JPH07188227A - Thiazolidine derivative and oxazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new thiazolidine derivative having excellent hypoglycemic action and circulating action in blood and useful as an agent for the prevention and treatment of diabetes and hyperlipemia. CONSTITUTION:This thiazolidine derivative is a compound expressed by formula I [R is a (substituted)condensed heterocyclic group; R1 is H, OH or a lower alkyl; R2 is a lower alkyl] or its pharmacologically permissible salt, e.g. 5-[4-[2-[2-(2-benzothienyl)-5-methyl-4-oxazolyl]ethoxy]benzyl]-2,4-thi azolidinedione. The compound can be produced by using an aspartic acid ester derivative of formula II (R<31> is carboxyl-protecting group such as benzyl) as a starting raw material through the path shown by the reaction formula via an oxazole derivative of formula VIII such as 2-[2-(2-benzothienyl)-5-methyl-4-oxazolyl)ethanol as a new intermediate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel thiazolidine derivative and an oxazole derivative useful as an intermediate compound thereof, more specifically, it has a blood glucose lowering action and a blood lipid lowering action, and diabetes and its The present invention relates to a novel thiazolidine derivative useful as a therapeutic drug for complications, a therapeutic drug for hyperlipidemia and related diseases, and an intermediate thereof.

[0002]

BACKGROUND OF THE INVENTION Generally, non-insulin dependent diabetes mellitus (NIDDM) is treated by diet, exercise, insulin or in combination with orally active hypoglycemic agents. Currently, such orally active hypoglycemic agents include sulfonylurea drugs such as tolbutamide, chloropropamide, acetohexamide, glibenclamide and tolazamide, or phenformin, buformin,
Biguanide drugs such as metformin are known. However, sulfonylurea drugs have a strong hypoglycemic effect, but often cause severe and persistent hypoglycemia, and may lose their effectiveness when used chronically. . Further, biguanide drugs are prone to cause serious lactic acid-acidosis, and therefore, caution should be exercised when using these drugs. On the other hand, in Japanese Patent Application Laid-Open No. 61-85372, [5- [4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzyl] -2,
4-thiazolidinedione] and the like.
Japanese Unexamined Patent Publication No. 60-51189 discloses [(±) -5-
[4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy) benzyl] -2,4
-Thiazolidinedione] and thiazolidine derivatives, and JP-A-58-219269 discloses [5-methyl-2
-Styryl-4-oxazoleacetic acid] has a hypoglycemic effect. However, a thiazolidine derivative having a condensed heterocyclic group such as the compound of the present invention has not been known.

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventors have diligently studied to provide a novel compound effective for the treatment of diabetes and its complications and hyperlipidemia as in the previous period, and as a result, compared with known compounds. As a result, they have found a new thiazolidine derivative having a very strong and extremely low toxicity effect of lowering blood glucose and blood lipid, and completed the present invention.

[0004]

That is, the present invention relates to novel thiazolidine derivatives and intermediate compounds thereof shown in the following (1) to (12).

(1) General formula (I)

[0006]

[Chemical 3]

(Wherein R is a condensed heterocyclic group which may be substituted, R ₁ is a hydrogen atom, a hydroxyl group or a lower alkyl group, and R ₂ is a lower alkyl group). A thiazolidine derivative or a pharmaceutically acceptable salt thereof.

(2) The novel thiazolidine derivative according to the above (1) or a pharmaceutically acceptable salt thereof, wherein R is a condensed heterocyclic group in which a carbocycle and a heterocycle are condensed and which may be substituted.

(3) R is a benzene ring and a fused 5- to 6-membered heterocyclic group containing 1 to 2 heteroatoms selected from sulfur atom, oxygen atom and nitrogen atom, which may be substituted and may be substituted. Which is a novel thiazolidine derivative or a pharmaceutically acceptable salt thereof according to the above (1).

(4) R ₁ is a hydrogen atom or a hydroxyl group,
The novel thiazolidine derivative described in (1) above, wherein R ₂ is a lower alkyl group, or a pharmaceutically acceptable salt thereof.

(5) R is benzothienyl group, alkoxybenzothienyl group, hydroxybenzothienyl group, dialkoxybenzothienyl group, benzofuranyl group, dihydroxybenzothienyl group, hydroxybenzofuranyl group, 6-hydroxy-2,5, 7,8-Tetramethyl-
A novel thiazolidine derivative or a pharmaceutically acceptable salt thereof according to (1) above, which is selected from a chromanyl group.

(6) General formula (VIII)

[0013]

[Chemical 4]

An oxazole derivative represented by the formula (wherein R is a condensed heterocyclic group which may be substituted, R ₁ is a hydrogen atom, a hydroxyl group or a lower alkyl group, and R ₂ is a lower alkyl group). .

(7) The oxazole derivative according to the above (6), wherein R is a condensed heterocyclic group in which a carbocycle and a heterocycle are condensed and which may be substituted.

(8) R is a fused heterocyclic group which may be substituted with a 5- to 6-membered heterocycle containing a benzene ring and 1 to 2 heteroatoms selected from sulfur atom, oxygen atom and nitrogen atom. The oxazole derivative according to (6) above, which is

(9) R is a benzothienyl group, an alkoxybenzothienyl group, a dialkoxybenzothienyl group, a benzofuranyl group, a hydroxybenzofuranyl group, or a 6-hydroxy-2,5,7,8-tetramethylchromanyl group. The oxazole derivative according to (6) above, which is selected.

(10) The oxazole derivative according to the above (6), wherein R ₁ is a hydrogen atom and R ₂ is a lower alkyl group.

(11) 5- [4- [2- [2- (2-benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5-
[4- [2- [2- (5-Methoxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5- [4- [2
-[2- (5-hydroxy-2-benzothienyl) -5
-Methyl-4-oxazolyl] ethoxy] benzyl]-
2,4-thiazolidinedione; 5- [4- [2- [2-
(5,6-dimethoxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,
4-thiazolidinedione; 5- [4- [2- [2-
(5,6-Dihydroxy-2-benzothienyl) -5-
Methyl-4-oxazolyl] ethoxy] benzyl]-
2,4-thiazolidinedione; 5- [4- [2- [2-
(2-Benzofuranyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5- [4- [2- [2- (5-hydroxy-2-benzofuranyl) -5-methyl -4-Oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5-
[4- [2- [2- (6-hydroxy-2,5,7,8
-Tetramethyl-2-chromanyl) -5-methyl-4-
Oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5- [4- [2-hydroxy-2- [2
-(6-hydroxy-2,5,7,8-tetramethyl-
2-Chromanyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione, a novel thiazolidine derivative described in (1) above or a pharmaceutically acceptable salt thereof.

(12) 2- [2- (2-benzothienyl) -5-methyl-4-oxazolyl] ethanol; 2
-[2- (5-Methoxy-2-benzothienyl) -5-
Methyl-4-oxazolyl] ethanol; 2- [2-
(5-Hydroxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethanol; 2- [2- (5,6
-Dimethoxy-2-benzothienyl) -5-methyl-4
-Oxazolyl] ethanol; 2- [2- (5,6-dihydroxy-2-benzothienyl) -5-methyl-4-
Oxazolyl] ethanol; 2- [2- (2-Benzofuranyl) -5-methyl-4-oxazolyl] ethanol; 2- [2- (5-Hydroxy-2-benzofuranyl) -5-methyl-4-oxazolyl] ethanol; Two
-[2- (6-Hydroxy-2,5,7,8-tetramethyl-2-chromanyl) -5-methyl-4-oxazolyl] ethanol; 2-hydroxy-2- [2- (6-hydroxy-2) , 5,7,8-Tetramethyl-2-chromanyl) -5-methyl-4-oxazolyl] ethanol, the oxazole derivative according to (5) above.

The term "fused heterocyclic group" used herein means 4 to 6
Membered carbocycle, preferably a 4- to 6-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atoms as ring-constituting atoms and condensed with benzene ring A ring, which is a ring in which 4- to 6-membered heterocycles containing 1 to 3 heteroatoms selected from nitrogen atom, oxygen atom, and sulfur atom in addition to carbon atoms as atoms constituting the ring are condensed Good. Specifically, furisoxazolyl group, imidazothiazolyl group, thienoisothiazolyl group, thienothiazolyl group, thienothiazolyl group, imidazopyrazolyl group, cyclopentapyrazolyl group, pyrrolopyrrolyl group, cyclopentathienyl group, thienothienyl group, oxadiazo Lopyrazinyl group, benzoflazanyl group, thiadiazolopyridinyl group, triazolothiazinyl group, triazolopyrimidinyl group, triazolopyridinyl group, benzotriazolyl group, oxazolopyrimidinyl group, oxazolopyridinyl group A benzoxazolyl group,
Thiazolopyridazinyl group, thiazolopyrimidinyl group, benzisothiazolyl group, benzothiazolyl group, pyrazolotriazinyl group, pyrazolothiazinyl group, imidazopyrazinyl group, purinyl group, pyrazolopyridazinyl group , A pyrazolopyriminidyl group, an imidazopyridinyl group, a pyranopyrazolyl group, a benzimidazolyl group, an indazolyl group,
Benzoxathiolyl group, benzodioxalyl group, dithiolopyrimidinyl group, benzodithiolyl group, indolizinyl group, indolyl group, isoindolyl group, furopyrimidinyl group, furopyridinyl group, benzofuranyl group, isobenzofuranyl group, thienopyrazinyl group, thienopyrimidinyl group , Thienodioxinyl group, thienopyridinyl group, benzothienyl group, isobenzothienyl group, cyclopentaoxazinyl group, cyclopentafuranyl group, benzothiadiazinyl group, benzotriazinyl group, pyridooxazinyl group , A benzoxazinyl group, a pyrimidothiazinyl group, a benzothiazinyl group, a pyrimidopyridazinyl group, a pyrimidopyrimidinyl group, a pyridopyridazinyl group,
Pyridopyrimidinyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, benzoxatiynyl group, benzodioxinyl group, benzodithinyl group, naphthyridinyl group, isoquinolinyl group, quinolinyl group, benzopyranyl group, benzothiopyranyl group, chromanyl group, isochromanyl group , Indolinyl group and the like, preferably benzoxazolyl group, benzisothiazolyl group, benzothiazolyl group, benzimidazolyl group, indazolyl group, benzoxathiolyl group, benzodioxolyl group, benzodithiolyl group, indolyl group, isoindolyl group. , Benzofuranyl group, isobenzofuranyl group, benzothienyl group, isobenzothienyl group, benzothiadiazinyl group,
Benzotriazinyl group, benzooxazinyl group, benzothiazinyl group, cinnolinyl group, quinazolinyl group, quinoxalinyl group, benzoxatiinyl group, benzodioxinyl group, benzodithinyl group, isoquinolinyl group, quinolinyl group, benzopyranyl group, benzo A thiopyranyl group,
Chromanyl group, isochromanyl group, indolinyl group, particularly preferably indolyl group, isoindolyl group,
A benzofuranyl group, an isobenzofuranyl group, a benzothienyl group, an isobenzothienyl group, an isoquinolinyl group, a quinolinyl group, a benzopyranyl group, a benzothiopyranyl group, a chromanyl group and an isochromanyl group.

The "lower alkyl group" means an alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isoptyl group, sec-butyl group. Group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert
-Pentyl group, hexyl group, isohexyl group, neohexyl group and the like. Preferred is an alkyl group having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec.
A butyl group and a tert-butyl group. A methyl group is particularly preferred.

The term "may be substituted" means that it may be substituted with 1 to 5 substituents, which may be the same or different. Specifically, lower alkyl groups such as methyl group, ethyl group, propyl group, butyl group and tert-butyl group; lower alkoxy groups such as methoxy group, ethoxy group, propoxy group, butoxy group, tert-butoxy group; halogen atom Nitro group; cyano group; hydroxyl group;
Formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, benzoyl group, naphthoyl group and other acyl groups; formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, benzoyloxy group, etc. Acyloxy group; aralkyloxy group such as benzyloxy group, phenethyloxy group and phenylpropyloxy group; mercapto group; alkylthio group such as methylthio group, ethylthio group, propylthio group, butoxythio group, isobutoxythio group and tert-butoxythio group An amino group; an alkylamino group such as a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group and a butylamino group; a dimethylamino group, a diethylamino group, a dipropylamino group, a diisopropylamino group, Dialkylamino group such as butylamino group; alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group; amide group; trifluoromethyl group; phosphoryl Group; sulfonyl group; sulfonyloxy group; sulfamoyl group; alkylphosphonamide group such as methylphosphonamide group, ethylphosphonamide group, propylphosphonamide group, isopropylphosphonamide group; methylenedioxy group; methoxyphosphoryl group, ethoxyphosphoryl group, Alkoxyphosphoryl group such as propoxyphosphoryl group and isopropoxyphosphoryl group; methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group , Tert-
Alkylsulfonyl group such as butylsulfonyl group; methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, butylsulfonylamino group,
an alkylsulfonylamino group such as a tert-butylsulfonylamino group, and the like, preferably a hydroxyl group, a lower alkyl group, a lower alkoxy group, an aralkyloxy group, a mercapto group, a lower alkylthio group, a nitro group, a halogen atom, a trifluoromethyl group, An amino group, a dialkylamino group, an alkylamino group, an acyl group, a cyano group, a carbamoyl group, an acyloxy group, a sulfonyl group, a carboxyl group and an alkoxycarbonyl group, and particularly preferably a hydroxyl group, a lower alkyl group and a lower alkoxy group.

The "pharmaceutically acceptable salt" may be any salt as long as it forms a non-toxic salt with the novel thiazolidine derivative represented by the general formula (I). Alkali metal salts such as salts and potassium salts; Alkaline earth metal salts such as magnesium salts and calcium salts; Ammonium salts; Trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, N′-dibenzylethylenediamine Examples thereof include organic base salts such as salts; amino acid salts such as lysine salts and arginine salts.

The compound of the present invention has excellent hypoglycemic action and hypolipidemic action and is useful not only as a prophylactic and therapeutic drug for diabetes and hyperlipidemia but also as an arteriosclerosis preventive drug. Be expected. When the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt is used as a pharmaceutical preparation comprising an active ingredient, it is usually a known pharmacologically acceptable carrier, excipient, Diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, flavoring agents, solubilizing agents, other additives, specifically water. , Vegetable oil, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin,
Mixing with carbohydrates such as lactose and starch, magnesium stearate, talc, lanolin, petrolatum, etc., tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, It can be administered orally or parenterally in the form of an aerosol, elixir, suspension, emulsion, syrup and the like. The dosage is
Type and degree of disease, compound to be administered and administration route,
Although it may vary depending on the age, sex, body weight, etc. of the patient, when administered orally, the compound (I) is usually 0.0
It is preferred to administer 1 to 1000 mg, especially 0.05 to 100 mg.

Further, the compound represented by the general formula (I) is
It has one or two or more asymmetric carbons, and in the case of one, a pure optically active substance, a mixture in any proportion thereof, or a racemate exists, and in the case of two or more, Exists as an optically pure diastereomer, a racemate thereof, or a mixture thereof, and a mixture in any ratio, and all of them belong to the scope of the present invention. The compound of the present invention can be synthesized, for example, by the following method, but it goes without saying that the method for producing the compound of the present invention is not limited thereto.

[0027]

[Chemical 5]

(Step 1) Compound (III) (wherein R ₃₁ represents a carboxyl-protecting group such as benzyl group and R ₁ and R ₂ are as described above) is an aspartic acid ester derivative. (II) (wherein R ₁ and R ₃₁ are as described above) at room temperature in the presence of a base such as pyridine or triethylamine and 4-dimethylaminopyridine in an acid anhydride such as acetic anhydride or propionic anhydride. Alternatively, it can be synthesized by reacting under heating and treating with water.

(Step 2) Compound (IV) (In the formula, R ₃ represents an alkyl group, and R ₁ and R ₂ are as described above.)
Is a compound (III) (wherein R ₁ , R ₂ and R ₃₁ are as described above) heated in an acidic solvent such as hydrochloric acid to eliminate the N-acetyl group, and further hydrogen chloride and the like. It can be synthesized by reacting in an alcohol solvent such as methanol, ethanol or propanol in the presence of the acid to esterify.

(Step 3) Compound (VI) (wherein R,
R ₁ , R ₂ and R ₃ are as described above, and the compound (I
V) (wherein R ₁ , R ₂ and R ₃ are as described above) and compound (V) (wherein Y represents a halogen atom and R is as described above), triethylamine, In the presence of a base such as pyridine or N-methylmorpholine, under cooling in an organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethoxyethane, pyridine or acetone, or a mixed solvent thereof. Alternatively, it can be synthesized by reacting at room temperature.

(Step 4) Compound (VII) (wherein R,
R ₁ , R ₂ and R ₃ are as described above, and the compound (V
I) (wherein R, R ₁ , R ₂ and R ₃ are as described above) in the presence of an acid catalyst such as sulfuric acid or p-toluenesulfonic acid and a dehydrating agent such as acetic anhydride, benzene, toluene, It can be synthesized by reacting with an organic solvent such as acetonitrile, chloroform or tetrahydrofuran or without solvent at room temperature or under heating, preferably under heating.

(Step 5) Compound (VIII) (wherein R, R
₁ and R ₂ are as described above) is a compound (VII)
(In the formula, R, R ₁ , R ₂ and R ₃ are as described above.)
Can be synthesized by a conventional method using a reducing agent such as diisobutylaluminum hydride in an organic solvent such as benzene, toluene, ether, dioxane or tetrahydrofuran.

(Step 6) Compound (IX) (wherein Z is p-
A toluenesulfonyloxy group, a benzenesulfonyloxy group, a methanesulfonyloxy group or the like or a leaving group such as a halogen atom is meant, and R, R ₁ and R ₂ are as described above, and the compound (VIII) , R, R ₁ and R ₂
Is as described above) and sulfonyl chlorides such as p-toluenesulfonyl chloride, benzenesulfonyl chloride or methanesulfonyl chloride or phosphorus tribromide or thionyl chloride and the like, and a base such as triethylamine, 4-dimethylaminopyridine or pyridine. In the presence of benzene, toluene, dichloromethane,
Synthesize by reacting in an organic solvent such as chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone or ethyl acetate, or a mixed solvent thereof or without a solvent under cooling or heating. You can

(Step 7) Compound (I) (in the formula, R, R ₁
And R ₂ are as described above) is a compound (IX) (wherein R, R ₁ , R ₂ and Z are as described above) and 5-
Benzene, toluene, (4-hydroxy) benzyl-2,4-thiazolidinedione (X) in the presence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine or chargeable soda. Dichloromethane, chloroform, ether, dioxane, tetrahydrofuran,
It can be synthesized by reacting in an organic solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane or dimethoxyethane under cooling or heating. A compound in which the substituent of R is a hydroxyl group (for example, a 5-hydroxybenzothienyl group,
5,6-dihydroxybenzothienyl group or 6-hydroxy-2,5,7,8-tetramethylchromanyl group)
In the case of, a compound having a methoxy group, a benzyloxy group or the like as a substituent (for example, 5-methoxybenzothienyl group, 5,6-dimethoxybenzothienyl group or 6-benzyloxy-2,5,7,8-tetra It can be synthesized by hydrolyzing a methylchromanyl group and the like) under acidic conditions. Compound (I) thus obtained
Can be isolated and purified by a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization and chromatography. The above method is particularly useful when R ₁ is a hydrogen atom or a lower alkyl group and R ₂ is a lower alkyl group.

In the compound (I), the compound (I ') in which R ₁ is a hydroxyl group can be synthesized by the following method.

[0036]

[Chemical 6]

(Step 1 ') The compound (XII) can be synthesized by adding an aqueous sodium nitrite solution to acetylacetone (XI) in an acidic solvent such as acetic acid.

(Step 2 ′) Compound (XIV) (wherein R is as described above) is benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, Compound (XIII) (wherein R is as described above) is dehydrated to compound (XII) in an organic solvent such as dimethoxyethane, pyridine, acetone or ethyl acetate, water or a mixed solvent thereof under acidic conditions. , Can be synthesized by reduction.

(Step 3 ′) Compound (XV) (wherein R and Y are as described above) is compound (XIV) (wherein
R is as described above), chloroform, carbon tetrachloride, benzene, toluene, dichloromethane, ether,
In a solvent such as dioxane, anhydrous tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, sulfolane, dimethoxyethane, pyridine, acetone or ethyl acetate, chlorine, bromine, iodine, etc. are added at 30 to 60 ° C, or benzene, toluene, dichloromethane. , Chloroform, ether, dioxane, anhydrous tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, dimethoxyethane, pyridine, acetone or ethyl acetate in an organic solvent to react with dibromomeldrumic acid.

(Step 4 ') Compound (XVII) (wherein R is as described above) is compound (XV) (wherein R and Y are as described above) and 5- (4- Hydroxy) benzyl-2,4-thiazolidinedione (XVI) in the presence or absence of a base such as sodium hydride, potassium hydride, sodium amide, sodium alkoxide, potassium alkoxide, triethylamine, caustic soda, baking soda or sodium carbonate. Organic solvent such as benzene, toluene, dichloromethane, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, dimethoxyethane, pyridine, acetone or ethyl acetate, water or a mixed solvent thereof with or without cooling. By reacting under temperature It can be formed.

(Step 5 ′) Compound (I ′) (wherein R is as described above) is prepared by converting compound (XVII) (wherein R is as described above) into benzene, toluene, ether, In a solvent such as dioxane or tetrahydrofuran, sodium borohydride, lithium aluminum hydride,
It can be synthesized by reduction with a catalyst such as lithium borohydride or dibutylaluminum hydride. A compound in which the substituent of R is a hydroxyl group (for example, 5-hydroxybenzothienyl group, 5,6-dihydroxybenzothienyl group or 6-hydroxy-2,
5,7,8-tetramethylchromanyl group),
A compound having a methoxy group, a benzyloxy group or the like as a substituent (for example, 5-methoxybenzothienyl group, 5,
6-dimethoxybenzothienyl group or 6-benzyloxy-2,5,7,8-tetramethylchromanyl group) can be synthesized by hydrolyzing under acidic conditions. The compound (I) thus obtained can be separated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization,
It can be isolated and purified by recrystallization, chromatography and the like.

Hereinafter, the present invention will be described more specifically with reference to examples.

【Example】

Example 1 Step 1) Synthesis of benzyl 3-acetamido-4-oxopentanoate (Compound (III); R ₁ = H, R ₂ = M
e, R ₃₁ = Bn) L-aspartic acid β-benzyl ester (400
g, 1.79 mol) to triethylamine (748 m
1, 5.37 mol), and acetic anhydride (676 ml, 7.16 mol) was added dropwise thereto at 0 ° C. with stirring. After stirring for 30 minutes, 4-dimethylaminopyridine (20.0 g, 0.16 mol) was added little by little under ice cooling. Next, after stirring overnight at room temperature, ice was added under ice cooling, and after the exotherm subsided, water (700 ml) was further added. A 7.5N-potassium hydroxide aqueous solution was added little by little to adjust the pH to 9. 3 with ethyl acetate (1000 ml)
The organic layer was extracted twice with 1N-hydrochloric acid (1000 ml).
2 times with saturated aqueous sodium hydrogen carbonate solution (500 ml)
This was washed once with saturated saline (500 ml). The organic layer was dried over magnesium sulfate and concentrated to dryness to give the title compound (390 g).

Step 2) Synthesis of methyl 3-amino-4-oxopentanoate.hydrochloride (Compound (IV); R ₁ =
H, R ₂ = Me, R ₃ = Me) Compound synthesized in the above step 1) (390 g, 1.50 m
Ol), 6N-hydrochloric acid (700 ml) was added, and the mixture was stirred under reflux for 2 hours. After cooling to room temperature, the reaction solution was washed twice with dichloromethane (500 ml), and the aqueous layer was concentrated to dryness.
Under ice-cooling, hydrochloric acid methanol (1500 ml) was added thereto, and the mixture was stirred, the temperature was gradually raised, and the mixture was stirred at room temperature overnight. This was concentrated to dryness to obtain a crude product (247 g). The crude product (60 g) was recrystallized from isopropanol to give the title compound (3
0 g) was obtained.

Step 3) Synthesis of methyl 3- (benzothiophene-2-carboxamido) -4-oxopentanoate (Compound (VI); R ₁ = H, R ₂ = Me, R ₃ = M
e, R = benzothiophene-2) The compound (9.40 g, 51.3) synthesized in the above step 2).
(mmol) was suspended in dichloromethane (200 ml) at 0 ° C, benzothiophene-2-carbonyl chloride was added thereto, and N-methylmorpholine (20.8 g, 0.2 mol) was slowly added dropwise under stirring. did.
After stirring for 3.5 hours, water (100 ml) was added and the organic layer was separated. Further, from the water layer, dichloromethane (100 m
The organic layer was extracted in l). Combine the extracted organic layers,
1N-hydrochloric acid aqueous solution (100 ml) and water (100 ml)
After sequentially washing with, it was dried with magnesium sulfate.
The title compound (14.0 g) was obtained by concentrating to dryness.

Step 4) Synthesis of methyl [2- (2-benzothienyl) -5-methyl-4-oxazolyl] acetate (Compound (VII); R ₁ = H, R ₂ = Me, R ₃ = M
e, R = benzothienyl) The compound (14.0 g, 45.9) synthesized in the above step 3).
Acetic anhydride (70 ml) was added to and dissolved in (mmol) and concentrated sulfuric acid (1.0 ml) was added dropwise with stirring. This is 9
After stirring at 0 ° C for 3 hours, the mixture was cooled to room temperature. Water (100 ml) was added to the reaction mixture, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then extracted with dichloromethane (100 ml). The extract was dried over magnesium sulfate and concentrated to dryness to give the title compound (12.8 g).

Step 5) Synthesis of 2- [2- (2-benzothienyl) -5-methyl-4-oxazolyl] ethanol (Compound (VIII); R ₁ = H, R ₂ = Me, R = benzothienyl) Toluene solution of diisobutylaluminum hydride (133 ml, 133.20 mmol) at 0 ° C. under nitrogen stream
In addition, the compound (12.80 g, 4
A solution of 4.40 mmol) in toluene (200 ml) was added dropwise, and after 2 hours, methanol (100 ml) was added dropwise. Next, 2N-hydrochloric acid (700
ml) was added and dissolved, and ethyl acetate (500 ml) was added.
It was extracted 4 times. The extracted organic layers were combined, washed with saturated brine (200 ml), and dried over magnesium sulfate. By concentrating to dryness, the title compound (2.
60 g) was obtained.

Step 6) Synthesis of 2- [2- (2-benzothienyl) -5-methyl-4-oxazolyl] -1-ethyl tosylate (Compound (IX); R ₁ = H, R ₂ = Me,
R = benzothienyl, Z = p-toluenesulfonyloxy) The compound synthesized in the above step 5) (2.30 g, 8.80).
pyridine (10 ml) was added to a dichloromethane solution (15 ml) of (mmol) and p-toluenesulfonyl chloride (1.76 g, 9.24 mmol) was further added at 0 ° C.
Was gradually added. After stirring for 2 hours, dilute hydrochloric acid (30 m
l) was added and neutralized. This was separated, and the organic layer was combined with saturated aqueous sodium hydrogen carbonate solution (50 ml) and saturated brine (5
It was sequentially washed with 0 ml). After drying over magnesium sulfate, the mixture was concentrated to dryness to give the title compound (3.15).
g) was obtained.

Step 7) Synthesis of 5- [4- [2- [2- (2-benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione (Compound (I) R ₁ = H, R ₂ = Me, R = benzothienyl) Sodium hydride 60% oil (268 m
g, 6.7 mmol) was washed twice with n-hexane (2 ml), dimethylformamide (5 ml) was added thereto, and the mixture was cooled to 0 ° C. Under stirring, 5- (4-hydroxybenzyl) -2,4-thiazolidinedione (1.5
0 g, 6.70 mmol) was added slowly. After stirring for 10 minutes, the compound (2.77) synthesized in the above Step 6) was used.
g, 6.70 mmol) in dimethylformamide solution (10 ml) was added dropwise. The temperature was raised to room temperature and the mixture was stirred overnight. Next, dilute hydrochloric acid (50 ml) was added to this solution,
Neutralized. Ethyl acetate (100 ml) was added to this solution, and after liquid separation, the organic layer was washed with brine (100 ml),
It was dried over magnesium sulfate. After concentration to dryness, the residue was separated and purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 2: 1) to obtain the title compound (679 mg).

Reference Example Step A) Synthesis of Methyl 6-hydroxy-2,5,7,8-tetramethylchroman-2-carbonate Trolox (98.8 g, 0.383 mol) was dissolved in methanol (700 ml), It was saturated with hydrogen chloride. After 1 hour, the precipitated solid was collected by filtration, and methanol (3
(00 ml) to give the title compound (97.2 g) as a white solid.

Step B) Methyl 6-benzyloxy-
Synthesis of 2,5,7,8-tetramethylchroman-2-carbonate Sodium hydride 60% oil (1
5.44 g, 0.386 mol) was added to n-hexane (5 m
l) and washed twice with dimethylformamide (30
0 ml) was added and the mixture was cooled to 0 ° C. The compound (97.1 g, 0.368 m) synthesized in the above step A) was added thereto with stirring.
ol) was added. After stirring for 10 minutes, benzyl bromide (45.9 ml, 0.386 mol) was added dropwise. After 1 hour, the reaction solution was extracted with ethyl acetate, and this extract solution was washed with water,
Washed with brine. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained solid compound was washed with hexane to give the title compound (10
7.6 g) was obtained.

Step C) 6-Benzyloxy-2,5
Synthesis of 7,8-Tetramethylchroman-2-methanol Lithium borohydride (4.61
g, 0.211 mol) of tetrahydrofuran (200
ml) suspension in the compound (50.
0 g, 0.141 mol) and methanol (6.75)
g, 0.211 mol) of tetrahydrofuran (300
ml) solution was added dropwise at the same time. After the reaction solution was refluxed for 1 hour, ethyl acetate and water were added to terminate the reaction. It was diluted with ethyl acetate, and this diluted solution was washed with water and saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (49.0 as a white solid).
g) was obtained.

Step D) 6-Benzyloxy-2,5
Synthesis of 7,8-tetramethylchroman-2-formaldehyde Dimethyl sulfoxide (2
2.0 ml, 0.310 mol) of dichloromethane (5
0 ml) solution to oxazyl chloride (13.34 m
1, 0.155 mol) of dichloromethane (150 m
l) Slowly added dropwise to the solution. The compound (49.16 g, 0.141 mo) synthesized in the above step C) was added to this mixed solution.
A solution of l) in dichloromethane was added dropwise. After 1 hour, triethylamine (98.6 ml, 0.705 mol) was added slowly. The reaction solution was diluted with dichloromethane (200 ml), and this was washed with water, 1N-hydrochloric acid, saturated sodium hydrogen carbonate, and saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (46.5 g) as a white solid.

Example 2 Step 1 ') Synthesis of N-hydroxy-2,4-dioxo-3-iminopentane Acetylacetone (48.65 g, mol) acetic acid (1
50 ml) solution was added to an aqueous solution of sodium nitrite (16.77 g), and the mixture was stirred overnight at room temperature. This was diluted with ethyl acetate, and this extract was washed with water and saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (52.8 g).

Step 2 ') 2- (6-hydroxy-2,
Synthesis of 5,7,8-tetramethylchromanyl) -4-acetyl-5-methyloxazole (Compound (XIV); R
= 6-hydroxy-2,5,7,8-tetramethylchromanyl) The compound (46.
5 g, 0.140 mol) and the compound (18.5 g, 0.140 mol) synthesized in the above step 1 ′) in acetic acid (1
00 ml) solution was saturated with hydrogen chloride. 40 minutes later,
The reaction mixture was poured into ether, the precipitate was filtered off and the residue was washed with ether. The obtained solid compound was converted into acetic acid (2
It was dissolved in 100 ml) and zinc (42 g) was added. After stirring this mixture at 100 ° C. for 1.5 hours, the reaction mixture was cooled to room temperature. This was diluted with ethyl acetate, and this extract was washed with water, saturated sodium hydrogen carbonate, and saturated saline. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solvent ethyl acetate: hexane = 2:
The title compound (1
9.0 g) was obtained.

Step 3 ') 2- (6-benzyloxy-
Synthesis of 2,5,7,8-tetramethylchromanyl) -4-bromoacetyl-5-methyloxazole (Compound (XV); R = 6-benzyloxy-2,5,7,8-tetramethylchromanyl , Y = bromo) Under a nitrogen stream, sodium hydride 60% oil (1.24 g, 3
1.1 mmol) was washed twice with n-hexane (2 ml), dimethylformamide (100 ml) was added thereto, and the mixture was cooled to 0 ° C. The compound (9.28 g, 29.6 mmol) synthesized in the above step 2 ′) was added thereto with stirring. After stirring for 10 minutes, benzyl bromide (5.32
g, 31.1 mmol) was added dropwise. After 1 hour, the reaction solution was extracted with ethyl acetate, and the extract was washed with water and brine. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained solid compound was washed with hexane to give 2- (6-benzyloxy-2,2) as a white solid.
5,7,8-Tetramethylchromanyl) -4-acetyl-5-methyloxazole (12.4 g) was obtained. This was dissolved in ether (60 ml), dibromomeldrumic acid (4.45 g, 14.8 mmol) was further added, and the mixture was stirred at room temperature for 2 days. Dilute the reaction solution with ethyl acetate,
This diluted solution was washed with water and saturated saline. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent ethyl acetate: hexane = 1: 19) to give the title compound as a white solid. (5.54g)
Got

Step 4 ') 5- [4- [2- [2- (6-
Synthesis of benzyloxy-2,5,7,8-tetramethylchromanyl) -5-methyl-4-oxazolyl] -2-oxoethoxy] benzyl] -2,4-thiazolidinedione (compound (XVII); R = 6-benzyloxy-2,
5,7,8-Tetramethylchromanyl) Sodium hydride 60% oily product (36
5 mg, 9.12 mmol) in n-hexane (2 ml)
It was washed twice with dimethylformamide (50m
1) was added and cooled to 0 ° C. While stirring, 5- (4
-Hydroxybenzyl) -2,4-thiazolidinedione (1.02 g, 4.56 mmol) was added. After stirring for 20 minutes, the compound (2.0
0 g, 4.15 mmol) was added dropwise. After stirring for 1 hour, this solution was extracted with ethyl acetate, and the extract was added with water,
Washed with brine. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained solid compound was washed with hexane to give the title compound (77) as a white solid.
0 mg) was obtained.

Step 5 ') 5- [4- [2- [2- (6-
Synthesis of hydroxy-2,5,7,8-tetramethylchromanyl) -5-methyl-4-oxazolyl] -2-hydroxyethoxy] benzyl] -2,4-thiazolidinedione (compound (I ′); R = 6-hydroxy-2,
5,7,8-Tetramethylchromanyl) The compound (770 mg) synthesized in the above step 4 ') was dissolved in methanol-tetrahydrofuran (20 ml, 1: 1), and sodium borohydride (93 mg, 2.
46 mmol) was added in small portions. After stirring for 1 hour at 0 ° C., this was diluted with ethyl acetate, and this diluted solution was washed with water and saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a white solid compound 5- [4- [2- [2- (6-benzyloxy-2,5,7,8-tetramethylchromanine]. ) -5
Methyl-4-oxazolyl] -2-hydroxyethoxy] benzyl] -2,4-thiazolidinedione (554
mg) was obtained. Then this compound (550 mg, 1.23
mmol) in thioanisole (6 ml),
Cooled to 0 ° C. Trifluoroacetic acid (60m
1) and trifluoromethanesulfonic acid (0.6 ml) were sequentially added. After 20 minutes, the reaction solution was evaporated under reduced pressure and extracted with ethyl acetate. The extract was washed with water, saturated sodium hydrogen carbonate and saturated saline. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent chloroform: methanol = 50: 1) to give the title compound as a white solid ( 280 mg) was obtained.

Examples 3 to 9 The compounds of Examples 3 to 9 were obtained in the same manner as in Example 1.
In addition, Example 4, Example 6 and Example 8 were synthesized by hydrolyzing Example 3 and Example 5 obtained in the same manner as Example 1.

[0059]

[Table 1]

[0060]

[Table 2]

Further, the compounds shown in Table 3 were obtained as production intermediates in step 5) of the above-mentioned example.

[0062]

[Table 3]

Needless to say, the present invention is not limited to the above-mentioned examples, and the compounds shown in Tables 4 to 22 below are also included in the present invention.

[0064]

[Table 4]

[0065]

[Table 5]

[0066]

[Table 6]

[0067]

[Table 7]

[0068]

[Table 8]

[0069]

[Table 9]

[0070]

[Table 10]

[0071]

[Table 11]

[0072]

[Table 12]

[0073]

[Table 13]

[0074]

[Table 14]

[0075]

[Table 15]

[0076]

[Table 16]

[0077]

[Table 17]

[0078]

[Table 18]

[0079]

[Table 19]

[0080]

[Table 20]

[0081]

[Table 21]

[0082]

[Table 22]

Test Example 1 In the pharmacological test, diabetic mice (C57B) that genetically show the pathological conditions of obesity, hyperglycemia and hyperlipidemia.
L / Ksj-db / db, male, Jackson Laboratories / CLEA Japan, 13 weeks old) and (KK-Ay, male,
(CLEA Japan, 13 weeks old) was used. In addition, as a target, the hypoglycemic agent CS-045 [(±) -5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-
Il-methoxy) benzyl] -2,4-thiazolidinedione] (Diabetes. 37.
roll. 1549 (1988)) was used. Immediately before the start of administration on the first day, the body weight of the mouse was measured and a blood sample was collected. Serum glucose and triglyceride were measured and divided into each group so that there was no difference in average body weight, average serum glucose value and triglyceride value (one group 6-8).
). All test samples were suspended in 0.5% sodium carboxymethyl cellulose solution,
Oral administration was given twice daily (the second administration was 6 hours after the first administration). The vehicle control group was orally administered with 0.5% sodium carboxymethylcellulose solution.
On day 5, blood samples were taken again to measure serum glucose and triglycerides. Under ether anesthesia, blood samples of 400 μl each were collected from the fundus vein and kept under ice temperature. After separation into serum (12,000 rpm, 5 minutes), serum glucose was converted to hexokinase method (glucose / HK /
Test "BMY": Boehringer Mannheim Yamanouchi), using serum triglyceride by enzymatic method (Triglycar II
I "BMY": Boehringer Mannheim Yamanouchi). An automatic analyzer COBAS FARA (Roche) was used as a measuring instrument. The percent change in each group from the vehicle control group serum glucose and serum triglyceride levels on day 5 was determined as follows.

[0084]

[Equation 1]

[0085]

[Equation 2]

The results are shown in Table 23.

[0087]

[Table 23]

As shown in Table 23, the compound of the present invention markedly lowered the serum glucose level and the serum triglyceride level of diabetic mice of any strain as compared with the target compound. From the above, the compound of the present invention has excellent blood glucose and lipid lowering actions, and is effective in the prevention and treatment of diabetes and hyperlipidemia. Further, it is expected as a drug for preventing and treating complications of diabetes.

[0089]

INDUSTRIAL APPLICABILITY The thiazolidine derivative compound (I) and a salt thereof of the present invention are novel compounds and have an extremely potent and extremely low toxicity blood glucose lowering effect as compared with known thiazolidine derivatives or other diabetes drugs, and It is very useful as a remedy for and a therapeutic drug for hyperlipidemia. Also,
The compound of the present invention is expected to be useful for the prevention of diabetic complications, especially arteriosclerosis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 413/04 333 // (C07D 417/14 307: 78 263: 56 277: 34) (C07D 417 / 14 333: 52 263: 56 277: 34) (C07D 417/14 311: 72 263: 56 277: 34) (C07D 413/04 307: 78 263: 56) (C07D 413/04 333: 52 263: 56) ) (C07D 413/04 311: 72 263: 56) (72) Inventor Noboru Furukawa 1-1 No. 1 Murasaki-cho, Takatsuki-shi, Osaka Prefecture Pharmaceutical Research Institute, Japan Tobacco Co., Ltd. (72) Inventor Saizo Shibata Osaka Prefecture 1-1 Murasaki-cho, Takatsuki City Japan Tobacco Inc. Pharmaceutical Research Institute

Claims (12)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R is a condensed heterocyclic group which may be substituted, and R
₁ is a hydrogen atom, a hydroxyl group or a lower alkyl group, and R ₂ is a lower alkyl group), a novel thiazolidine derivative or a pharmaceutically acceptable salt thereof. 2. The novel thiazolidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is a condensed heterocyclic group which is a condensed carbocyclic ring and a heterocyclic ring and may be substituted. 3. R is a benzene ring and a sulfur atom, an oxygen atom,
A novel thiazolidine derivative or a pharmaceutically acceptable derivative thereof according to claim 1, which is a condensed heterocyclic group which is a condensed 5- to 6-membered heterocyclic ring containing 1 to 2 heteroatoms selected from nitrogen atoms and which may be substituted. Get salt. 4. The novel thiazolidine derivative according to claim ₁ , wherein R ₁ is a hydrogen atom or a hydroxyl group, and R ₂ is a lower alkyl group, or a pharmaceutically acceptable salt thereof. 5. R is a benzothienyl group, an alkoxybenzothienyl group, a hydroxybenzothienyl group, a dialkoxybenzothienyl group, a dihydroxybenzothienyl group, a benzofuranyl group, a hydroxybenzofuranyl group,
The novel thiazolidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from a 6-hydroxy-2,5,7,8-tetramethylchromanyl group. 6. A general formula: (In the formula, R is a condensed heterocyclic group which may be substituted, and R
₁ is a hydrogen atom, a hydroxyl group or a lower alkyl group, and R ₂ is a lower alkyl group). 7. The oxazole derivative according to claim 6, wherein R is a condensed heterocyclic group in which a carbocycle and a heterocycle are condensed and which may be substituted. 8. R is a benzene ring and a sulfur atom, an oxygen atom,
The oxazole derivative according to claim 6, which is a condensed heterocyclic group which is a condensed 5- to 6-membered heterocycle containing 1 to 2 heteroatoms selected from nitrogen atoms and which may be substituted. 9. R is a benzothienyl group, an alkoxybenzothienyl group, a dialkoxybenzothienyl group, a benzofuranyl group, a hydroxybenzofuranyl group, a 6-benzyloxy-2,5,7,8-tetramethylchromanyl group. The oxazole derivative according to claim 6, which is selected. 10. The oxazole derivative according to claim 5, wherein R ₁ is a hydrogen atom and R ₂ is a lower alkyl group. 11. 5- [4- [2- [2- (2-Benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5-
[4- [2- [2- (5-Methoxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5- [4- [2
-[2- (5-hydroxy-2-benzothienyl) -5
-Methyl-4-oxazolyl] ethoxy] benzyl]-
2,4-thiazolidinedione; 5- [4- [2- [2-
(5,6-dimethoxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,
4-thiazolidinedione; 5- [4- [2- [2-
(5,6-Dihydroxy-2-benzothienyl) -5-
Methyl-4-oxazolyl] ethoxy] benzyl]-
2,4-thiazolidinedione; 5- [4- [2- [2-
(2-Benzofuranyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5- [4- [2- [2- (5-hydroxy-2-benzofuranyl) -5-methyl -4-Oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5-
[4- [2- [2- (6-hydroxy-2,5,7,8
-Tetramethyl-2-chromanyl) -5-methyl-4-
Oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione; 5- [4- [2-hydroxy-2- [2
-(6-hydroxy-2,5,7,8-tetramethyl-
The novel thiazolidine derivative according to claim 1, which is selected from 2-chromanyl) -5-methyl-4-oxazolyl] ethoxy] benzyl] -2,4-thiazolidinedione, or a pharmaceutically acceptable salt thereof. 12. 2- [2- (2-benzothienyl)-
5-Methyl-4-oxazolyl] ethanol; 2- [2
-(5-Methoxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethanol; 2- [2- (5-hydroxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethanol; 2- [2- (5,6-Dimethoxy-2-benzothienyl) -5-methyl-4-oxazolyl] ethanol; 2- [2- (5,6-dihydroxy-2-benzothienyl) -5-methyl-4- Oxazolyl] ethanol; 2- [2- (2-benzofuranyl)
-5-Methyl-4-oxazolyl] ethanol; 2-
[2- (5-hydroxy-2-benzofuranyl) -5-
Methyl-4-oxazolyl] ethanol; 2- [2-
(6-Benzyloxy-2,5,7,8-tetramethyl-2-chromanyl) -5-methyl-4-oxazolyl]
The oxazole derivative according to claim 6, which is selected from ethanol.