44 44 44

Grade B;)

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

By an analogous procedure to that described above in Example 22), Step D), using methyl 3-(4-(2-propyl-4-(4-methylsulfonylphenoxy)phenoxy)butoxy)mendelate (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDG12):

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 r g e s (G)

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

By an analogous procedure to that described above in Example 22), Step E), using ethyl alpha-chloro-3-(3-(2-propyl-4-(4-methylsulfonylphenoxy)phenoxy)butoxy)phenylacetate (obtained in the previous, above-described Step B), as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC1-j):

delta, 8.20,. ( w.s., IH ), 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 · • · • · • 00

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)phenoxypropoxy)phenyl)-2,4-thiazolidinedione

Grade A)

Preparation of 2-propyl-5-phenoxyphenol

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

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

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

9494

99 99

4 9 9 4 4 9 4 9 4 4

4 4 4 99 4 9 4 4

4 4 4 4 4 9 9 4 4 4 9

4 9 4 ♦ ♦ · · · ♦ · • ·« · »· ·· ·< ·» ··

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

¹ H-NMR, (400 MHz, OBC1 ₃ ):

delta, 7.16 - 7.01, ( m., 6H ), 6.54, ( d.d., 1H, J = 6.20 Hz, and J = 2.30 Hz ), 6.45, ( d., 1H, 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 ).

(Grade B.)

Preparation of methyl-3-(3-(2-propyl-5-phenoxyphenoxy)-propoxy)-phenyl acetate

By an analogous procedure to that described above in Example 1), Step C), using 2-propyl-5-phenoxyphenol (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GBC1 ₃ ):

delta, 7.31 - 6.82, ( m., 10H ), 6.55, ( d., 1H, J = 2.30 Hz ), 6.52, ( d.d., 1H, J = 8.20 Hz, 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, ( hex., 2H, J = 7.40 Hz ), 0.90, ( t., 3.H, J = 7.30 Hz

432

Grade C)

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

By an analogous procedure to that described above in Example 1), Step C), using methyl 3-(3-(2-propyl-5-phenoxyphenoxy)propoxy)phenylacetate (obtained in the previous, above-described Step B), as the starting material, the desired title compound was prepared.

¹ H NMR (400 MHz, CD12):

delta,. 7.95, (w.s., 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 • · · · • · · ·· ·» ·« ·· ·· ·· • · « · • · · ·

9 9 4

6 4 6

96

434

Grade A)

Preparation of 2-propyl-3-phenoxyphenol

Intermediate 2), (2.81 g), obtained by the procedure described above in Example 55), Step A), was hydrogenated in methanol, using 0.61 g, of the catalyst, i.e. palladium on activated carbon.

After the reaction mixture was filtered through diatomaceous earth, all volatile components of the filtrate were removed, and the desired title compound was obtained.

¹ H-NMR (400 MHz, CDCl ₃ ):

delta, 7.34 - 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 ).

Degree Bu

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

By an analogous procedure to that described above in Example 1), Step B), using 2-prop1-3-phenoxyphenol (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared. ¹ H-NMR, (400MHz, CDCl3):

delta, 7.29 - 6.85, ( 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 t e r g e O

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

By an analogous procedure to that described above in Example 1), Step G.), using methyl-3-(3-(2-propyl-3-phenoxyphenoxy)propoxy)phenylacetate (obtained in the previous, above-described Step B) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, C.DG1 ₃ );

delta, 8.05, ( w.s., 1H ), 7.32 * 6.88, ( m., 10H ), 6.64, ( d., 1H, J = 7.40 Hz ), 6.49, ( d., 1H, J = 7.30 Hz ), 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 57)

Preparation of 5-/3- (4- (2-pr opy 1-3-(phenoxyphenoxy ? butoxy )phenyl/-2,4^ thiazolidinedione ·· ···· ·· ·· ·· ·· ·· • · · · ···· ··· ··· • ·

By an analogous procedure to that described above in Example 22), Steps B), to E), using ethyl 3-(4-bromobutoxy)-mandelate, and 2-propyl-3-phenoxyphenol, (prepared by the procedure described above in Example 56), Step A), as starting materials, the desired title compound was prepared.

¹ H-NMR, ( 400 MHz, CDCl^b delta, 7.96, ( w.s., 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)propoxyphenyl1/2,4-thiazolidine dione • ·

Grade A)

Preparation of 2-(2-propenyl)-4-phenoxyphenol

A solution prepared by dissolving 11.00 g of 1-phenoxy-(4-propenyloxy)-benzene in 150.0 ml of ortho-dichlorobenzene was heated under reflux for 24.0 hours.

The reaction mixture was then cooled to room temperature, and after chromatography on silica gel, the desired title compound was obtained in an amount of 10.3 g.

¹ H-NMR, (400 MHz, CDCl3::

delta, 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 ^A

Grade S)

Preparation of 5-/3-(3-(2-(2-propenyl)-4-(phenoxyphenoxy)propoxyphenyl/2,4-thiazolidinedione

By an analogous procedure described above in Example 22),

Steps B) to E), using ethyl 3-(3-bromopropoxy)-mandelate, and 2-(2-propenyl)-4-phenoxyphenol, (obtained in the previous, above-described Step A), as starting materials, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDC1 ₃ ):

delta, 8.25, ( w.d., 1H ), 7.35 - 6.83, ( m., 1 2H ), 5.97 5.88, ( m., 1H ), 5.32, ( s., 1H ), 5.05 - 5.00, ( m., 4H ),

4.47, (d.t., 4H), 2.28, (m., 2H).

Example, 59)

Preparation of 5-/3-(3-(1-fluoropropyl)-4-phenoxyphenoxy)propoxyphenyl/

2,4-thiazolidinedione

Grade A)

Preparation of 2-(1-fluoropropyl)-4-phenoxyphenol

To a solution prepared by dissolving 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:

A solution of borane methyl sulfide (1.25 M equivalents) in tetrahydrofuran was added at 0°C, and the resulting reaction mixture was stirred for 3.0 hours, during which time 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, and then 4.50 ml of 30% hydrogen peroxide was carefully added. The reaction mixture was then partitioned between water and ether. After separating the organic and aqueous phases, the ether extract was washed successively with water and brine, and after drying with sodium sulfate and concentration under reduced pressure, the residue was chromatographed on silica gel, and the desired intermediate was obtained, 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 = 6.80 Hz ),

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 previous, above-described 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 adding an aqueous sodium bicarbonate solution, it was washed with water, and after drying with sodium sulfate, it was concentrated, and the residue was chromatographed on silica gel to give the desired title 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 and 5.90 H _z ), 2.74, ( t., 2H, J = 7.30 Hz), 2.05, ( m., 2H ).

Grade B)

Preparation of 5-/3-(3-O-fluoropropyl)-4-(phenoxyphenoxy)-propoxyphenyl/2,4-thiazolidinedione

By an analogous procedure to that described above in Example 22), Steps B to E), using ethyl 3-(3-bromopropoxy)-mandelate and 2-(1-fluoropropyl)-4-phenoxyphenol (obtained in the previous, above-described Step Aj) as starting materials, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CHCl 3 ):

delta, 7.94, ( w.s., 1H ), 7.40 - 6.80, ( m., 12H ), 5.35, ( s.,

1H ), 4.44, ( d.t., 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 • · ««#· φ φ φ · « φ φ · φφ

the

cook ₂ hours ₅

Grade A)

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

Grade A ₁ )

Preparation of (4*.<4Áethoxycarbonylphenoxy)-phenyl-allyl ether

A solution prepared by dissolving 10.00 g of 4-yloxyphenol, 12.33 g of 4-fluoroethylbenzoate, and 2.91 g of sodium hydride (60% dispersion in mineral oil) in 50.0 ml of dimethyl sulfoxide was stirred at T50.1 ^° C for 24.0 _hours .

The reaction mixture was then cooled, and the excess was carefully destroyed using 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, it was filtered, and evaporated.

The residue in the form of an oily substance was chromatographed on silica gel to give the desired 4-(4-ethoxycarbonylphenoxy)phenylallyl ether.

Grade A2)

199 9

4 4 «· • · · » * · · ·>·· ·· 9 I 99 4 9 4 4 • ··· · 9 4 4 9 4 4 · φ 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)phenylallyl ether (obtained in the previous, above-described Step Aj) in 50.0 ml of 1,2-dichlorobenzene was heated under reflux for 30.0 hours.

Then, after cooling to room temperature, the mixture was chromatographed on silica gel, and 3.46 g of the intermediate was obtained, which was hydrogenated in 130.0 ml of ethanol in the presence of.

0.30 g, palladium on activated carbon. The reaction mixture was then filtered through diatomaceous earth and concentrated in vacuo.

The desired title compound was obtained.

¹ H-NMR, (400 MHz, CHCl 3 ):

delta, 7.99, ( d., 2H, J = 9.00 Hz ), 6.93, ( d., 2H, J = 9.00 Hz )„ 6.87, ( s.1H ), 6.80, ( d.d., 2H ), 4.36, ( k., 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 ).

Grade B)

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

By an analogous procedure to that described above in Example 22), Steps B) to E), using ethyl 3-(3-bromopropoxy)-mandelate with 2-propyl-4-(4-ethoxycarbonyl)-phenoxyphenol (obtained in the previous, above-described Steps A), respectively A^)} as starting materials, the desired title compound was prepared.

/// ¹ H-NMR, ( 400 MHz, CDCLj):

delta, 8.00, ( d; s w.a., 3H ), 7.40 - 6.80, ( m., 9H ), 5.35, ( s·, 1H ), 4.36, ( k., 2H, J = 7.00 Hz ), 4.22, ( t., 2H, J χ

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]-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 22), Steps B) to E), but using ethyl-4-(3-bromopropoxy)-mendelate, and 4-(1,2-benzisoxazol-3-yl)-2-propylphenol, (International Patent Application WO-97/28,115), as starting materials, the desired title compound was prepared.

4 4 4 4

4/

H-NMR,. ( 400 MHz,. (Ml·})::

Example 62)

Preparation of 5-[3-(4-((1,2-benzisoxazol-3-yl)-2-propylphenoxy)butoxy)phenyl]-2- _[ 4-thiazolidinedione]

By an analogous procedure to that described above in Example 22), using ethyl 3-(4-bromobutoxy)-mandelate and 4-(0,2-benzisoxazol-3-yl)-2-propylphenol (International Patent Application WO-97/28.115) as starting materials, the desired title compound was prepared.

¹ H-NMR _ø (400 MHz,. GECl^):

• » · • · · ·

( m., 2Η ), 0.96, ( t., 3H, J - 7.30 Hz ).

A p p e n d 1 a d 63)

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

H

0'

Grade A)

Preparation of 1-diaz-4-phenyl-2-butanone

A 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 ethereal solution of diazomethane, (85.60 g, Disaldu = N-methyl-N-nitroso*9 99 99 99 • 9999 94·· ► 9 9 99 « 9 4 « «·♦ ·9 99« * · * w

p-toluenesulfonamide in 100.0 ml, dried ethyl ether) at 0°£.

The resulting reaction mixture was then maintained at 0°C until degassing was complete (15.0 minutes), and then warmed to room temperature over 15.0 minutes. 5.0 ml of acetic acid was then added to the reaction mixture, and the mixture was partitioned between phthalate buffer pH 4.0 and methyl tert-butyl ether. After separation of the organic and aqueous phases, the organic layer was washed with water, and after drying with magnesium sulfate, it was filtered and evaporated.

The desired title compound was obtained in the form of an oily substance, which was used as crude product without any purification or delay.

¹ H-NMR, (400 MHz, CHCl ₃ ):

delta, 7.32 - 7.18, ( mult., 5H ), 5.19, a.s.s., 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, i.e. 1-diaz-4-phenyl-2-butanone, in 150.0 ml of dried dichloromethane (obtained in the previous, above-described Step A), and cooled to 0°C, was mixed dropwise with 36.0 ml of a 48% hydrobromic acid solution.

After the evolution of gas in the reaction mixture had ceased, 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, it was filtered and evaporated.

The desired title compound was obtained in the form of

4444 ♦ 4 4» 44 4*4#

444 44 4 4 4 44 4 • · · · 4 · 4 4444

4444 «4 44 *4 44 44

ΥΥΖ substances have an oily consistency, which crystallizes when left at rest.

¹ H-NMR,„ ( 400 MHz,. GD-Gl-j):

delta, 7.30 - 7.16, ( mult., 5H ), 3.83, ( s., 2H ), 2.97 - 2.91, ( mult., _: 4H ).

Grade 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 in Step A above) in 225.0 ml of dried dimethylformamide was treated with added diisopropylethylamine (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, then partitioned between isopropyl acetate and pH 4.0 phthalate buffer.

After separation of the organic and aqueous phases, the organic layer was washed twice with water, and after drying with magnesium sulfate, it was filtered, and concentrated.

The residue was chromatographed on silica gel, using a mixture of hexane and dichloromethane, (5.0:1.0), as eluent, to give the desired title compound.

¹ H-NMR, (400 MHz, CuCl^:

delta, 7.26 - 7.12, ( mult., 6H ),. 6.83, (d.d., 2H, J = 4.70,

2.20 Hz ). 6.73, ( d.d., 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 • 9 99

9 9 9

49

49

9 · ·

9 9 9 • 9 9 ·

9 9 9

9«

Grade H)

Preparation of 3-(2-phenylethyl)-6-methoxy-benzothiophene

A solution prepared by dissolving 495.0 g of 1-(3-methoxyphenyl)thio-4-phenyl-2-butanone (obtained in the previous, above-described Step O) in 85.0 ml of dried dichloromethane was added dropwise, at 0°C, to a solution obtained by mixing 17.0 ml of methanesulfonic acid with 34.0 ml of dichloromethane.

The resulting reaction mixture was then left at 0°C for 20/0 minutes, and then warmed to room temperature, and then quickly poured into a vigorously stirred, cooled mixture of excess 5N sodium hydroxide solution and methyl tert-butyl ether. After separation of the organic and aqueous phases, the organic layer was dried with magnesium sulfate, filtered, and concentrated.

The residue was chromatographed on silica gel, using a mixture of hexane:dichloromethane, (5.0:1.0), as eluent.

The desired title compound was obtained as a clear, oily substance. ¹ H-NMR (400 MHz, GDC12):

delta, 7.66,, ( d., 1H, J = 8.80 Hz ), 7.37 - 7.20, ( mult.,„6H ), 7.05,. ( d.d., 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 ).

Grade E)

Preparation of 3-(2-phenylethyl)-6-hydroxy-benzothiophene

4444

Μ 44 44 ·» ♦ * « 4444 4 4 4 4 ♦ « 44 44 4444

444 44 444 «4 β

44 4444 4444

4444 44 44 44 44 44

W

A solution prepared by dissolving 5.483 g of 3-(2-phenylethyl)-6-methoxy-benzothiophene (obtained in the previous, above-described Step D) in 60.0 ml of dried dichloromethane was mixed with a 1M solution of bromine triboride (20.81 ml of dichloromethane solution) under constant stirring at a temperature of minus 10.0°C.

After 2.0 hours, the reaction mixture was rapidly warmed to room temperature, and then partitioned between isopropyl acetate and aqueous sodium bicarbonate. After separating the organic and aqueous phases, the organic layer was washed once with water, and after drying with magnesium sulfate, it was filtered, and evaporated.

The residue, in the form of a semi-solid, was chromatographed on silica gel using a mixture of hexane: ethyl acetate, (2.5:1.0), as eluent.

The desired title compound was obtained as a pale yellow solid.

¹ H-NMR, (400 MHz, CDCl^:

delta, 7.60, ( d., 1H, J = 8.80 Hz ), 7.35 - 7.23, ( mult,, 6H),

6.94, ( d.d., 1H, J = 8.70, 2.30 Hz ), 6.88, ( s., 1H ), 5.40, ( s., 1H ), 3., 13 - 3.02, ( mult., 4H ).

Grade E?)

Preparation of 3-(2-phenylethyl)-6-allyloxy-benzothophene

A solution prepared by dissolving 4.651 g of 3-(2-phenylethyl)-6-hydroxy-benzothiophene (obtained in the previous, 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 another 6.26 grams of cesium carbonate.

After 2.50 hours at room temperature, the reaction mixture was partitioned 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 after drying with magnesium sulfate, it was filtered and evaporated.

The resulting residue was chromatographed on silica gel, using hexane:dichloromethane (3.0:1.0) as eluent, to give the desired title compound as a _clear , oily substance.

¹ H-NMR, (400 MHz, COCl2:

delta, 7.73, ( d., 1H, J = 8.80 Hz ), 7.47 - 7.34, ( mult., 6H ),

7.19, ( d.d., 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., IH, J = 10.50, 1..40 Hz ), 4.69» ( t., 1H,, J = 1.50 Hz ), 4.67» ( t., IH, J = 1.50 Hz ), 3.25 - 3.12, ( mult.„ 4H ).

G e r g e s (G)

Preparation of 3-(2-phenylethyl)-6-hydroxy-7-allyl-benzothiophene

A solution prepared by dissolving 4.373 g of 3-(2-phenylethyl)-6-allyloxy-benzothiophene (obtained in the previous, above-described Step F) in 45.0 ml of 1,2-dichlorobenzene was heated to reflux under a nitrogen atmosphere for 8.50 hours.

_After the reaction mixture was cooled to a temperature of approximately 50.0°C, the solvent was removed from the mixture under high vacuum until the residue solidified.

The solid residue was then dissolved in 100.0 ml of dichloromethane,

• · φ « * * · Φ

Φ Φ · ·· ΦΦ

156 and after isolation of 8 and subsequent evaporation, the residue was chromatographed on silica gel, using dichloromethane as eluent.

After evaporation of the appropriate fractions collected, the desired title compound was obtained as a pale yellow solid.

¹ H-NMR, (400MHz, GEC1 ₃ ):

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.j-), 1H, J = 7.10, 3.90 Hz ), 5.23, (d. 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 ), 3/3-3.01, ( mult., 4H ), 1.27, ( t., 3H, J = 7.20 Hz).

Grade H)

Preparation of 3-(2-phenylethyl)-6-hydroxy-7-propyl-benzothiophene

Solutions; prepared by dissolving 3.062 g of 3-(2-phenylethyl)-6-hydroxy-7-yl-benzothiophene (obtained in the previous, above-described Step G) in 60.0 ml of methyl tert-butyl ether, were placed in a hydrogenation vessel, 8 after adding 306.0 mg of 5% palladium on activated carbon, the reaction mixture was hydrogenated in a Parr apparatus, at a pressure of 0.098 MPa, for 1.0 hour.

After the reaction mixture was filtered through diatomaceous earth, it was evaporated to give the desired title compound as a yellow-colored, oily substance.

Upon subsequent standing, a faintly yellow solid emerged, which did not require any further purification.

0« ♦ ·«· >0 • 0 00 • 000 • 0 0 0 00 00

0 0 0

0 0 0

0 0 · • 0 0 0

00 ¹ H-NMR, (400 MHz, ODGl^):

delta, 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, ( d.d., 2H, J = 7.70, 1.60 Hz ), 1.74, ( hex., 2H, J = 6.00 Hz ), 1.02, ( t., 3H, J = 7.40 ).

S t e g e I)

Preparation of methyl-4-/3-(3-(2-phenylethyl)-7-propyl-benzothiophen-6yl-oxy)-1-propoxy/-phenylacetate

By an analogous procedure to that described above in Example 1), Step B), using 3-(2-phenylethyl)-6-hydroxy-7-propylbenzothiophene (obtained in the previous, above-described Step H) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400, MHz, CDG1 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-propyl-benzothiophen-6-yloxy)-1-propoxy)/-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

By an analogous procedure to that described above in Example 1), Step G), except using methyl [4-(3-(7-propyl-3-(2-phenylethyl)-benzothiophen-6-yloxy)-1-propoxy]-phenylacetate (obtained in the previous, above-described Step I) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDO 2 ):

delta, 9.46, ( w.s., 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, ( w.O,. quart., 4H, J - 5.503 Hz ), 3.11, (v.

y in

w. fifth 4H ), 2.91, ( N.d.d., 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-propyl-benzothiophene-1,1dioxide-6-yl-oxy)-1-butoxy)/-phenyl-2,4-thisolidinedione

O

• 4 44 44 • · · 4 * 4 4 4444

4 44 44 444» • 4 4 4 4 4 444 4» 4

44 4444 4444

4444 44 44 44 44 44

T/

Grade A)

Preparation of 3-(2-phenylethyl)-6-hydroxy-7-propyl-benzothiophene-1,1-dioxide

A solution prepared by dissolving 3.515 g of 3-(2-phenylethyl)-6-hydroxy-7-propyl-benzothiophene (obtained in Example 63, Step H) in 40.0 ml of dichloromethane was cooled to 0°C and, with constant stirring, was added portionwise to 5.457 g of 75% m-chloroperbenzoic acid (in solid form).

After 15.0 minutes, the reaction mixture was warmed 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, and after separating the organic and aqueous phases, the organic layer was washed with aqueous sodium bicarbonate, then with water, and after drying with magnesium sulfate, it was filtered and evaporated.

The residue, in the form of a solid, was chromatographed on silica gel using a mixture of hexane:ethyl acetate, (5.0:1.0), as eluent.

The desired title compound was obtained as a white solid.

¹ H-NMR, (400 MHz, CEGl^)::

delta, 7.35 - 7.19, ( m., 4H ), 7.04, ( a., 1H, J = 8.10 Hz ),

6.89, ( ά., 1H, J = 8.20 Hz ), 6.63, ( v.h.s., 1H ),6.29, ( t., 1H, ď = 1.50 Hz ), £2.97 2.78, ( m., 6í£ ), 1.74, ( d.sex., 2H,

J = 7.20, 2.90 Hz ), 1.03, ( t., 3H, J = 7.40 Hz ).

Degree ()

9 ·*·· ·* 99 «· ·· • 9 · «··« 9 9 9 9 • 9 · 9 ·· 4 9 4 9 • 9 9 · ·· 9 9 9 9 9 ·

9« 9999 999«

9999 99 *9 99 9« 99

Preparation of methyl 1-3-(4-(7-propyl-3-(2-phenylethyl)-benzothiophen1,1-dioxide-6-yloxy)-1-butoxy)-phenylacetate

By an analogous procedure to that described above in Example 1), Step B), using 3-(2-phenylethyl)-6-hydroxy-7-propylbenzothiophene-1,1-dioxide (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

’η-ΝΜΒ, ( 400 MHz, 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, ( a.,. IH ), 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 C)

Preparation of 5-[3-(4-(3-(2-phenylethyl)-7-propyl-benzothiophen-1,1-dioxide-6-yloxy)-1-butoxy)/-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step &), but using methyl-3-((4-(7-propyl-3-(2-phenylethyl)-benzothiophen-1-dioxide-6-yl)-oxy-4-1- _butoxy )-phenylacetate, (obtained in the previous, above-described Step B), as the starting material, the desired title compound was prepared. ¹ H-NMR, (400 MHz, _CTC13 )::

delta, 8.42, ( w.s., 1H ), 7.32 - 7.19, ( m., 6H ), 7.12, ( d.,

1Ητη J - 8.30 Hz ), 6.98, ( d., 1Η,, J = 8.10 Hz ), 6.91 - 6.85, ( m., 4H ),. 6,,30, ( p., 1H ), 5,30,, ( p., 1H ), 4,04, ( w.quart.,

4H,. J = 6.30 Hz ), 2.94 - 2.88, ( m.,.. 4H ), 2.02 - 1.98, ( ur. _r

4H )„ 1.69, < hex., 2H,. J = 5.20 Hz ), 0.99,. ( t., 3H, J = 7.30 Hz).

• 4 99 99 99

9 4 4 4 · 4 4444

4 4 4 99 4444 • 444 44 444 4« 4

44 44-4 4 4444

4444 44 44 44 44 44

Example; 65)

Preparation of 5-/4-(3-(7-propyl-3-(2-phenylethyl)-benzothiophen-1,1 dioxid-6-yloxy)-1-propoxy)/phenyl-2,4-thiezolidindione

Grade A)

Preparation of methyl-4-(3-(7-propyl-3-(2-phenylethyl)-benzothiophen1,,1-dioxid-6-yl-oxy)-1-propoxy-4-phenylacetate

ΦΦΦΦ

ΦΦ ΦΦ ΦΦ ΦΦ • * Φ ΦΦΦΦ ΦΦΦΦ

Φ Φ · Φ ·Φ φφφφ

Φ ΦΦΦ ΦΦ «ΦΦ · Φ Φ

Φ ΦΦ Φ·Φ· φφφφ ΦΦΦΦ ΦΦ *· ·· Φφφ φφ

462

By an analogous procedure to that described above in Example 1), Step B), using 3-(2-phenylethyl)-6-hydroxy-7-propylbenzothiophene-1,1-dioxide (obtained in the previous, above-described Example 64), Step A), as the starting material, the desired title compound was prepared.

¹ H-NMR, ( 400 MHz, CDGl^ ):delta, 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).

Grade Β;)

Preparation of 5-/4-(3-(3-(2-phenylethyl)-7-propyl~benzothiophen-1,1dioxide-6-yl-oxy)-1-propoxy)/-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step C), using methyl 4-(3-(3-(2-phenylethyl)-7-propyl benzothiophen-1,1-dioxid-6-yloxy)-1-propoxy)-phenylacetate (obtained in the previous, above-described Step A) as starting material, the desired title compound was prepared. ¹ H-N1R„ (400 MHz, CDGl^):

delta, 8.87, ( w.s., 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., IH, 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, (m., 2H, J = 7.70 Hz), 2.29;

9999 99 99 49 94 • 4 · 4 9 9 4 9 9 4 4

9 4 4 ·4 4 9 4 4

4 4 4 4 4 9 9 4 4 4 · • · · ♦ 9 4 4 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-phenylethyl)-7-propyl-benzothiophen-1-oxide-6-yloxy)-1-butoxy)/-phenyl-2,4-thiazolidinedione

Grade A)

Preparation of 3-(2-phenylethyl)-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 in Example 63, Step H, above) 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 cooled to 0°C, and with constant stirring was mixed in portions with 1.567 g, 75% m-chloroperbenzoic acid, (in solid form)*

After 15.0 minutes, the reaction mixture was warmed to room temperature, and stirred at this temperature for 1.50 hours. The reaction mixture was then partitioned between isopropyl acetate, aqueous sodium bicarbonate, and after separating the organic and aqueous phases, the organic layer was washed with aqueous sodium bicarbonate, then with water, and after drying with magnesium sulfate, it was 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), hexane:ethyl acetate (5.0:2.0), and hexane:ethyl acetate methanol (5.0:2.0:0.35).

The desired title compound was obtained as a white solid.

¹ H-NMR, (400 MHz, GDC1 ₃ ):

delta, 8.53, ( w.s., 1H, ), 7.33 - 7.18, ( mult., 5H ), 7.01, ( d., 1Η» 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., 2H, J =

7.60 Hz )» 0.95» ( t., 3H, J = 6.70 Hz).

Grade B)

Preparation of methyl-3-(4-(3-(2-phenylethyl)-7-propyl-benzothiophen-oxid-5-yloxy)-1-butoxy)-phenylacetate

By an analogous procedure to that described above in Example 1), Step B), using 3-(2-phenylethyl)-6-hydroxy-7-propylbenzothiophene-1-oxide (obtained in the previous, above ·· 9··· ·· ·· • ·

¹ H-MR,, (400 MHz, CJM1):

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

7.19 - 7.16, ( dl, 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/^= 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*30 Hz).

S t u p e r O

Preparation of 5-/3-(4-(3- (2-phenylethyl)-7-propyl-benzothiophen-1-oxid6-yloxy)-1-butoxy)/-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step C), using methyl 3-(4-(3-(2-phenylethyl)-7-propyl-benzothiophen-1-oxid-6-yl-oxy)-1-butoxy)-phenylacetate (obtained in the previous, above-described Step B) as starting material, the desired title compound was prepared. 1H-NMR* (400 MHz, CDCl^* diastereoisomeric pair):

delta, 9.62 - 9.53, ( m.s.s., 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, w.hex., 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-propyl-benzofuran-6-yl-oxy)-1-propoxy)/-phenyl-2,4-thiazolidinedione

Grade 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 ethereal solution of diazomethane (obtained from 20.0 g of Diazald = N-methyl-N-nitroso-p-toluenesulfonamide), cooled to 0°C.

After the resulting reaction mixture was stirred for 30.0 minutes, it was warmed to room temperature over a further 30.0 minutes. After 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, it was filtered and concentrated.

The desired title compound was obtained in the form of

4β7 substances of oily consistency, which was used further without further purification.

¹ H-NMR, (400 MHz, CD.01^:

delta, 5.18, ( w.s., 1H ), 2.15, ( w.s., 2H ), 1.01, ( s., 9H ).

Grade 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 in the previous, above-described Step A), in 12.0 ml of dichloromethane, and cooled to minus 10.0°C, was treated with, dropwise, 1.14 ml of a 48% solution of hydrobromic acid, while stirring continuously.

After the gas evolution in the reaction mixture had ceased, the mixture was stirred at room temperature for 15.0 minutes, and then partitioned between isopropyl acetate and water. After separating the organic and aqueous phases, the organic layer was washed once with water, and after drying with magnesium sulfate, it was filtered, and evaporated.

The desired title compound was obtained in the form of an oily substance, which was used further without any further processing.

¹ H-NMR, ( 400 MHz, CDC1 ₃ )::

delta, 3.85, ( s., 2H ), 2.50, ( s., 2H ), 1.01, ( s., 9H ).

Grade C)

Preparation of 1-(3-methoxyphenoxy)-4,4-dimethyl-2-pentanone

A solution, prepared by dissolving 1.626 g of 1-bromo-4,4-dimethyl-2-pentanone (obtained in the previous, above-described Step B) in 18.0 ml of dimethylformamide, was mixed with 1.256 g of 3-methoxyphenol, 8 3.292 g of cesium carbonate, and the resulting reaction mixture was stirred for 2.50 hours.

The reaction mixture was then partitioned 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, dried over magnesium sulfate, filtered, and concentrated.

The residue, an oily substance, was chromatographed on silica gel using hexane:ethyl acetate (4.0:1.0) as eluent to give the title compound.

¹ H-NMR, (400 MHz, CBCl 2 ):

delta, 7.18, ( d.d.d., 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 ).

Grade B)

Preparation of 3-(2,2-dimethylpropyl)-ε-methoxybenzofuran

A solution prepared by dissolving 1.408 g of 1-(3-methoxyphenoxy)4,4-dimethyl-2-pentanone (obtained in the previous Step C above) 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 2x with 30.0 ml of xylenes each, and then concentrated under high vacuum.

The non-volatile components were partitioned between isopropyl acetate and aqueous sodium bicarbonate. After separating the organic and aqueous phases, the organic layer was washed with aqueous sodium bicarbonate, and after drying with magnesium sulfate, it was filtered.

After removal of the solvents, a residue was obtained which was chromatographed on silica gel using a mixture of hexane:dichloromethane, (3.0:1.0), as eluent, to give the desired title compound, ¹ H-NMR, (400 MHz, GDC12):

delta,. 7.40, ( d., 1H, J = 8.60 Hz ), 7.31, ( s., 1H ), 7.00, ( d., TH, J - 2.20 Hz ), 6.88, ( d.d., 1H, J = 8.60, 2.40 Hz ),

3.85,, ( s·, 3H ), 2.52, ( s., 2H ), 0.98, ( s., 9H )..

Grade 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 in the previous, above-described Step D) in 35.0 ml of dried dichloromethane, and cooled to minus 10.0°C, was added 3.70 ml of a 1M solution of bromine triboride in dichloromethane, and after the reaction mixture was warmed to room temperature, it was stirred for 1.0 hour.

The reaction mixture was then partitioned between isopropyl acetate and aqueous sodium bicarbonate. After separating the organic and aqueous phases, the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and the volatiles were removed.

The residue was chromatographed on silica gel, using hexane:ethyl acetate (5.0:1.0) as eluent, to give the desired title compound.

//7/ ¹ H-NMR, (400 MHz, CUCl-j):

delta, 7.34, ( d., 1H, J » 8.4© Hz ), 7.28, Os., 1H ), 6.93, ( d., 1H,. J - 2.20 Hz ), 6.76, ( d.d., 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-sylyloxybenzofuran

A solution prepared by dissolving 2.880 g of 3Ϊ-(2,2-dimethylpropyl)-6-hydroxychlorofuran (obtained in the previous, above-described Step E) in 30.0 ml of dried dimethylformamide was mixed with constant stirring first with 1.282 g of allyl bromide, and then with 4.828 g of cesium carbonate.

After 2.0 hours, the reaction mixture was partitioned between isopropyl acetate and phthalate buffer pH 4.0. After separating the organic and aqueous phases, the organic layer was washed twice with water, and after drying with magnesium sulfate, it was filtered and concentrated.

The desired title compound was obtained and was sufficiently pure that further work-up was not necessary. ¹ H-NME, ( 400 MHz, CB€1 ₃ ):

delta, 7.37, ( d., 1H, ď = 8.60 Hz ), 7.28, ( s., 1® ), 6.99, ( d. „ 1H, ď = 2.20 Hz ), 6.87, ( d.d., 1H, J = 8.60, 2.20 Hz ), 6.07, ( mult., 1H ), 5.43, ( d.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 ), 4.55, ( t., 1H, j: = 1.50 Hz ), 2.49, ( s., 2H ), 0.95, ( s ·,. 9H.).

• 4

4

777

S degree. G.)

Preparation of 3-(2,2-dimethylpropyl)-6-hydroxy-7-allyl-benzofuran

A solution prepared by dissolving 3.226 g of 3-(2,2-dimethylpropyl)-6-yloxybenzofuran (obtained in the previous Step IP described above) in 1,2-dichlorobenzene was heated under reflux for 8.0 hours.

After the reaction mixture was cooled to a temperature of about 50.0°C, the solvent was distilled off under high vacuum, and the residue, in the form of a solid, was dissolved in cyclohexane heated to reflux under a condenser. The resulting solution was then cooled to room temperature and filtered.

The mother liquor was evaporated and chromatographed on silica gel using hexane:ethyl acetate (2.5:1.0) as eluent to give additional solid which was added to the previously prepared product to give all of the desired title compound.

¹ H-NMR, (400 MHz, CECl2):

delta, 7.32, (s., 1H), 7.26, (d., 1H, ď - 8.30 Hz), 6.80, (d., _; 1H, Jí - 8.40 Hz), 6.09, (t.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 e g e r HO

Preparation of 3>(2,2-dimethylpropyl)-6-hydroxy-7-propyl-benzofuran · ··· ·

A solution prepared by dissolving 1.912 g of 3-(2,2-dimethylpropyl)-6-hydroxy-7-allyl-benzofuran (obtained in the previous, above-described Step G) was mixed in a hydrogenation vessel with a catalyst, i.e. 200.0 mg of 5% palladium on activated carbon.

The resulting reaction mixture was hydrogenated in a Parr apparatus at 0.098 MPa for 1.0 hours. After removing 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 2 )::

delta, 7.28, ( s., 1H ), 7.17, ( d., 1H, J = 8.30 Hz ), 6.72, ( d.,, 1H, «I - 8.40-Hz ), 4.82, ( s., IH ), 2.83» ( t., 2H, J =

7.70 Hz ). 2.48, ( s., 2H )» 1.70, ( hex., 2H, J = 9.20 Hz ),

0.99, ( t., 3H, J. = 7.50 Hz ), 0..95, ( s., 9H ).

S' level I )

Preparation of methyl-4-(3-(3-(2,2-dimethylpropyl)-7-propyl-benzofuran-6-yloxy)-1-propoxy)-phenylacetate

By an analogous procedure to that described above in Example 1), Step B1), using 3-(2,2-dimethyl-1-propyl)-6-hydroxy-7-propyl-benzofuran (obtained in the previous, above-described Step H) as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, 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, » · • ·

ΖΪ3 ( a., 2H ), 2.95, ( t., 2H, J = 7.40 Hz ), 2.29, ( quint., 2H,

J = 6.3O: Hz ), 1.71, ( hex., 2H, J = 5.90 Hz ), 1.0.1, ( t., 3K, J = 7.30 Hz).

Degree (T)

Preparation of 5-/4-(3-(3-(2,2-dimethylpropyl)-7-propyl-benzofuran-6- _yl- oxy)-1-propoxy)/-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step O), using methyl-4-(3-(3-(2,2-dimethyl-1-propyl)-7-propyl-benzofuran-6-yloxy)-1-propoxy)-phenylacetate (obtained in the previous, above-described Step I) as the starting material, the desired, title compound was prepared.

¹ H-NMR, (400 MHz, CDG12):

delt8, 8.43, (w.s., 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., 1ff),

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-propyl-benzofuran-6-yl-oxy)-1-butoxy)/-phenyl-2,4-thiazolidinedione

T'/

4 44 4 4 • ·· · ··

4« ·· ♦· * · « · » · « • · · · · · I

4 4 4 4 4 4 4 4 • 4 4 4 4 4 4 4 •4 44 44

£? t u p e ň A')

Preparation of methyl-3-(4-(3-(2,2-dimethylpropyl)-7-propyl- _benzofuran -6-yl-oxy)-1-butoxy)-phenylacetate

By an analogous procedure to that described above in Example 1), Step B), using 3-(2,2-dimethyl-1-propyl)-6-hydroxy-7-propyl-benzofuran (obtained by the procedure described above in Example 67), Step H), as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CD3 Cl2):

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-ffiz ), 2.29, ( quint., 2H, J = 6.30.} Hz ), 1.71, < hex., 2H, J = 5.90 Hz ), 1.01, ( t., 3H, <J = 7.30 Hz ).

Step® B) • 444

Preparation of 5-/3-(4-(3-(2,2-dimethylpropyl)-7-propyl-benzofuran-6-yl-oxy)-1-butoxy)/-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step C), using methyl-3-(4-(7-propyl-3-(2,2-dimethyl-1-propyl)-benzofuran-6-yloxy)-1-butoxy)-phenylacetate (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared.

¹ H-NMR, ( 400'MHz, CDG1 _J? ) r

Example 6.9)

Preparation of 5-[3-(4-(3-(2-phenylethyl)-7-propyl-benzofuran-6-yl-oxy)-1-butoxy]-phenyl-24-thiazolidinedione

O,

HN

• 99« * * 9 9 « • 9 «9 « h

Grade A)

Preparation of 1-(3-methoxyphenoxy)-4-phenyl-2-butanone

A solution prepared by dissolving 5.519 g of 1-bromo-4-phenyl-2-butanone (prepared as described above in Example 63), Grade EK), in air-dried dimethylformamide was mixed first with 3.608 g of 3-methoxyphenol, and then with

9.481 g, cesium carbonate.

Then, the resulting reaction mixture was stirred at room temperature for 2.0 hours, partitioned between isopropyl acetate and phthalate buffer at pH 4.0. After separating the organic and aqueous phases, the organic layer was washed twice with water, dried over magnesium sulfate, filtered, and concentrated.

The residue was chromatographed on ηβ silica gel, using a mixture of hexane:ethyl acetate, (5.0::1.0), as eluent.

The desired title compound was obtained as a yellow solid.

¹ H-NMR, (400 MHz, CEC1 ₃ ):

delta, 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, ( d.d., 1H, J = 8.10, 2.50 Hz), 4.49, ( s., 2H 1, 3.76, ( s., 3H), 2.93, ( s., 2H, overlapping d.t., IH), 2.70, ( d.t.,· 1H, J = 7.90, 10.50 Hz)

Grade B)

Preparation of 3-(2-phenylethyl)-6-methoxy-benzofuran

To a solution prepared by mixing 10.0 ml of dichloromethane with 5.68 ml of methanesulfonic acid, and cooled to minus 10.0°C, was added dropwise to the solution obtained ♦

and tt tt9 *

» ♦ · « · · by dissolving 2.368 g _of 1-(3-methoxyphenoxy)-4-phenyl-2-butanone, (obtained in the previous, above-described Step AU, in 25.0 ml of dried dichloromethane, and the resulting reaction mixture was warmed to room temperature, and then stirred for 30.0 minutes. Then the reaction mixture was quickly poured into an intensively stirred, and cooled mixture, prepared from a mixture of an excess of 5N sodium hydroxide solution and methyl tert.-butyl ether. After separating the organic and aqueous phases, 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 desired title compound was obtained in the form of a clear substance of oily consistency.

¹ H-NMR, (400 MHz, GDC1-j):

delta, 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 - 2.91, ( mult., 4H ).

Grade 0)

Preparation of 3:-(2-phenylethyl)-6-hydroxy-benzofuran

A solution prepared by dissolving 2.066 g of 3-(2-phenylethyl)-6-methoxy-benzofuran (obtained in the previous, above-described Step E) in 20.0 ml of dried dichloromethane, cooled to minus 10.0°C, was mixed with a solution obtained by dissolving bromide triboride in dichloromethane (total 8.40 ml of 1M bromide triboride solution) while stirring.

After 15 minutes, the resulting reaction mixture was warmed to room temperature and then stirred for another 15.0 minutes. After partitioning between isopropyl acetate and phosphate buffer pH 7.0, the organic and aqueous phases were separated, and the organic layer was washed twice with pH 7.0 buffer, and after subsequent drying with magnesium sulfate, it was filtered and evaporated.

The residue, in the form of an oily substance, was chromatographed on silica gel, using a gradient elution with dichloromethane (100%), up to a mixture of dichloromethane:ethyl acetate, (40.0:1.0).

The desired title compound was obtained as a pale yellow solid.

¹ H-NMR, (400 MHz, COG12):

delta, 7.32, ( d., 1H, J = 8.40 Hz ), 7.30 - 7.19, ( mult.,6H), 6.93, ( d., 1H, J = 2.20 Hz ), 6.76, ( d.d., 1H, J = 8.40,2.20; Hz ), 4.88, ( v.s.s., 1H; ), 3.01 - 2.90, ( mult., 4H ).

Grade D)

Addition 3 - (2-fěny 1 e t hy 1) - 6 -a 1 l.y 1 oxy-benz of ura nu

To a solution prepared by dissolving 1.128 g of 3-(2-phenylethyl)-6-hydroxy-benzofuran (obtained in the previous, above-described Step C) in 15.0 ml of dried dimethylformamide, first 0.43 ml of allyl bromide and then 1.620 g of cesium carbonate were added with constant stirring.

After the resulting reaction mixture was stirred at room temperature overnight, the mixture was partitioned 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 after drying with magnesium sulfate, it was filtered and evaporated.

The desired title compound was obtained, which did not require further purification.

·*»« » · · 4444 4 9 4 « • * 44 44 4444 • 444 44 444 44 4 «4 4444 »44»

4444 44 44 »4 44 4« w

¹ H-NMR·;, (400 MHz,. CnCl-^):

delta,, 7.36, ( d.,1H, J = 8.60 Hz ), 7.30 - 7.18, ( mult. , 6ffi), 7„oo;, ( d., 1H„ J = 2.20 Hz ), 6.89, ( d.d., IH, 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, ( d.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 ).

Step E)

Preparation of 35-(2-phenylethyl)-6-hydroxy-7-allyl-benzofuran

A solution prepared by dissolving 1.245 g of 3-(2-phenylethyl)-6-allyloxy-benzofuran (obtained in the previous, above-described Step D) in 20.0 ml of 1,2-dichlorobenzene was heated at reflux under a nitrogen atmosphere for 11.0 hours.

After cooling the solution to a temperature of approximately 50.0°C, the solvent was removed using 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 a mixture of hexane:ethyl acetate (5.0:1.0) as eluent.

After evaporation of the appropriate fractions, the desired title compound was obtained as a pale yellow solid.

¹ H-NMR, ( 400 MHz,, CDCl^ ) delta, 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, in the direction of decreasing field J % 17.20, 1.70 HzJ in the direction of increasing field <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

4 9444 4 9 4 4

4 4 4 4 4 4 4 4 4 4 4

4 9 4 4 4 4 9 4 4 4

4444 99 44 44 49 44

770

3.70, (t., 1H, J = 1.60 Hz ), 3.06 -2.92, ( mult., 4H ).

Step F)

Preparation of 3-(2-phenylethyl)-6-hydroxy-7-propyl-benzofurene

A solution prepared by dissolving 1.116 g of 3-(2-phenylethyl)6-hydroxy-7-silyl-benzofuran (obtained in the previous, above-described Step E) in 12.0 ml of methyl tert-butyl ether was placed in a hydrogenation vessel, and after adding 110.0 mg of 5% palladium on activated carbon as a catalyst, the reaction mixture was hydrogenated in a Parr apparatus at a hydrogen pressure of 0.098 MPa for 0.50 hour.

The reaction mixture was then filtered through diatomaceous earth, and after evaporation of the filtrate the desired title compound was obtained in the form of a yellow-colored substance of oily consistency, which, on standing, solidified to a pale yellow-colored solid, requiring no further purification.

¹ H-NMR, ( 400 MHz, CUClyl) t delta, 7.36 - 7.22, ( mult., 7H ), 6.78, ( dl, 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).

Grade G)

Preparation of methyl 1-3-(4-(3-(2-phenylethyl)-7-propyl-benzofuran-6-yloxy)-1-but oxy)-pheny1β cetate ♦'* φφφφ φφ φφ φ* φφ φ · · * * φ· φ φφ φ • * φ · ♦· φ φ · ♦ • φφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφφ φφ ·· φφ φφ

By an analogous procedure to that described above in Example 1), Step (b), using 3-(2-phenylethyl)-6-hydroxy-7-propylbenzofuran (obtained in the previous, above-described Step F) as the starting material, the desired title compound was prepared.

1H^NMR, ( 400 MHz, CBC1 ₃ ) with 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, ( p., 1H ),. 4.21 - 4.16, ( m., 4H ), 3.67, ( s., 3H ),

3.54.

Grade H)

Preparation of 5-[3-(4-(1-(2-phenylethyl)-7-propyl-benzofuran-6-yloxy)-1-hydroxy]-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example T), Step C), using methyl 4-(4-(3-(2-phenylethyl)-7-propyl-benzofuran-6-yloxy)-1-butoxy)-phenylacetate (obtained in the previous, above-described Step G) as starting material, the desired title compound was prepared. ¹ H-NMR, (400 MHz, CBO1^):

delta, 8.67, ( w.s., 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, ( s.m., 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-2,4-1-thiazolidine indion

Grade A)

Preparation of methyl 1-3-(4-(3-(2-phenylethyl)-7-propyl-benzothiophen-6-yl-oxy)-1-butoxy)-phenylacetate

By an analogous procedure to that described above in Example 1), Step B), using 3-(2-phenylethyl)-6-hydroxy-7-propylbenzothiophene (obtained in Example 63), Step H), as the starting material, the desired title compound was prepared.

(400 MHz, GDO1^):

delta, 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, ( s.t.,, 2H, J = 5.20 Hz ), 4.08, ( s.t., 2H, J = 5.50 Hz ), 3.71, ( s., 3H ), 3.62, ( s., 2H ),

3.13 - 3.06, ( mult., 4H ), 2.91, ( d.d., 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

.

Grade B)

Preparation of 5-/3-(4-(3-(2-phenylethyl)-7-propyl-benzothiophen-6-yloxy)-1-butoxy)/-phenyl-2,4-thiazolidinedione

By an analogous procedure to that described above in Example 1), Step O), using methyl 3-(4-(3-(2-phenylethyl)-7-propyl-benzothiophen-6-yloxy)-1-butoxy)-phenylacetate (obtained in the previous, above-described Step A) as the starting material, the desired title compound was prepared. ¹ H-NMR, ( 400 MHz, CDOl^r delta, 9.41, ( w.s., 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, ( s.s., 1H ), 4.1 2, ( s.s., 2H ), 4.07, ( s.s., 2H ), 3.08, ( s.quart., 4H ), 2.90, ( s.t., 2H, J = 7.50 Hz ), 2.04, ( s.s., 4H ), 1.76, ( w.hex., 2H, J = 7.60 Hz ),.

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

Example; 71)

Preparation of 5-/4- (3-(3-(2-phenylethyl)-7-propyl-benzothiophene-1-oxide 6-yloxy)-1-propoxy)/-phenyl-2,4-thiazolidinedione

4 W44 · • 4

By an analogous procedure to that described above in Example 66), Step A), using 5-[3-(4-(3-(2-phenylethyl)-7-propylbenzothiophen-5-yloxy)-1-butoxy]/-phenyl-2,4-thiazolidinedione as starting material, the desired title compound was prepared.

H-WR,. (400 MHz, CEC.1^?; diastereoisomeric pair):

delta, 8.83, ( w.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, ( w.t,, 4H, J = 5.90 Hz ),

3.07 - 2.92, ( mult., 4H ), 2.87, ( s.t., 2H,' J = 7.60 Hz ),

2.33, ( pent., 2H, J = 5.80 Hz ),. 1.70, (w.hex., 2H, J = 7.8Q:

Hz ), 1.01, (d.t., 3H, J = 7.30, 1.70 Hz ).

Example 72)

Preparation of 5-/4- (3-(2-propyl-4-(4-fluorophenoxy)-phenoxy)propoxy)phenyl/-2,4-thiazolidinedione • 9 #9«·

4 • * 9 • 9 •999 «4

99 99 »· • 9 9 9 9 99 4 • 9 49 4 4 4 «

49 944 44 ·

49 9 9 44 4 ·· ·· 44 44

S- grade A')

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

The title compound was prepared by an analogous procedure to that described above in Example 22, Step G) using 2-propyl-4-(4-fluorophenoxy)-phenol (obtained by the procedure described above in Example 23, Step A) using 4-fluorophenol as starting material) and then by an analogous procedure to that described above in Example 23, Step D). ¹ H-NMR (400 MHz, CDO12):

delta. 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 ♦ ·*· ·· 4» 44 ·4 * · * 4 4 4 4 4444

4 44 44 4 4 4 4

444 44 <44 44 4

44 4444 4444

4444 «4 44 44 44 44

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

Grade A)

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

A solution prepared by dissolving 5.0 g, (33.30 mmol), 4-allyloxyphenol, (prepared as described above in Example 22), Step Ap, 5.17 g, (36.60 mmol), 4-fluoro-1-nitrobenzene; 6.90 g, (49.90 mmol), potassium carbonate, and 20.0 mL, dimethylacetamide, was heated under reflux to over.

The reaction mixture was then partitioned between ethyl acetate and water. After separation of the organic and aqueous phases, the organic layer was dried over sodium sulfate and concentrated. The resulting residue was chromatographed on silica gel, using dichloromethane and hexane (20% to 50%) as eluent.

7.30 g of the intermediate product (i.e. "compound A") was obtained in the form of a yellow-colored substance of oily consistency.

► 9 »·»*· • * • 9

9999 ·· 9« • 9 * 9

9 * 9 • 9 99

9 9 9

9 9 9 • 9 9 <

9 9 9 «9 99 /η

The intermediate product, i.e. the compound designated A ₁ , in the form of a yellow-colored oily substance (7.30 g), obtained in the previous operation described above, was taken up in 30.0 ml of dichlorobenzene, and the resulting solution was heated under reflux overnight.

The reaction mixture was then concentrated to a black oily substance which was chromatographed on silica gel using a mixture of 15% acetone in hexane as eluent.

4.90 g of intermediate product (compound A^) was obtained in the form of an orange-colored substance of oily consistency.

In the previous operation described above, the compound A(1) obtained in the form of an orange-colored oily substance (£.0 g, 3.68 mmol) was dissolved in 5.0 ml of dimethylformamide containing 626.0 mg, (9.20 mmol) of imidazole.

After addition of 468.0 mg, (4.42 mmol), of t-butyldimethylchlorosilane, 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 a yellow-colored, oily substance, 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.

Then the reaction mixture was filtered through diatomaceous earth, and the obtained filtrate was concentrated,

1.42 g of another intermediate, designated as compound A^), was obtained in the form of an orange-colored substance of oily consistency.

In the previous, above-described operation, the word obtained is 9»99 ♦ 9 9 *9

9» • 9

9999 99

9 · · • 9 99 «9 Compound A' ₃ ), (700.0 mg, 1.96 mmol), in the form of an orange-colored oily substance, was dissolved in 5.0 ml, dichloromethane, and 0.40 ml, (4.90 mmol), pyridine, and to the resulting solution were added 448.0 mg, (2.35 mmol), tosyl chloride, toluenesulfonyl chloride, and 10.0 mg, N,N-dimethylaminopyridine, and the resulting reaction mixture was stirred overnight.

The reaction mixture was then partitioned between ethyl acetate and water. After separating the organic and aqueous phases, the organic layer was dried with sodium sulfate, and concentrated.

800.0 mg of another intermediate, designated as compound A^), was obtained in the form of an orange-colored substance of oily consistency.»

In the previous operation described above, compound A, prepared was dissolved in 5.0 ml of tetrahydrofuran, cooled to 0 C, and 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 separating the organic and aqueous phases, the organic layer was dried with sodium sulfate, and concentrated.

440.0 mg of the desired title compound was obtained in the form of an orange-colored substance of oily consistency, i.e. 2-propyl-4-(4-tolylsulfonamidophenoxy)-phenol.

¹ H-NME, ( 400 MHz, CDdl^):delta, 7.37, ( d., 2H ), 6.92, ( d., 2H ), 6.85, ( m., 3H ), 6.79, ( w.s., 2H ), 7.41, ( w.s., 1H ), 3.04, ( s., 3H ), 2.57, (t., 2H ), . 1.65, (m., 2H), 0.97, (m., 3H).

φφ φφφφ

429 • « φφφφ

ΦΦ «9 • Φ · • ΦΦ φφ • φ · φ · · •φ φ

« • φφφφ φ* φφ

Grade B)

Preparation of ethyl 1-4-(3-(2-propyl-4-(4-tolylsulfonamidophenoxy)phenoxy)propoxy)-mandelate

By an analogous procedure to that described above in Example 22), Step G), the desired title compound was prepared using 2-propyl-4-(4-tolyl sulfonamidophenoxy)phenol, (19.0 g, 62.00 mmol), (obtained in the previous, above-described Step A), and ethyl 4-(3-bromopropoxy)-mandelate, (19.50 g, 58.90 mmol), (prepared by the procedure described above in Example 22), Step B), as starting materials.

Grade C)

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

By an analogous procedure to that described above in Example 22), Step G), using ethyl 4-(3-(2-propyl-4-(4-tolylsulfon-amidophenoxy)phenoxy)propoxy)mandelate (16.80 g, 20.18 mmol), obtained in the previous, above-described Step B), as starting material, the desired title compound was prepared.

¹ H-NMR, (400MHz, CD12):

delta, 7.37, ( d., 2H ), 7.23, ( m., 6H ), 6.91, ( d., 2H ),

6.82, ( m., 3H ), 6.73, ( w.s., 2H ), 5.27, ( w.s., 1H ), 4.73, ( w.s., 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, (m., 3H), 0.95, (m., 3H).

//0

9 9

9 • · • · 9

9999 ·· ·· ·· • · 9 9 9 9

9 9

M

99

Degree Π)

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

By an analogous procedure to that described above in Example 1), Step C), second paragraph), using ethyl alpha-chloro4-(3-(2-propyl-4-(4-tolylsulfonamidephenoxy)phenoxy)propoxy)phenylacetate, obtained in the previous, above-described Step C), as the starting material, the desired title compound was prepared.

¹ H-NMR , ( 400 Mffiz, , cnc 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, ( s.s. r 2H: ), 5.30, ( 3. , 1H), 4.67, ( s.s. > 1H), 4.01 ,. ( i.e. » 2H ) r 3.84, ( i.e., 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

Grade 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 instead of 4-fluoronitrobenzene, chloropyrazine was used as the starting material in the reaction.

¹ H-NMR, (400 MHz, CDCl 3 ):

delta, 8.36, ( s., 1H ), 8.21, ( s., 1H ), 8.10, ( d., 1H ),

6.90.

Grade B)

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

By an analogous procedure to that described above in Example 22), Step O), using 2-propyl-4-pyrizinyloxyphenol (19.0 g, 62.0 mmol), obtained in the previous, above-described Step A), and 19.50 g, (58.90 mmol), ethyl 4-(3-bromopropoxy)mandelate (prepared by an analogous procedure to that described above in Example 22), Step O), as starting materials, the desired title compound was prepared.

Grade C) • · · · • · · · · · · · • · ·» · · · ·

/AZ.

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

By an analogous procedure to that described above in Example 22, Step D), using 16.80 g (30.18 mmol) of ethyl 4-(3-(2-propyl-4-pyrazinyloxyphenoxy)propoxy)mandelate (obtained in the previous, above-described Step B) as starting material, the desired title compound was prepared.

Grade: ^Ώ ·)

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

By an analogous procedure to that described above in Example 1), Step O), second paragraph), but using ethyl alpha-chloro4-(3-(2-propyl-4-pyrazinyloxyphenoxy)propoxy)phenylacetate as the starting material, the desired title compound was prepared.

¹ H-NMR, (400 MHz, GDG12):

delta, 8.35,. ( s., 1H ), 8.20, ( s., 1H ), 8.07, ( d., 1H ),

7.95, ( w.s.,, 1H ), 7.32,. ( d., 2H ), 6.93, ( m., 3H ), 6.85, ( m.,. 2H ), 5.32 _ø ( 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

Grade A)

Preparation of 2-cyclopropylmethyl 1-4-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, 20.0 ml of a solution of diazomethane (0.70M solution in ethyl ether) was added under a nitrogen atmosphere. After stirring for five minutes, palladium acetate (catalyst 2.0 mg) was added to the resulting reaction mixture. After 10.0 minutes, another amount of diazomethane (6.0 ml, 0.70M solution in ether) was added and the reaction mixture was stirred at room temperature for 30.0 minutes.

The reaction mixture was then filtered through a pad of diatomaceous earth, and ether was stripped from the filtrate under vacuum. The residue was purified by flash chromatography on silica gel using 10% ethyl acetate in hexane. After evaporation of the purified fractions, the solvent was removed under vacuum to give the title compound.

• · · · ¹ H-NMR, (400 MHz, CDGl^):

delta, 7.32 - 6.77, ( ar., 8H ), 4.82, ( s., 1H ), 2.53, ( d., 2H, J = 6.65 Hz ), 0.55, ( m., 2H ).

Degree®)

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

By an analogous procedure to that described above in Example 2(1), Steps B) to D), using methyl 3-(3-bromopropoxy)-mendelate and 2-cyclopropylmethyl-4-phenoxyphenol (prepared by the procedure described above in the preceding Step A) as starting materials, the desired title compound was prepared.

¹ H-NMR, (400 MHz, CDCl3)::

delta, 7.35 - 6.83, ( ar., 12 H ), 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).