WO1997032863A1

WO1997032863A1 - Thiazolidine-2,4-dione derivatives

Info

Publication number: WO1997032863A1
Application number: PCT/JP1997/000639
Authority: WO
Inventors: Seizo Taira; Atsushi Sugimoto
Original assignee: Torii Pharmaceutical Co., Ltd.
Priority date: 1996-03-08
Filing date: 1997-03-03
Publication date: 1997-09-12
Also published as: AU2231397A

Abstract

Novel thiazolidine-2,4-dione derivatives represented by general formula (I); salts of the derivatives; and diabetes remedies containing the same, wherein R1 is cycloalkyl, substituted or unsubstituted phenyl, naphthyl, or a heterogeneous mono- or bicyclic group containing one or more atoms selected from among nitrogen, oxygen and sulfur; R2 and R3 are each independently hydrogen, lower alkyl, cycloalkyl, alkoxy, halogeno, hydroxy, (optionally protected) amino, phenyl or -(CH2)n- (wherein n is 2 to 6); and A is an amide linkage.

Description

Description Thiazolidine-1,2,4-dione derivative

Industrial applications

The present invention relates to a novel thiazolidine-2,4-dione derivative and a therapeutic agent for diabetes containing the same. Further, the present invention relates to an intermediate for producing the derivative.

Conventional technology

Use of sulfonylurea and biguanides as antidiabetic agents <<Sulfonylurea causes severe hypoglycemia, biguanides cause severe lactic acidosis May cause Therefore, the use of these drugs requires great care, and biguanides are rarely used. Therefore, development of a new antidiabetic drug that does not have these drawbacks is desired.

Problems to be solved by the invention

Recently, drugs that improve hyperglycemia by reducing insulin resistance in peripheral tissues have attracted attention. A typical example of such a drug is C S— 0 4

Pioglitazone (Takeda, Chem. Pharm. Bull., 39, 1440 (1991)), englitazone (Faiisa, Chem. Pharm, Bull. , 34,

319, (1991)). In addition, JP-A-3-9007, JP-A-2-1

No. 6 7225, JP-A-5-92972, JP-A-5-239091, JP-A-6-150053, JP-A-6-503 There are 53 and so on. Insulin desensitizers that have been used to date have not yet been satisfied with weak or side effects, and there is a need for the development of drugs that are stronger and have no side effects.

Means for solving the problem

The present inventors synthesized various compounds and proceeded with screening, and as a result, the compound of formula (I)

(I)

Wherein R is a cycloalkyl group, an unsubstituted or substituted phenyl group, a naphthyl group, or at least one of nitrogen, oxygen, and sulfur atoms. Represents a monocyclic or bicyclic heterocyclic ring containing at least one, and one or both of R ₂ and R ₃ are hydrogen, a lower alkyl group, a cycloalkyl group, an alkoxy group, a halogen atom, a hydroxy group, an amino group ( Which may be protected by a protecting group), a phenyl group, or — (CH ₂ ) n-(n = 2 to 6), and A represents an amide bond.] A thiazolidine-2,4-dione derivative represented by However, they have found that they have excellent blood sugar lowering action and lipid lowering action, and completed the present invention.

In the present specification, the cycloalkyl group represented by R, includes cyclopentane, cyclohexane, cycloheptane and the like. Examples of the unsubstituted or phenyl group having one or more substituents represented by are phenyl, 2-, 3-, or 4-chlorophenyl, 2-, 3-, or 4-fluorophenyl, 2-, 3- , Or 4-bromophenyl, 2-, 3-, or 4-nitrophenyl, 2-, 3-, or 4-tritolyl, 2-, 3-, or 4-methoxyphenyl, 2-, 3-, or 4- Ethoxyphenyl, 2-, 3-, or 4-benzyloxyphenyl, 2-, 3-, or 4-hydroxyphenyl, 2-, 3-, or 4-biphenyl, 2-, 3- or 4-dimethylaminophenyl, 4- (p-toluenesulfonylamide) phenyl, 2,4-dinitrophenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 4-hydroxy 1-3 2-Trophenyl group etc. I can do it. Examples of the unsubstituted or naphthyl group having one or more substituents represented by R and are 1-naphthyl, 2-naphthyl, 4-methoxy-1-naphthyl, 6-methoxy-2-naphthyl, 1-naphthyl , 2,3,4-tetrahydro-2-naphthyl group and the like. An unsubstituted or a monocyclic or bicyclic heterocyclic ring containing at least one of nitrogen, oxygen, and sulfur atoms having at least one substituent represented by R and Examples include 2-pyridyl, 3-pyridyl, 2-phenyl, 3-phenyl, 3-inyl, 2-methyl-3-indolyl, 5-hydroxy-1-3-indolyl, 5-methoxy-2-methyl-3. Examples include indolyl, 1,2,3,4-tetrahydro-13-isoquinolyl and quinolyl groups.

In the present specification, the lower alkyl group of R ₂ and R ₃ represents a straight-chain or branched-chain methyl, ethyl, propyl, butyl, pentyl, hexyl group and the like. The cyclic alkyl group of R ₂ and R ₃ represents a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl group or the like. The alkoxy group for R ₂ and R ₃ represents methoxy, ethoxyquin, or a methoxy group. The halogen atom of R ₂ and R ₃ represents an atom such as fluorine, chlorine, and bromine.

Preferred R, is cyclohexyl, phenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 2,4-dinitrophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl. , 4-tolyl, 3-tolyl, 2-tolyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-phenyl Droquinphenyl, 3—hydroxyphenyl, 2—hydroxyphenyl, 4-dimethylaminophenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 2-phenyl, 3-phenyl, 3-phenyl —Indolyl, 2—Methyl-3—Indolyl, 2-Methyl-5—Methoxy-3—Indolyl group.

Preferably, one or both of R ₂ and R ₃ are hydrogen, fluorine, bromine, methyl, ethyl, cyclopentyl, cyclohexyl, phenyl, hydroxy, methoxy, or-(CH ₂ ) ₂ -,-( CH ₂ ).

Embodiment of the Invention

The present invention provides a novel thiazolidine-1,2, dione derivative having an excellent blood glucose lowering action and lipid lowering action. Further, the present invention provides an intermediate useful for producing the compound.

According to the present invention, the thiazolidine-1,2,4-dione derivative represented by the formula (I) is compounded with a compound represented by the formula (Π) and a compound represented by the formula (III) as shown in Scheme 1. It is obtained by condensing the compound (X ≠ Y).

The compound (I la, X 2 NH ₂ ) can be synthesized by a known method (Chem. Pharm. Bui 1., 30, 3580, (1982)). The compound (I lb, X = C0OH) can be synthesized by the method shown in Scheme 1. That is, the aniline derivative (IV) is diazotized with a diazotizing agent such as sodium nitrite in the presence of a hydrohalic acid such as hydrochloric acid, hydrobromic acid, etc. The ester derivative (V) can be obtained by reacting with an acrylate in the presence of a copper catalyst. The compound (VI, X = C00H) can be obtained by hydrolyzing the compound (VII) obtained by reacting the compound (V) with thiourea (VI). All compounds are purified by ordinary purification means, for example, recrystallization, thin-layer chromatography such as silica gel, column chromatography, high-performance liquid chromatography, and the like.

Scheme 1

NHz

(TV) (V) (VI)

(YD) (Π-b)

Y = COOH X = NH ₂

A = CONH

Y = NH. X = COOH A = HCO Compound (IH) is known per se or can be synthesized by a known method. Compound (II) and compound (III) are reacted in the presence of a suitable base or a condensing agent. This reaction is carried out in a solvent such as dioxane, dimethylformamide, or pyridine, using dimethylaminopyridine, triethylamine, pyridine, or the like as a base, and H0BT (1-hydroxybenzotriazole), Using HOSU (N-hydroxysuccinimide) and the like, DCC (dicyclohexylcarbodiimide) and WSC. HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) as condensing agents Used. The reaction temperature is between 0 and 100 ° C, but it is usually carried out at room temperature. The reaction time is between 0.5 and 24 hours. The compound represented by the formula (I) is purified by ordinary purification means, for example, recrystallization, thin-layer chromatography such as silica gel, column chromatography, high-performance liquid chromatography and the like. You.

The compound (I) of the present invention forms a salt since it has an acidic nitrogen on the thiazolidine ring. The salt is formed into a salt by a known method, for example, a neutralization method or an ion exchange resin method. Salts include alkali metal salts such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and pharmaceutically acceptable amines. Examples of such amines include organic compounds such as methylamine, ethylamine, dimethylamine, getylamine, triethylamine, isopropylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, lysine, and arginine. Bases.

The compound of the present invention has one or more asymmetric carbon atoms and thus has optical isomers. The present invention also includes those optical isomers and racemates.

Example

The following examples illustrate some of the present invention, but the present invention is not limited by these examples. In the examples, "NMR" and "MS" represent "nuclear magnetic resonance spectrum" and "mass spectrometry spectrum (FAB-MS :)", respectively. All NMR measurements were taken with dimethylsulfoxide d6.

Example 1 Synthesis of 5- (4-carboxybenzyl) thiazolidine-l, 4-dione (II-lb) 16.5 g of aminoethyl benzoate are added to a mixture of acetone and water (165 ml, 55 ml), and then 106 ml of concentrated hydrochloric acid are added. To this mixture, 25 ml of an aqueous solution of 9.34 g of sodium nitrite was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. Then, 80 ml of ethyl acrylate is added to the mixture, 1.6 g of cuprous oxide is gradually added at about 40 ° C with stirring, and the mixture is further stirred for 2 hours. After the generation of nitrogen gas was completed, ethyl acetate was added and extracted twice. The extract was purified by silica gel chromatography to give 17.78 g (yield 63%) of compound (V) as an oil. 12.7 g of the compound (V) obtained above, 10.2 g of thioperia (VI) and 11.0 g of sodium acetate in a propanol solution (40 ml) are heated under reflux for 9 hours. After cooling, the precipitate was collected by filtration, washed with cold propanol, and dried, yielding 9.5 g of compound (VII). The obtained compound (VII) 4.0 was dissolved in a mixture of 30 ml of 4N hydrochloric acid and 350 ml of ethanol, and the mixture was heated under reflux for 8 hours. Then, ethanol was distilled off under reduced pressure, 20 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 8 hours. After cooling, the precipitate was collected and washed with water to give 3.5 g of the desired compound.

Awake (ppm); 3.23 (1H, dd), 3.45 (1H, dd), 4.97 (1H, dd), 7.40 (2H, d), 7.89 (2H, d),

12.07 (1H, bs), 12.90 (1H, bs).

MS (M-1); 250

Example 2 Synthesis of 5- (4- (2-cyclohexylacetamide) benzyl) thiazolidin-1,2,4-dione

5- (4-aminobenzyl) thiazolidine mono 2,4-dione 1.5g, cyclohexyl S1 acid 960nig, HOBT 1.03g, WSC. It was dissolved in 20 ml and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, an aqueous solution of saturated sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 1.7 g of 5- (4- (2-cyclohexylacetamide) benzyl) -1,000azolidine-1,2,4-dione.

R (ppm); 0.94-1. 40 (5H, m), 1.71-1.90 (5H, m), 2.25 (2H, d), 3.14 (1H, dd),

3.40 (1H, dd), 4.95 (1H, dd), 7.23 (2H, d), 7.60 (2H, d), 9.9K1H, s), 12.09 (1H, bs ).

MS (M + 1); 347 Example 3 Synthesis of 5- (4- (2-phenylacetamide) benzyl) thiazolidine-1, 4-dione

1.25 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 735 mg of phenylacetic acid, 0.83 g of H0BT, and 1.04 of WSC.HC1 were dissolved in 20 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 1.32 g of 5- (4- (2-phenylacetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.06 (1H, dd), 3.31 (1H, dd), 3.62 (2H, s), 4.87 (1H, dd),

7.16 (2H, d), 7.26 (1H, m), 7.32 (4H, m), 7.53 (2H, d),

10.16 (1H, s), 12.00 (1H. Bs)

MS (M + 1); 341

Example 4 Synthesis of 5- (4- (2- (2-nitrophenyl) acetamide) benzyl) thiazolidine-l, 4-dione

2.0 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.8 g of 2-difluoroacetic acid and 2.06 of DCC were suspended in 50 ml of methylene chloride and stirred at room temperature for 5 hours. The precipitate was removed by filtration, and ethyl acetate was added to the filtrate. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 1.2 g of 5- (4- (2- (2-ditrophenyl) acetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.15 (1H, dd), 3.41 (1H, dd), 4.20 (2H, s), 4.96 (2H, dd),

7.22 (2H, d), 7.53 (2H, d), 7.61-7.68 (2H, m), 7.80 (1H, dt), 8.14 (1H, dd), 10.3 (1H, s), 12.09 (1H, bs)

MS (M + 1); 386

Example 5 Synthesis of 5- (4- (2- (3-ditrophinyl) acetamide) benzyl) thiazolidine-1, 4-dione

5- (4-aminobenzyl) thiazolidine-1,2 dione 1.5 g, 3-nitro 1.5 g of phenylacetic acid and 1.54 g of DCC were suspended in 40 ml of methylene chloride and stirred at room temperature for 24 hours. The precipitate was removed by filtration, ethyl acetate was added to the filtrate, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 2.25 g of 5- (4- (2- (3-ditrophenyl) acetamide) benzyl) thiazolidine-1,2,4-dione.

N R (ppm); 3.15 (1H, dd), 3.40 (1H, dd), 3.92 (2H, s), 4.96 (1H, dd),

7.25 (2H, d), 7.62 (2H, d), 7.72 (1H, t), 7.86 (1H, d),

8.22 (1H, dd), 8.32 (1H, d), 10.34 (1H, s), 12.09 (1H, bs)

MS (M + 1); 386

Example 6 Synthesis of 5- (4- (2- (412-trophinyl) acetamide) benzyl) thiazolidine-12,4-dione

1.0 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 820 mg of 412-mouth phenylacetic acid and 935 mg of DCC were suspended in 40 ml of methylene chloride and stirred at room temperature for 24 hours. The precipitate was removed by filtration, and ethyl acetate was added to the filtrate. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 1.35 g of 5- (4- (2- (412-trophinyl) acetamide) benzyl) thiazolidine-1,4-dione.

NMR (ppm); 3.15 (1H, dd), 3.40 (1H, dd), 3.90 (2H, s), 4.96 (1H, dd),

7.26 (2H, d), 7.61 (2H, d), 7.69 (2H, d), 8.28 (2H, d),

10.34 (1H, s), 12.08 (lH, bs)

MS (M + 1); 386

Example 7 Synthesis of 5- (4- (2- (2,4-dinitrophenyl) acetamide) benzyl) thiazolidine-l, 4-dione

5- (4-Aminobenzyl) thiazolidine 1.5 g of 2,4-dione, 1.53 g of 2,4-dinitrophenylacetic acid, 1.03 g of HOBT, 1.3 g of WSC.HCl were dissolved in 20 ml of DMF and stirred at room temperature for 24 hours. . Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate Is distilled off, and the residue is dissolved in methanol and dropped into water, whereby a powder is precipitated. The powder was collected by filtration and dried to give 1.78 g of 5- (4- (2- (2,4-dinitrophenyl) acetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.07 (1H, dd), 3.33 (1H, dd), 4.28 (2H, s), 4.87 (1H, dd),

7.18 (2H, d), 7.48 (2H, d), 7.89 (1H, d), 8.54 (1H, dd), 8.78 (1H, d)

10.32 (1H, s), 12.0K1H, bs)

MS (M + 1); 431

Example 8 Synthesis of 5- (4- (2- (2-methoxyphenyl) acetamide) benzyl) thiazolidine-l, 4-dione

2- (4-aminobenzyl) thiazolidine-1,4-dione was added to 2 g, 897 mg of 2-methoxybenzoylacetic acid, 0.83 g of H0BT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF, and the mixture was stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is dropped into water. The powder was collected by filtration and dried to obtain 0.96 g of 5- (4- (2- (2-methoxyphenyl) acetamide) benzyl) thiazolidine-1,2,4-dione.

R (ppm); 3.06 (1H, dd), 3.32 (1H, dd), 3.61 (2H, s), 3.76 (3H, s), 4.87 (1H, dd), 6.87-6.98 (2H, m), 7.14 -7.26 (2H, m), 7.53 (2H, d), 10.02 (1H, s),

12.0K1H, bs)

MS (M + 1); 371

Example 9 Synthesis of 5- (4- (2- (3-methoxyphenyl) acetamide) benzyl) thiazolidine-l, 4-dione

1.5-g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.12 g of 3-methoxydifluroic acid, 1.03 g of HOBT and 1.3 g of WSC.HC1 were dissolved in 20 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is dropped into water. The powder was collected by filtration and dried to obtain 1.8 g of 5- (4- (2- (3-methoxyphenyl) acetamide) benzyl) thiazolidine-1,2 dione. NMR (ppm); 3.14 (1H, dd), 3.40 (1H, dd), 3.67 (2H, s), 3.83 (3H, s),

6.89 (1H, dd), 6.92-7.00 (2H, m), 7.23-7.62 (2H, m), 7.60 (2H, d),

10.21 (1H, s), 12.08 (1H, bs)

MS (M + 1); 371

Example 10 Synthesis of 5- (4- (2- (4-Methoxyphenyl) acetamide) benzyl) thiazolidine-1,2-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 0.9 g of 4-methoxyphenylacetic acid, 0.83 g of HOBT and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane. The powder was collected and dried to obtain 1.64 g of 5- (4_ (2- (4-methoxyphenyl) acetamide) benzyl) thiazolidine-1,2-dione.

NMR (ppm); 3.06 (1H, dd), 3.31 (1H, dd), 3.54 (2H, s), 3.72 (3H, s), 4.87 (1H, dd)

6.88 (2H, d), 7.16 (2H, d), 7.24 (2H, d), 7.52 (2H, d),

10.08 (1H, s), 12.00 (1H, bs)

S (M + 1); 371

Example 1 Synthesis of 15— (4— (2— (2-tolyl) acetamide) benzyl) thiazolidine-1,2 dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 0.81 g of 2-tolylacetic acid, 0.83 g of HOBT and 1.04 g of WSC.HC1 were dissolved in 20 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane. The powder was collected by filtration and dried to obtain 1.5 g of 5- (4- (2- (2-tolyl) acetamido) benzyl) thiazolidine-12,4-dione.

NMR (ppm); 2.29 (3H, s), 3.05 (1H, dd), 3.32 (111, dd), 3.67 (2H, s), 4.85 (1H, dd),

7.12-7.25 (6H, m), 7.53 (1H, d), 10.14 (1H, s), 12.05 (1H, bs) SCM + 1); 355 Example 1 Synthesis of 25- (4- (2- (3-tolyl) acetamido) benzyl) thiazolidine-l, 4-dione

1.5 g of 5- (4-aminobenzyl) thiazolidine-1,2-dione, 0.81 g of 3-tolylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HCl were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 1.37 g of 5- (4- (2- (3-tolyl) acetamido) benzyl) thiazolidine-1,2 dione.

N R (ppm); 2.29 (3H, s), 3.06 (1H, dd), 3.31 (1H, dd), 3.57 (2H, s), 4.87 (1H, dd),

7.04-7.23 (6H, m), 7.53 (2H, d), 10.13 (1H, s), 12.01 (1H, bs) MS (MH); 355

Example 13 Synthesis of 35— (4- (2- (4-tolyl) acetamide) benzyl) thiazolidine-1,2 dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 0.81 g of 4-trinoleacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HCl were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane. The powder was collected by filtration and dried to obtain 1.46 g of 5- (4- (2- (4-tolyl) acetamido) benzyl) thiazolidine-1,2 dione.

R (ppm); 2.27 (3H, s), 3.06 (1H, dd), 3.32 (1H, dd), 3.56 (2H, s), 4.86 (1H, dd),

7.10-7.22 (6H, m), 7.52 (2H, d), 10.11 (1H, s), 12.00 (1H, bs) MS (M + 1); 355

Example 1 Synthesis of 45— (4- (2- (2-fluorophenyl) acetamide) benzyl) thiazolidine-l, 4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 832 mg of 2-fluorophenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HCl were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate is added to the reaction solution, and water and 5% aqueous solution of citric acid are added. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is dropped into water. The powder was collected by filtration and dried to obtain 1.55 g of 5- (4- (2- (2-fluorophenyl) acetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppra); 3.07 (1H, dd), 3.32 (1H, dd), 3.71 (2H, s), 4.87 (1H, dd),

7.13-7.20 (4H, m), 7.27-7.41 (2H, m), 7.53 (2H, d),

10.19 (1H, s), 12.00 (1H, bs)

MS (M + 1); 359

Example 1 Synthesis of 55- (4- (2- (3-fluorophenyl) acetamide) benzyl) thiazolidine-l, 4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 832 mg of 3-fluorophenylacetic acid, 0.83 g of H0BT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into water. The powder was collected by filtration and dried to obtain 1.51 g of 5- (4- (2- (3-fluorophenyl) acetamide) benzyl) thiazolidine-1,2-dione.

Marauder R (ppm); 3.06 (1H, dd), 3.31 (1H, dd), 3.62 (2H, s), 4.87 (1H, dd),

7.11-7.18 (4H, m), 7.33-7.38 (2H, m), 7.52 (2H, d), 10.15 (1H, s),

12.00 (1H, bs)

MS (Mil); 359

Example 16 Synthesis of 65- (4- (2- (4-fluorophenyl) acetamide) benzyl) thiazolidine-1,2 dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 832 mg of 4-fluorophenylacetic acid, 0.83 g of H0BT, and 1.01 of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is dropped into water. The powder is collected by filtration and dried to give 5- (4-(2- (4-monofluorophenyl) acetamide). De) Benzyl) thiazolidine-1,2,4-dione (1.54 g) was obtained.

NMR (ppm); 3.07 (1H, dd), 3.32 (1H, dd), 3.67 (2H, s), 4.87 (1H, dd),

7.04-7.18 (4H, m), 7.33-7.41 (2H, m), 7.52 (2H, d), 10.17 (1H, s), 12.01 (lH, bs)

MS (M + 1); 359

Example 1 Synthesis of 75_ (4- (2- (2-chlorophenyl) acetamide) benzyl) thiazolidine-1,2 dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 921 mg of 2-chlorophenylacetic acid, 0.83 g of H0BT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane. The powder was collected by filtration and dried to obtain 1.58 g of 5- (4- (2- (2-chlorophenyl) acetamido) benzyl) thiazolidine-1,2,4-dione.

NMR (ppm); 3.07 (1H, dd), 3.33 (1H, dd), 3.82 (2H, s), 4.88 (1H, dd),

7.17 (2H, d), 7.29-7.32 (2H, m), 7.40-7.46 (2H, m), 7.54 (2H, d),

10.21 (1H, s), 12.0K1H, bs)

S (M + 1); 375

Example 1 Synthesis of 85- (4- (2- (3-chlorophenyl) acetamide) benzyl) thiazolidine-2,4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 921 mg of 3-chlorophenylacetic acid, 0.83 g of H0BT and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is dropped into water. The powder was collected by filtration and dried to obtain 1.3 g of 5- (4- (2- (3-chlorophenyl) acetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.06 (1H, dd), 3.32 (1H, dd), 3.66 (2H, s), 4.87 (1H, dd),

7.17 (2H, d), 7.27-7.40 (4H, m), 7.52 (1H, d), 10.18 (1H, s), 12. OKIH, bs)

MS (M + 1); 375

Example 19 Synthesis of 5- (4- (2- (4-chlorophenyl) acetamide) benzyl) thiazolidine-l, 41-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 921 mg of 4-chlorophenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HCl were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is dropped into water. The powder was collected by filtration and dried to obtain 1.6 g of 5- (4- (2- (4-chlorophenyl) acetamide) benzyl) thiazolidine-1,2,4-dione.

NMR (ppm); 3.07 (1H, dd), 3.32 (1H, dd), 3.64 (2H, s), 4.87 (1H, dd),

7.17 (2H, d), 7.33-7.38 (2H, m), 7.52 (2H, d), 10.18 (1H, s), 12.0K1H, bs)

S (M + 1); 375

Example 20 Synthesis of 5- (4- (2- (2-hydroxyphenyl) acetamide) benzyl) thiazolidine-1,2-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.64 g of 2-hydropenxyphenylacetic acid, 1.66 g of HOBT, and 2.08 g of WSC.HCl were dissolved in 15 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 490 mg of 5- (4- (2- (2-hydroxyphenyl) acetamide) benzyl) thiazolidin-1,2,4-dione.

NMR (ppm); 3.06 (1H, dd), 3.32 (1H, dd), 3.58 (2H, s), 4.87 (1H, dd),

6.17-6.80 (2H, m), 7.03-7.17 (4H, m), 7.54 (2H, d), 9.48 (1H, s),

10.05 (1H, s), 12.0K1H, bs)

MS (M + 1); 357

Example 2 15— (4- (2- (3-hydroxyphenyl) acetamide) Ben Synthesis of thiazolidine-1,2,4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 822 mg of 3-hydroxyphenylacetic acid, 0.83 g of H0BT and 1.04 of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 1.41 g of 5- (4- (2- (3-hydroxyphenyl) acetamide) benzyl) thiazolidine-12,4-dione.

NMR (ppm); 3.08 (1H, dd), 3.31 (1H, dd), 3.52 (2H, s), 4.87 (1H, dd),

6.62-6.66 (1H, m), 6.74-6.76 (2H, m), 7.08-7.18 (3H, m),

7.52C1H, d), 10.06 (1H, s), 12.00 (1H, bs)

MS (M + 1); 357

Example 2 Synthesis of 25- (4- (2- (4-hydroxyphenyl) acetamide) benzyl) thiazolidine-1,2,4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 822 mg of 4-hydridoxyxinodioleacetic acid, 0.83 g of H0BT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. . Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. The ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (chloroform: ethanol = 15: 1) to give 5_ (4- (2- (4-hydroxyphenyl) acetamide) benzyl). 1.49 g of thiazolidine-1,2-dione was obtained as a powder.

NMR (ppm); 3.05 (1H, dd), 3.31 (1H, dd), 3.47 (2H, s), 4.86 (1H, dd), 6.70 (2H, d),

7.10-7.17 (4H, m), 7.52 (2H, d), 9.24 (1H, s), 10.05 (1H, s), 12.00 (1H, bs)

MS (Mil); 357

Example 2 Synthesis of 35- (4- (2- (4-biphenylyl) acetamide) benzyl) thiazolidine-l, 4-dione

5-(4-aminobenzyl) thiazolidine- 1, 2, 4-dione 222mg, bifueni 212 mg of rilacetic acid, 153 mg of HOBT, and 192 mg of WSC.HC1 were dissolved in 5 ml of DMF and stirred at room temperature for 6 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane. The powder was collected by filtration and dried to obtain 322 mg of 5- (4- (2- (4-biphenyl) acetamide) benzyl) thiazolidine-1,2 dione.

N R (ppm); 3.06 (1H, dd), 3.31 (1H, dd), 3.68 (2H, s), 4.86 (1H, dd),

7.17 (2H, d), 7.32-7.67 (11H, m), 10.19 (1H, s), 12.00 (1H, bs) S (+1); 417

Example 2 Synthesis of 45— (4- (2- (4-dimethylaminophenyl) acetamide) benzyl) thiazolidine-l, 4-dione

1.2 g of 5 _ (4-aminobenzyl) thiazolidine-1,4-dione, 968 mg of 4-dimethylaminophenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. The ethyl acetate was distilled off and the residue was purified by silica gel column chromatography (form: ethanol = 20: 1) to give 5- (4- (2- (4-dimethylaminoamino) acetamide). ) Benzyl) 1.22 g of thiazolidine-1,2 dione as powder o

NMR (ppm); 2.85 (6H, s), 3.05 (1H, dd), 3.3K1H, dd), 3.46 (2H, s), 4.86 (1H, dd),

6.68 (2H, d), 7.12-7.16 (4H, m), 7.52 (2H, d), 10.03 (1H, s), 12.00 (1H, bs)

MS (MU); 384

Example 2 Synthesis of 5- (4- (2- (1-naphthyl) acetamide) benzyl) thiazolidine-1,2 dione

1.5 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.39 g of naphthylacetic acid, 1.03 g of HOBT, and 1.3 g of WSC.HC1 were dissolved in 15 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off and the residue When dissolved in methanol and dropped into water, powder precipitates. The powder was collected by filtration and dried to give 1.88 g of 5- (4- (2- (1-naphthyl) acetoamide) benzyl) thiazolidine-12,4-dione.

NMR (ppm); 3.15 (1H, dd), 3.37-3.48 (1H, m), 4.23 (2H, s), 4.96 (1H, dd),

7.26 (2H, d), 7.53-7.67 (6H, m), 7.91-8.04 (2H, m), 8.21 (1H, d),

10.40 (1H, s), 12.07 (1H, bs)

S (M + 1); 391

Example 2 Synthesis of 65- (4- (2- (2-naphthyl) acetamide) benzyl) thiazolidine-1, 4-dione

1.5 g of 5- (4-aminobenzyl) thiazolidine 1,2-dione, 1.39 g of 2-naphthylacetic acid, 1.03 g of HOBT, and 1.3 g of WSC.HCl were dissolved in 15 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 1.98 g of 5- (4- (2- (2-naphthyl) acetamide) benzyl) thiazolidine-1,2 dione.

Garden R (ppm); 3.14 (1H, dd), 3.40 (1H, dd), 3.90 (2H, s), 4.95 (1H, dd), 7.55 (2H, d),

7.52-7.86 (5H, m), 7.91-7.99 (4H, m), 10.32 (1H, s), 12.09 (1H, bs) MS (M + 1); 391

Example 27 Synthesis of 5- (4- (2- (2-pyridyl) acetamide) benzyl) thiazolidine-1,2 dione

5- (4-aminobenzyl) thiazolidine 1,2,4-dione 1.5 g, 2-pyridyl acetic acid hydrochloride 1.17 g, triethylamine 0.9½1, HOBT 1.03 g, WSC.HCl 1.3 g are dissolved in DMF 15 ml, and it is left overnight at room temperature. Stirred. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane, whereby powder is deposited. The powder was collected by filtration and dried to obtain 1.26 g of 5- (4- (2- (2-pyridyl) acetoamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.05 (1H, dd), 3.33-3.41 (1H, m), 3.82 (2H, s), 4.86 (1H, dd), 7.16 (2H, d), 7.23-7.39 (2H, m), 7.53 (2H, d), 7.71-7.77 (2H, m),

8.47-8.50 (2H, m), 10.21 (1H, s), 11.78 (1H, bs)

S (M + 1); 342

Example 28 Synthesis of 5- (4- (2- (3-pyridyl) acetamide) benzyl) thiazolidine-1, 4-dione

1.5 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.17 g of 3-pyridylacetic acid hydrochloride, 0.94 ml of triethylamine, 1.03 g of HOBT, and 1.3 g of WSC.HC1 are dissolved in 10 ml of DMF in 10 ml of DMF. And stirred all day and night. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, an aqueous solution of sodium hydrogen carbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane. This powder was collected by filtration and dried to obtain 488 mg of 5- (4- (2- (3-pyridyl) acetamide) benzyl) thiazolidine-1,2,4-dione.

NMR (ppm); 3.06 (1H, dd), 3.20-3.30 (1H, m), 3.69 (2H, s), 4.87 (1H, dd),

7.17 (2H, d), 7.35 (1H, dd), 7.52 (2H, d), 7.73 (1H, d),

8.45-8.52 (2H, m), 10.23 (1H, s), 11.94 (1H, bs)

MS (M + 1); 342

Example 29 Synthesis of 5- (4- (2- (2-Chenyl) acetamide) benzyl) thiazolidine-1, 4-dione

1.5 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 960 mg of 2-phenylacetic acid, 1.03 g of HOBT, and 1.3 g of WSC.HC1 were dissolved in DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane, whereby powder is deposited. The powder was collected by filtration and dried to obtain 1.7 g of 5- (4- (2- (2-phenyl) acetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.07 (1H, dd), 3.29-3.32 (1H, m), 3.35 (2H, s), 4.87 (1H, dd),

6.97 (2H, t), 7.18 (2H, d), 7.38 (1H, dd), 7.52 (2H, d), 10.19 (1H, s), 12.0K1H, bs)

MS (M + 1); 347 Example 30 Synthesis of 5- (4- (2- (3-Chenyl) acetamide) benzyl) thiazolidine-l, 4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 768 mg of 3-phenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HCl were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, an aqueous solution of saturated sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 1.49 g of 5- (4- (2- (3-Chenyl) acetamide) benzyl) thiazolidine-12,4-dione.

NMR (ppm); 3.06 (1H, dd), 3.32 (1H, dd), 3.64 (2H, s), 4.87 (1H, dd),

7.08 (1H.dd), 7.15-7.18 (2H, m), 7.31 (1H, d), 7.46-7.54 (3H, m), 10.1K1H, s), 12.00 (1H, bs)

MS (M + 1); 347

Example 3 Synthesis of 15— (4- (2- (3-indolyl) acetamide) benzyl) thiazolidine-1,2 dione

1.5 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.18 g of 3-indolylacetic acid, 1.03 g of HOBT and 1.3 g of WSC.HCl were dissolved in DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 2.08 g of 5- (4- (2- (3-indolyl) acetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.05 (1H, dd), 3.31 (1H, dd), 3.70 (2H, s), 4.86 (1H, dd), 6.98 (1H, s),

7.07 (1H, t), 7.15 (2H, d), 7.25 (1H, d), 7.35 (1H, d), 7.53 (2H, d), 7.60 (2H, d), 10.07 (1H, s), 10.90 (1H, bs), 11.99 (1H, bs)

MS (M + 1); 380

Example 3 Synthesis of 25- (4- (2- (2-methyl-3-indolyl) acetamide) benzyl) thiazolidine-l, 4-dione

5- (4-aminobenzyl) thiazolidin-1,2,4-dione 1.5 g, 2-methyl Lou 3-Indolyl acetic acid 1.02g, HOBT 0.83g, WSC.HCl 1.04g were dissolved in DMF 10ml and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into water, whereby powder is precipitated. This powder was collected by filtration and dried to obtain 1.74 g of 5- (4- (2- (2-methyl-3-indolinyl) acetamide) benzyl) thiazolidine-1, 4-dione.删 R (ppm); 2.38 (3H, s), 3.05 (1H, dd), 3.31 (1H, dd), 3.66 (2H, s), 4.86 (1H, dd),

6.89-7.00 (2H, m), 7.15 (2H, d), 7.23 (1H, d), 7.49-7.54 (3H, m),

10.04 (1H, s), 10.81 (1H, bs), 12.01 (1H, bs)

MS (M + 1); 394

Example 3 Synthesis of 35— (4_ (2- (5-Methoxy-2-methyl-3-indolyl) acetamide) benzyl) thiazolidine_2,4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 5.18 g of 5-methoxy-3-indolinoleacetic acid, 1.18 g of HOBT, 0.83 g of HOBT, 1.01 g of WSC. And stirred all day and night. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (cloform form-ethanol: 30: 1) to give 5- (4- (2- (5-methoxy-2-methyl-3-indolyl)). 1.46 g of acetoamide / benzyl / thiazolidine-1, 4-dione was obtained as a powder.

R (ppm); 2.36 (3H, s), 3.05 (1H, dd), 3.0K1H, dd), 3.62 (2H, s), 3.71 (3H, s),

4.86 (1H, dd), 6.62 (1H, dd), 7.08 (1H, d), 7.15 (2H, d), 7.53 (2H, d), 10.04 (1H, s), 10.64 (1H, s), 12.01 (1H, bs)

MS (M + 1); 424

Example 3 Synthesis of 45— (4- (2-methyl-2- (R) -phenylacetamide) benzyl) thiazolidine-1,2,4-dione

Dissolve 1.48 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, l.Og of 2- (R) -phenylpropionic acid, 1.02 g of HOBT, and 1.28 g of WSC.HCl in 15 ml of DMF and bring to room temperature. And stirred all day and night. Ethyl acetate is added to the reaction solution, and water and 5% The extract was washed with an aqueous acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in ethyl acetate and dropped into hexane, whereby powder is deposited. The powder was collected by filtration and dried to obtain 1.76 g of 5- (4- (2-methyl-1- (R) -phenylacetamide) benzyl) thiazolidine-1, 4-dione.

NMR (ppm); 1.41 (3H, d), 3.05 (1H, dd), 3.31 (1H, dd), 3.82 (1H, q), 4.86 (1H, dd),

7.15 (2H, dd), 7.19-7.41 (5H, m), 7.53 (2H, d), 10.03 (1H, s), 11.99 (1H, bs)

MS (M + 1); 355

Example 3 Synthesis of 55- (4- (2-methyl-2- (S) -phenylacetamide) benzyl) thiazolidine_2,4-dione

1.48 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, l.Og of 2- (S) -phenylpropionic acid, 1.02 g of HOBT, and 1.28 g of WSC.HC1 are dissolved in 15 ml of DMF at room temperature. Stirred all day and night. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in ethyl acetate and dropped into hexane, whereby powder is deposited. The powder was collected by filtration and dried to obtain 1.68 g of 5- (4- (2-methyl-1- (S) -phenylacetamide) benzyl) thiazolidin-1,2, dione.

NMR (ppm); 1.41 (3H, d), 3.05 (1H, dd), 3.31 (1H, dd), 3.81 (1H, q), 4.86 (1H, dd),

7.18 (2H, d), 7.20-7.41 (7H, m), 7.53 (2H, d), 10.04 (1H, s), 11.99C1H, bs)

MS (H); 355

Example 36 Synthesis of 5- (4- (2-ethyl-2-furanacetamide) benzyl) thiazolidine-1,2 dione

1.5 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.2 g of 2-phenylbutyric acid, 1.03 g of HOBT and 1.3 g of WSC.HC1 were dissolved in 20 mi of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. This powder was collected by filtration and dried to give 5- (4- (2-ethyl-2-phenylacetamide) benzyl). 2.12 g of thiazolidine_2,4-dione was obtained.

NMR (ppm); 0.94 (3H, t), 1.70-1.85 (1H, m), 2.02-2.21 (1H, m), 3.13 (1H, dd),

3.39 (1H, dd), 3.63 (1H, dd), 4.94 (1H, dd), 7.22 (2H, d), 7.28-7.49 (5H, m), 7.61 (2H, d), 10.16 (1H, s) , 12.09 (1H, bs)

S (M + 1); 369

Example 3 Synthesis of 75- (4- (2-cyclopentyl-12-phenylacetamide) benzyl) thiazolidine-1,2 dione

5- (4-aminobenzyl) thiazolidine- 1,2,4-dione 1.5g, 2-cyclopentyl-2-phenylacetic acid 1.4g, HOBT 1.03g, WSC.HC1 1.3g are dissolved in DMF 15ml and stirred at room temperature for 24 hours. did. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. The ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5- (4- (2-cyclopentyl-2-phenylacetamide) benzyl). 1.46 g of thiazolidine mono 2,4-dione were obtained by powdering.

NMR (ppm); 0.85-1.90 (8H, m), 2.48-2.70 (1H, m), 3.04 (1H, dd), 3.26-3.39 (3H, m),

4.85 (1H, dd), 7.11-7.53 (9H, m), 10, 05 (1H, s), 11.99 (1H, bs) MS (M + 1); 409

Example 3 Synthesis of 85— (4- (2-cyclohexyl-2-phenylacetamide) benzyl) thiazolidine-1,2-dione

5- (4-Aminobenzyl) thiazolidine-1,4-dione 0.75 g, 2-cyclohexyl-2-phenylacetic acid 833 mg, HOBT 620 mg, WSC.HC1 776 m are dissolved in DMF 10 ml and stirred at room temperature for 24 hours. did. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (chloroform: ethanol = 20: 1) to give 5- (4- (2-cyclohexyl-2-phenylacetamide). Benzyl) thiazolidine- 1,2-dione was obtained as a powder in an amount of 1. llg.

NMR (ppm); 0.74 (1H, m), 1.03-1.20 (5H, m), 1.58-1.81 (4H, m), 2.03 (1H, m), 3.04 (1H, dd), 3.27-3.33 (2H, m), 4.85 (1H, dd), 7.14 (2H, d),

7.20-7.40 (4H, m), 7.51 (2H, d), 10.07 (1H, s), 12.00 (1H, bs)

MS (M + 1); 423

Example 3 Synthesis of 5- (4- (2,2-diphenylacetamide) benzyl) thiazolidine-1,2 dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.15 g of diphenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to give 1.94 g of 5- (4- (2,2-diphenylacetamide) benzyl) thiazolidine-1,2 dione.

NMR (ppm); 3.07 (1H, dd), 3.32 (1H, dd), 4.87 (1H, dd), 5.16 (1H, s), 7.17 (2H, d),

7.21-7.38 (10H, m), 7.55 (2H, d), 10.40 (1H, s), 12.01 (1H, bs) MS (MI1); 417

Example 4 Synthesis of 5- (4- (2-Methoxy-12-phenylacetamide) benzyl) thiazolidine-1, 4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 897 mg of 2-methoxy-2-phenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF and stirred at room temperature for 24 hours. . Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated saline solution. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into water, whereby powder is precipitated. This powder was collected by filtration and dried to obtain 1.82 g of 5- (4- (2-methoxy-2-phenylacetamide) benzyl) thiazolidin-12,4-dione.

麵 (ppm); 3.06 (1H, dd), 3.32 (1H, dd), 3.36 (3H, s), 4.82 (1H, dd), 4.88 (1H, dd),

7.16 (2H, d), 7.32-7.36 (3H, m), 7.38-7.50 (2H, m), 7.61 (2H, d),

10.03 (1H, s), 12.02 (1H, bs)

MS (+1); 371

Example 4 15— (4— (2,2-Jetyl-1-2-phenylacetamide) benzene Jill) Synthesis of thiazolidine-2,4-dione

Dissolve 1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.04 g of 2-ethyl-2-phenylbutyric acid, 0.83 g of H0BT, and 1.04 of WSC.HC1 in 10 ml of DMF and heat to 60 ° C. And stirred all day and night. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. The ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5- (4- (2,2-getyl-2-phenylacetate). De) benzyl and thiazolidine-1,2 dione were obtained as a powder in an amount of 0.66 g.

NMR (ppm); 0.66 (6H, t), 1.94-2.16 (4H, m), 3.04 (1H, dd), 3.30 (1H, dd),

4.86 (1H, dd), 7.12 (2H, d), 7.20-7.38 (5H, m), 7.48 (2H, d),

8.97 (1H, s), 12.00 (1H, bs)

MS (Ml 1); 397

Example 4 Synthesis of 25- (4- (2,2,2-trifluoroacetamide) benzyl) thiazolidine-l, 4-dione

1.2 g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.56 g of triphenylacetic acid, 0.83 g of HOBT, and 1.04 g of WSC.HC1 were dissolved in 10 ml of DMF, and the mixture was stirred at 60 ° C for two days. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. The ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5- (4- (2,2,2-triphenylacetamide) benzyl) thiazolidine. 377 mg of 1,2,4-dione was obtained as a powder.

NMR (ppm); 3.05 (1H, dd), 3.30 (1H, dd), 4.87 (1H, dd), 7.14 (2H, d),

7.22-7.36 (15H, m), 7.46 (2H, d), 9.03 (1H, s), 12.01 (1H, bs)

MS (MI1); 493

Example 4 Synthesis of 35— (4- (2-Methyl-1- (2-ditrophenyl) acetamide) benzyl) thiazolidine-12,4-dione

5- (4-aminobenzyl) thiazolidine mono 2,4-dione 3.03 g, 2- (2-nitrophenyl) propionic acid 2.66 g, HOBT 2.lg, WSC.HCI 2.62 g are dissolved in DMF 30 ml and stirred at room temperature for 24 hours. did. Add ethyl acetate to the reaction solution, add water, The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate is distilled off, the residue is dissolved in methanol, and the solution is added dropwise to water. The powder was collected by filtration and dried to obtain 3.87 g of 5- (4- (2-methyl-2- (2--2-trophenyl) acetoamide) benzyl) thiazolidine-1,2,4-dione.

NMR (ppm); 1.57 (3H, d), 3.10 (1H, dd), 3.36 (1H, dd), 4.30 (1H, q), 4.90 (1H, dd),

7.20 (2H, d), 7.53 (2H, d), 7.55-7.60 (1H, m), 7.70-7.80 (2H, m)

8.00 (1H, d), 10.15 (1H, s), 12.01 (1H, bs)

MS (M + 1); 400

Example 4 Synthesis of 45- (4- (2-methyl-2-((412-trophenyl) acetamide) benzyl) thiazolidine-l, 4-dione

1.5-g of 5- (4-aminobenzyl) thiazolidine-1,4-dione, 1.3 g of 2- (4-tropinyl) propionic acid, 1.33 g of HOBT, 1.3 g of WSC.HC1 are dissolved in 10 ml of DMF. The mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off, and the residue is dissolved in methanol and dropped into hexane, whereby powder is deposited. The powder was collected by filtration and dried to give 2.21 g of 5- (4- (2-methyl-2- (412-trophinyl) acetamide) benzyl) thiazolidine-12, dione.

NMR (ppm); 1.46 (3H, d), 3.07 (1H, dd), 3.35 (1H, dd), 4.00 (1H, q), 4.86 (1H, dd),

7.16 (2H, d), 7.51 (2H, d), 7.66 (2H, d), 8.21 (2H, d), 10.18 (1H, s),

11.99 (1H, bs)

MS (M + 1); 400

Example 4 Synthesis of 55- (4- (1-phenyl-1-cyclopropanecarbonylamino) benzyl) thiazolidine-l, 4-dione

5- (4-aminobenzyl) thiazolidine-1,2,4-dione 1.2 g, 1-phenyl-1-cyclopropanecarboxylic acid 876 mg, HOBT 0.83 g, WSC. HC1 1.04 are dissolved in 10 ml of DMF and room temperature. For 24 hours. Ethyl acetate is added to the reaction solution, and the mixture is washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. did. Ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (closed form: ethanol 210: 1) to give 5- (4- (1-1-phenyl-1-cyclopropanecarbonylamino) benzyl) thiazolidine-1 , 4 dione was obtained as a powder to obtain 1.35 g.

NMR (ppm); 1.08-1.12 (2H, m), 1.41-1.45 (2H, m), 3.05 (1H, dd), 3.30 (1H, dd),

4.86 (1H, dd), 7.12 (2H, d), 7.24-7.48 (7H, m), 9.00 (1H, s),

11.99 (1H, bs)

MS (M + 1); 367

Example 4 Synthesis of 65- (4- (1-phenyl-1- 1-cyclopentanecarbonylamino) benzyl) thiazolidine-2,4-dione

5- (4-aminobenzyl) thiazolidine 1,2,4-dione 1.5 g, 1-phenyl-2-cyclopentanecarboxylic acid 960 mg, H0BT 1.03 g, WSC.HC1 1.3 g are dissolved in DMF 20 ml and brought to room temperature. And stirred all day and night. Ethyl acetate was added to the reaction solution, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. The ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1: 1) to give 5- (4- (1-phenyl-1-cyclopentanecarbonylamino) benzyl) thiazolidine-1 1.54 g of, 4 dione as a powder.

NR (ppm); 1.72-2.10 (5H, m), 2.70-2.80 (2H, m), 3.12 (1H, dd), 3.38 (1H, dd),

4.94 (1H, dd), 7.18-7.72 (9H, m), 9.24 (1H, s), 12.08 (1H, bs)

MS (I1); 395

Example 4 Synthesis of 75— (4-benzylaminoaminopropyl benzyl) thiazolidine-1,2,4-dione

330 mg of 5- (4-carboxybenzyl) thiazolidine-1,4-dione, 363 mg of benzylamine hydrochloride, 0.3 ml of triethylamine, 323 mg of HOBT, and 404 mg of WSC.HC1 were dissolved in 5 ml of DMF and stirred at room temperature for 24 hours. . Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate was distilled off under reduced pressure and triturated with ether-hexane to give 5- (4-benzylaminocarbonylbenzyl) thiazolidine-1, 4-dione. Was obtained as a powder in an amount of 670 mg.

NMR (ppm); 3.20 (1H, dd), 3.43 (1H, dd), 4.47 (2H, d), 4.97 (1H, dd),

7.20-7.36 (7H, m), 7.84 (211, d), 9.02 (1H, t), 12.07 (1H, bs)

MS (M + 1); 341

Example 4 Synthesis of 85— (4- (4-nitrobenzylaminocarbonyl) benzyl) thiazolidine-l, 4-dione

5-(4-Carboxybenzyl) thiazolidine-1,4 dione (251 mg), 4-nitrobenzylamine hydrochloride (189 mg), triethylamine (0.14 ml), HOBT (153 mg), WSC.HC1 (192 mg) were dissolved in DMF (5 ml). Stirred for hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated saline solution. Ethyl acetate was distilled off under reduced pressure and powdered from ether / hexane to give 315 mg of 5- (4- (4-nitrobenzylaminocarbonyl) benzyl) thiazolidine-2,4-dione as a powder.

NMR (ppm); 3.21 (1H, dd), 3.44 (1H, dd), 4.59 (2H, d), 4.97 (1H, dd), 7.37 (2H, d),

7.58 (2H, d), 7.85 (2H, d), 8.20 (2H, d), 9.17 (1H, t), 12.06 (1H, bs)

MS (M + 1); 386

Example 4 Synthesis of 95- (4- (2-nitrobenzylaminocarbonyl) benzyl) thiazolidine-1, 4-dione

251 mg of 5- (4-carboxybenzyl) thiazolidine-1,4-dione, 152 mg of 2-nitrobenzene benzylamine, 153 mg of HOBT, and 191 mg of WSC.HC1 were dissolved in 5 ml of DMF and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated saline solution. Ethyl acetate was distilled off under reduced pressure, and powdered from ether-hexane to give 235 mg of 5- (4- (2-nitrobenzylaminocarbonyl) benzyl) thiazolidine-12,4-dione as powder.

NMR (ppm); 3.22 (1H, dd), 3.45 (1H, dd), 4.60 (2H, d), 4.97 (1H, dd),

7.36-8.04 (8H, m), 9.20 (1H, t), 12.06 (1H, bs)

MS (M + 1); 386

Example 5 05— (4-((R) -α-methylbenzylaminocarbonyl) benzyl Nore) Synthesis of 1,2,4-dione thiazolidine

5-(4-Carboxybenzyl) thiazolidine- 1,2,4-dione l.Og, (R) -α-methylbenzylamine 482mg, HOBT 610mg, WSC.HC 1 766m are dissolved in DMF 10ml and at room temperature Stirred all day and night. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated saline solution. Ethyl acetate is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, dropped into hexane and stirred, and powder is deposited. The powder was collected by filtration and dried to obtain 1.25 g of 5- (4-((R) -α-methylbenzylaminocarbonyl) benzyl) thiazolidine-12,4-dione as a powder.

NMR (ppm); 1.47 (3H, d), 3.18 (1H, dd), 3.44 (1H, dd), 4.96 (1H, dd), 5.16 (1H, q),

7. 18-7. 41 (7H, m), 7.84 (2H, dd), 8.78 (1H, d), 12.06 (1H, bs) S (M + 1); 355

Example 5 Synthesis of 15— (4-((S) —α-methylbenzylaminocarbonyl) benzyl) thiazolidine-1,2, dione

5-(4-Carboxybenzyl) thiazolidine 1,2 dione 1.0 g, (S) HI methyl benzylamine 482 mg, HOBT 610 mg, WSC. HC1 766 mg are dissolved in DMF 10 ml and stirred at room temperature for 24 hours. did. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water, a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate, and saturated saline. Ethyl acetate is distilled off under reduced pressure, and the residue is dissolved in ethyl persulfate and dropped into hexane. The powder was collected by filtration and dried to obtain 1.22 g of 5- (4-((S) -α-methylbenzylaminocarbonyl) benzyl) thiazolidine-1,2-dione as a powder.

NMR (ppm); 1.47 (3H, d), 3.20 (1H, dd), 3.43 (1H, dd), 4.96 (1H, dd), 5.16 (1H, q),

7.18-7. 41 (7H, m), 7.84 (2H, dd), 8.77 (1H, d), 12.06 (1H, bs) S (M + 1); 355

Table 1 shows the chemical structural formulas of the compounds of Examples 2 to 51.

(Continued from Table 1)

44 0 _2- <O Me H CONH

8 0 ₂ ΐ 〇 'HH NHCO

Next, a blood glucose lowering effect test and a lipid lowering effect test of the compound of the present invention will be described.

Blood glucose lowering effect test

KK Six KK-Ay mice, confirmed to be positive for urinary sugar by Listaix (Bayer Sankyo), were orally administered 100 mg / kg of pioglitazone as a compound of the present invention and a control. Blood is collected from the tail vein immediately before administration and 24 hours after administration, and the amount of glucose in the serum obtained by centrifugation (Oorpm, lOmin) is measured by glucose B test (available from Wako Pure Chemical Industries, Ltd.). I asked. The results are shown in Table 2. The compound numbers correspond to the numbers in Examples, respectively.

Table 2 Compound No. Blood glucose lowering rate (%)

13 14

15 14

16 40

18 38

24 13

31 13

34 54

35 24

37 29

38 24

45 42

47 16

50 23

51 10

Pioglitazone 8 From the above results, it was revealed that the compound of the present invention exhibits an excellent hypoglycemic effect _c Lipid lowering effect

化合物 The compound of the present invention is orally administered to KK-Ay mice whose urinary sugar was confirmed to be positive by Listaix (Bayer Sankyo), and serum triglyceride was measured by triglyceride G test kit (Wako Pure Chemical) As a result, the compound of the present invention showed an excellent serum triglyceride lowering effect.

In order to use the compound of the present invention represented by the formula (I) or a salt thereof for the above purpose, various forms of pharmaceutical compositions for oral or parenteral administration, such as tablets, capsules, granules, and powders , Pills, suspensions, injections, suppositories and the like. At the time of formulation, it is manufactured by an ordinary method using a usual pharmaceutical carrier.

For the oral composition, ordinary excipients, lubricants, disintegrants, wetting agents and other additives can be used. The liquid may be in the form of an aqueous or oily suspension, emulsion, syrup, elixir or the like, or a lyophilized product which can be re-dissolved in water or another suitable solvent before use. Is raised. These liquid preparations may contain conventional additives such as suspending agents, wetting agents, flavors, diluents or emulsifiers.

When the compound of the present invention is administered to humans, the dosage is 0.05 mg to 400 mg Z days, preferably 0.05 mg to 16 O mgZ days. However, the dose when administered to a human for the purpose of treatment is appropriately adjusted depending on the severity of the disease, age, weight and the like.

As a result of the acute toxicity test, the compound of the present invention had no problem with respect to toxicity. The invention's effect

The compound represented by the formula (I) of the present invention exhibits excellent blood glucose lowering action and lipid lowering action. According to the present invention, a novel compound having excellent properties as a therapeutic agent for diabetes can be provided.

In addition, the compound represented by the formula (lib) is important as an intermediate in producing the compound represented by the formula (lb), and via this compound, the compound of the present invention represented by (lb) The compound could be easily prepared.

Claims

The scope of the claims

1 set

(I)

[In the formula, R is a cycloalkyl group, an unsubstituted phenyl group having one or more substituents, a naphthyl group, or at least one of nitrogen, oxygen, and sulfur atoms. Represents one or more monocyclic or bicyclic heterocycles, and one or both of R ₂ and R ₃ are hydrogen, lower alkyl, cycloalkyl, alkoxy, halogen, hydroxy, amino (protecting group) A phenyl group, or — (CH ₂ ) n — (n == 2 to 6), and 、 represents an amide bond. Its salt.

2. The thiazolidine-2,4-dione derivative and the salt thereof according to claim 1, wherein A is -NHCO-.

3. The thiazolidine-2,4-dione derivative and a salt thereof according to claim 1, wherein A is —CO HN—.

4.5— (4- (1-phenyl-1-cyclopropanecarbonylamino) benzyl) thiazolidine-1,2,4-dione and salts thereof.

5. A therapeutic agent for diabetes, comprising the thiazolidine-1,2,4-dione derivative according to any one of claims 1 to 4 or a salt thereof as an active ingredient.