JPH0570633B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a novel thiazolidinedione derivative having blood sugar and blood lipid lowering effects, a method for producing the same, and a therapeutic agent for diabetes or hyperlipidemia comprising the same. [Prior Art and Problems to be Solved by the Invention] Conventionally, various biguanite compounds and sulfonylurea compounds have been used as antidiabetic agents. However, biguanite compounds are rarely used because they cause lactic acidosis, and sulfonylurea compounds have a strong hypoglycemic effect but often cause severe hypoglycemia, so caution is required when using them. . The present inventors conducted various studies to find a compound that has a blood sugar lowering effect without such drawbacks, and as a result, they discovered a new thiazolidinedione derivative that has an excellent blood sugar and blood lipid lowering effect. [Means for solving the problems] The present invention has the following features: 1 General formula

[In the formula, R ¹ and R ² are the same or different and represent hydrogen or a lower alkyl group, R ³ represents hydrogen or an acyl group, and n represents 0 or 1. ] Thiazolidinedione derivative represented by 2 general formula

[In the formula, R ¹ , R ² and n have the same meanings as above, R ⁴ represents hydrogen or an acyl group, R ⁵ represents hydrogen or a lower alkyl group, and X represents a halogen atom. ] by reacting the compound represented by thiourea with the general formula

[C] [Each symbol in the formula has the same meaning as above. ] is obtained, which is then hydrolyzed,
A method for producing a thiazolidinedione derivative represented by the general formula (I), which is further acylated if necessary; and 3. Diabetes or hyperlipidemia comprising the thiazolidine derivative represented by the general formula (I) or a salt thereof. The present invention relates to a therapeutic agent for the disease. R ¹ in the general formula (I), () and (),
Examples of the lower alkyl group represented by ^R2 include those having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, etc. Among them, those having 1 to 3 carbon atoms are preferred, and these include those with a pyridine ring. may be substituted at any position.
Examples of the acyl group represented by R ³ include formyl,
For example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isopentanoyl,
Examples include alkylcarbonyl groups having 2 to 6 carbon atoms such as hexanoyl, aralkylcarbonyl groups having 8 to 9 carbon atoms such as phenyl acetyl and phenylpropionyl, and arylcarbonyl groups having 6 to 8 carbon atoms such as benzoyl and paratoluoyl; Aralkylcarbonyl and arylcarbonyl may have, for example, halogen (fluorine, chlorine, bromine, etc.), alkoxy (methoxy, ethoxy, etc.), trifluoromethyl, etc. as a substituent at any position on the ring. Examples of the acyl group represented by R ⁴ include those similar to the acyl group represented by R ³ . Examples of the lower alkyl group represented by R ⁵ include those similar to the lower alkyl groups represented by R ¹ and R ² above. Examples of the halogen atom represented by X include chlorine, bromine, and iodine. The thiazolidinedione derivative represented by the general formula (I) is an amphoteric compound having an acidic nitrogen in its thiazolidine ring and a basic nitrogen in its pyridine ring, and exists in both acid salts and base salts. Examples of salts of the thiazolidinedione derivative (I) include hydrochloride, hydrobromide, sulfate,
inorganic acid salts such as phosphates and methanesulfonates;
For example, organic acid salts such as toluenesulfonate, oxalate, malonate, maleate, fumarate, succinate, tartrate, malate, etc.
Examples of the base salt include metal salts such as sodium salt, potassium salt, aluminum salt, magnesium salt, and calcium salt. Specific examples of the thiazolidinedione derivatives represented by the general formula (I) and salts thereof according to the present invention include the following compounds. 5-{4-[2-hydroxy-2-(5-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-acetoxy-2-(5-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[3-acetoxy-2-(3-methyl-2-pyridyl)propoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[3-benzoyloxy-2-(3-
Methyl-2-pyridyl)propoxy]benzyl}
-2,4-thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridyl)-
2-hydroxyethoxy]benzyl}-2,4-
Thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridine)-
2-formyloxyethoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[2-acetoxy-2-(5-ethyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridyl)-
2-Propionyloxyethoxy]benzyl}-
2,4-thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridyl)-
2-Butyryloxyethoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridyl)-
2-isobutyryloxyethoxy]benzyl}-
2,4-thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridyl)-
2-valeryloxyethoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[2-benzoyloxy-2-(5-
Ethyl-2-pyridyl)ethoxy]benzyl}-
2,4-thiazolidinedione 5-{4-[2-(5-ethyl-2-pyridyl)-
3-hydroxypropoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[3-acetoxy-2-(5-ethyl-2-pyridyl)propoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[2-hydroxy-2-(2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione 5-{4-[2-acetoxy-2-(2-pyridyl)ethoxy ]Benzyl}-2,4-thiazolidinedione 5-{4-[2-propionyloxy-2-(2
-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione 5-{4-[2-benzoyloxy-2-(2-
pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione 5-{4-[3-hydroxy-2-(2-pyridyl)propoxy]benzyl}-2,4-thiazolidinedione 5-{4-[3-acetoxy -2-(2-pyridyl)propoxy]benzyl}-2,4-thiazolidinedione 5-{4-[2-hydroxy-2-(5-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-acetoxy-2-(5-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-(5-methyl-2-pyridyl)-
2-propionyloxyethoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[2-benzoyloxy-2-(5-
Methyl-2-pyridyl)ethoxy]benzyl}-
2,4-thiazolidinedione 5-{4-[3-hydroxy-2-(5-methyl-2-pyridyl)propoxy]benzyl}-2,
4-thiazolidinedione 5-{4-[2-hydroxy-2-(5-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-acetoxy-2-(3-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-benzoyloxy-2-(3-
Methyl-2-pyridyl)ethoxy]benzyl}-
2,4-thiazolidinedione 5-{4-[2-hydroxy-2-(4-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-acetoxy-2-(4-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione 5-{4-[2-hydroxy-2-(4,6-dimethyl-2-pyridyl)ethoxy]benzyl}-
2,4-thiazolidinedione 5-{4-[2-acetoxy-2-(4,6-dimethyl-2-pyridyl)ethoxy]benzyl}-
2,4-thiazolidinedione The reaction between the compound represented by the general formula () and thiourea is usually carried out using alcohols (e.g. methanol,
ethanol, propanol, 2-propanol,
(butanol, isobutanol, 2-methoxyethanol, etc.), dimethyl sulfoxide, sulfolane, and the like. Reaction temperature is usually 20℃
-180°C, preferably 60°C-150°C. The amount of thiourea used is 1 to 2 mol per 1 mol of compound (). In this reaction, hydrogen halide is produced as a by-product as the reaction progresses, but in order to capture this, a deoxidizing agent such as sodium acetate or potassium acetate may be added to the reaction. The deoxidizing agent is usually used in an amount of 1 to 1.5 mol per 1 mol of the compound ().
Such a reaction produces the compound (), which can be isolated if desired, but ()
may be directly introduced into the next hydrolysis step without isolation. Hydrolysis of compound () is usually carried out in a suitable solvent in the presence of water and a mineral acid. Examples of the solvent include those used in the reaction of the compound () with thiourea. Examples of mineral acids include hydrochloric acid, hydrobromic acid, and sulfuric acid, and the amount used is 0.1 to 10 mol, preferably 0.2 to 3 mol, per 1 mol of the compound (). The amount of water added is usually in large excess per mole of compound (). This reaction is usually carried out with heating or under heating, and the reaction temperature is usually 60 to 150°C. Heating time is usually several hours ~
It's more than ten hours. Through this reaction, a compound in which R ³ in formula (I) is hydrogen (hereinafter also referred to as hydroxyl compound (I')) can be obtained. The hydroxyl compound (I') may be subjected to the following acylation reaction if necessary. The acylation reaction of the hydroxyl compound (I') is usually carried out by reacting with an acylating agent in the presence of a base in a suitable solvent. Examples of the solvent include esters such as ethyl acetate, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane, and ketones such as acetone and methyl ethyl ketone. Examples include chlorinated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, as well as dimethylformamide. Examples of the acylating agent include formic acid, acid anhydrides or acid halides of aliphatic, araliphatic, or aromatic carboxylic acids. Examples of the aliphatic carboxylic acids include those having 2 to 6 carbon atoms, such as acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and hexanoic acid, and examples of the aromatic aliphatic carboxylic acids include phenyl acetic acid and phenylacetic acid. Examples of the aromatic carboxylic acids include those having 8 to 9 carbon atoms such as enylpropionic acid, and those having 7 to 8 carbon atoms such as benzoic acid and paramethylbenzoic acid. (eg, fluorine, chlorine, bromine, etc.), alkoxy (eg, methoxy, ethoxy, etc.), trifluoromethyl group, etc. may be substituted. The amount of acylating agent used is hydroxyl form (I') 1
The amount is usually 1 to 10 mol, preferably 1 to 2 mol. Examples of the base include amines such as pyridine and triethylamine, carbonates and bicarbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. The base is usually used in an equimolar amount or in excess of the acylating agent. When pyridine is used as a base, it can also serve as a solvent by using a large excess amount of pyridine. This reaction is usually carried out at -20℃
It is carried out at ~40°C, and the reaction time is usually 10 minutes to 24 hours. Through this reaction, a compound in which R ³ in formula (I) is an acyl group [hereinafter also referred to as acyl compound (I')] can be obtained. If necessary, the thiazolidinedione derivative (I) can be converted into a salt by reacting with an acid or base according to a conventional method. The thus obtained thiazolidinedione derivatives and their salts can be prepared by known separation methods such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution,
It can be isolated and purified by chromatography or the like. Compound (I) of the present invention and its salts can be administered to mammals (e.g. mice, dogs, cats, monkeys, horses, humans).
However, it shows excellent blood sugar and lipid lowering effects.
In addition, both acute and subacute toxicity are low, for example, 5-{4-[2-hydroxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione, 5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]benzyl}-2,4-thiazolidinedione,
5-{4-[2-(5-ethyl-2-pyridyl)-2
-hydroxy]benzyl}-2,4-thiazolidinedione, 5-{4-[2-(5-ethyl-2-pyridyl)-3-hydroxypropoxy]benzyl}
-2,4-thiazolidinedione, 5-{4-[2-
Acetoxy-2-(6-methyl-2-pyridyl)
Ethoxy]benzyl}-2,4-thiazolidinedione, 5-{4-[3-acetoxy-2-(5-ethyl-2-pyridyl)-propoxy]benzyl}-
All 2,4-thiazolidinediones had an LD ₅₀ of 5000 mg/Kg or more when administered orally to rats. From these points, the thiazolidinedione derivative (I) and its salts are expected to be useful in the treatment of human hyperlipidemia, diabetes, and their complications. The drug is usually administered orally in the form of tablets, capsules, powders, granules, etc., but in some cases it can also be administered parenterally in the form of injections, suppositories, pellets, etc. When used in adults as a diabetes treatment, the dose is usually 0.05mg per day.
~10mg/Kg orally, 0.01mg~10mg/Kg parenterally, and when used in adults as a hyperlipidemia treatment, usually 0.05mg~10mg/Kg orally per day.
0.05 mg to 10 mg/Kg can be administered parenterally, and this amount is preferably administered once a day or intermittently 2 to 4 times a week. The raw material compound () of the present invention can be produced, for example, by the following method. i Production of a compound in which n is 0 in the general formula ()

[ka]

[ka]

[ka]

[Formula] [In the formula, R ¹ , R ² and X have the same meanings as above,
R ⁴ ' has the same meaning as the acyl group represented by R ³ or R ⁴ , and R ⁵ ' has the same meaning as the lower alkyl group represented by R ⁵ . ] The oxidation reaction from compound () to compound (V) can be easily carried out by reacting compound () with hydrogen peroxide or an organic peracid. Examples of such organic peracids include performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, etc., and the oxidation reaction is carried out according to a general method known per se. can be done. The acylation reaction from compound (V) to compound (') is carried out by reacting compound (V) with an acylating agent, and usually by heating the acid anhydride or acid halide to 80°C to 150°C. easily done. The hydrolysis reaction from compound (') to compound ('') can be carried out by a conventional method using sodium hydroxide or potassium hydroxide. Production of a compound in which n is 1 in the general formula ()

【formula】

[ka]

[ka]

[ka]

〔Effect of the invention〕

Compound (I) according to the present invention has blood sugar and blood lipid lowering effects. Experimental data supporting this point will be described. Experimental example Blood sugar and lipid lowering effect in mice Test compound was fed to powdered feed (CE-2, CLEA Japan)
KKA ^y -mouse (male, 8~
(10 weeks old, 5 animals per group) were given ad libitum for 4 days. Water was provided ad libitum during this time. Blood was collected from the orbital vein, and the blood glucose level was determined by the glucose oxidase method, and the plasma triglyceride level was determined by quantifying glycerol produced by the enzymatic method using a Cleantech TG-S kit (Yatron). Each value was expressed as a reduction rate (%) relative to the drug-unadministered group.

〔Example〕

Example 1 Methyl 3-{4-[2-acetoxy-2-(6-methyl-2-pyridyl)ethoxy]phenyl}-2-bromopropionate (3.2 g), thiourea (558
mg), sodium acetate (599 mg), ethanol (30
ml) was heated under reflux for 4 hours, 6N-hydrochloric acid (30 ml) was added, and the mixture was further heated under reflux for 16 hours. After neutralization with an aqueous sodium bicarbonate solution, the mixture was extracted with chloroform, and the chloroform layer was washed with water and dried (MgSO ₄ ). Distill the solvent and transfer the residue to silica gel (100g)
5-{4-[2-hydroxy-2-(6-
Methyl-2-pyridyl)ethoxy]benzyl}-
2,4-thiazolidinedione was obtained as crystals.
The yield was 0.95 g, and colorless prism crystals were obtained by recrystallization from ethyl acetate-hexane. Melting point 154−
155℃ Elemental analysis value C ₁₈ H ₁₈ N ₂ O ₄ Calculated value: C, 60.32; H, 5.06; N, 7.82 Experimental value: C, 60.53; H, 5.24; N, 7.75 Example 2 (1) 2 -bromo-3-{4-[3-hydroxy-2
-(3-methyl-2-pyridyl)propoxy]
A mixture of methyl phenylpropionate (4.7 g), thiourea (875 mg), sodium acetate (943 mg), and ethanol (50 ml) was heated under reflux for 3 hours. The mixture was diluted with water, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off to give 5-{4-[3-hydroxy-2-(3
-methyl-2-pyridyl)propoxy]benzyl}-2-imino-4-thiazolidinedione was obtained as crystals. The yield was 2.5 g, which was recrystallized from chloroform-methanol to obtain colorless prism crystals. Melting point 213-214℃ Elemental analysis value C ₁₉ H ₂₁ N ₃ O ₃ Calculated value: C, 61.44; H, 5.70; N, 11.31 Experimental value: C, 61.14; H, 5.62; N, 10.99 (2) ( 5-{4-[3-hydroxy-2- obtained in 1)
(3-Methyl-2-pyridyl)propoxy]benzyl}-2-imino-4-thiazolidinedione (2.3 g) was dissolved in a mixture of 2N-hydrochloric acid (20 ml) and ethanol (20 ml) and heated under reflux for 4 hours. After neutralization with an aqueous sodium bicarbonate solution, the mixture was extracted with chloroform, and the chloroform layer was washed with water and dried (MgSO ₄ ). Distill the solvent and give 5-{4-[3-
Hydroxy-2-(3-methyl-2-pyridyl)
Propoxy]benzyl}-2,4-thiazolidinedione was obtained as crystals. The yield was 1.9 g, and colorless prism crystals were obtained by recrystallization from ethanol. melting point
182-183℃ Elemental analysis value C ₁₉ H ₂₀ N ₂ O ₄ Calculated value: C, 61.27; H, 5.41; N, 7.52 Experimental value: C, 61.57; H, 5.49; N, 7.74 Example 3 3- Methyl {4-[2-acetoxy-2-(5-ethyl-2-pyridyl)ethoxy]phenyl}-2-bromopropionate (10.0 g), thiourea (2.0 g), and sodium acetate (2.2 g) were carried out. 5-{4-[2-(5-ethyl-2
-pyridyl)2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione was obtained as crystals. Yield 6.2 g, recrystallized from ethyl acetate-hexane, colorless prismatic crystals, melting point 129-130°C Elemental analysis value as C ₁₉ H ₂₀ N ₂ O ₄ S Calculated value: C, 61.27; H, 5.41; N, 7.52 Experimental value :C, 61.36; H, 5.71; N, 7.08 Example 4 2-bromo-3-{4-[2-(5-ethyl-2
A mixture of methyl -pyridyl)-3-hydroxypropoxy]phenylpropionate (12.2 g), thiourea (2.2 g), sodium acetate (2.4 g), and ethanol (100 ml) was heated under reflux for 3 hours, and then 3N-hydrochloric acid (100 ml) was heated under reflux for 3 hours. ) was added thereto, and the mixture was further heated under reflux for 12 hours. After concentration, the mixture was neutralized with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and then the solvent was distilled off. The residue was chromatographed using silica gel (200 g).
5-{4-[2-(5-ethyl-2-
Pyridyl)-3-hydroxypropoxy]benzyl}-2,4-thiazolidinedione was obtained as an oil. Yield 4.8g (42.9%), which was dissolved in methanol (15ml) and matrium methylate (28%
A methanol solution (2.9 g) was added thereto, and then ethyl ether (150 ml) was added to obtain the sodium salt as crystals. Yield 4.8g (40.7%), recrystallized from ethanol-ethyl ether, colorless prismatic crystals, melting point 237-238℃ Elemental analysis value as C ₂₀ H ₂₁ N ₂ O ₄ SNa Calculated value: C, 58.81; H, 5.18 ; N, 6.86 Experimental value: C, 59.06; H, 4.94; N, 6.97 Example 5 5-{4-[2-hydroxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4
-thiazolidinedione (350 mg), pyridine (5
ml) and acetic anhydride (0.2 ml) was left at room temperature for 2 days, then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and then the solvent was distilled off. The residue was subjected to column chromatography using silica gel (20 g) and eluted with benzene-acetone (15:1, V/V) to give 5-{4-[2-acetoxy-2-(6- Methyl-2-pyridyl)ethoxy]benzyl}-2,
4-thiazolidinedione was obtained as an oil. Yield 360mg (89.8%). IR (Neat): 1740, 1690,
1230cm ^-1 ． NMR (CDCl ₃ ) δ: 2.11 (3H, s),
2.51 (3H, s), 3.02 (1H, dd, J=14 and 9Hz),
3.41 (1H, dd, J = 14 and 4Hz), 4.37 (2H, d,
J=5Hz), 4.44 (1H, dd, J=9 and 4Hz),
6.13 (1H, t, J = 5Hz), 6.83 (2H, d, J = 9
Hz), 7.09 (2H, d, J = 9Hz), 7.0-7.7 (3H,
m). Example 6 5-{4-[2-(5-ethyl-2-pyridyl)-
3-hydroxypropoxy]benzyl}-2,4
- A mixed solution of thiazolidinedione sodium salt (408 mg), pyridine (10 ml), and acetic anhydride (0.15 ml) was stirred at room temperature for 8 hours, then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (20 g). Elute with benzene-acetone (10:1, V/V) to give 5-{4-[3-acetoxy-2-(5-
ethyl-2-pyridyl)propoxy]benzyl}
-2,4-thiazolidinedione was obtained as an oil. Yield 350mg (81.8%), IR (Neat): 1740,
1690, 1230cm ^-1 . NMR (CDCl ₃ ) δ: 1.24 (3H,
t, J=7Hz), 2.00 (3H, s), 2.64 (2H, q,
J=7Hz), 3.03 (1H, dd, J=14 and 9Hz),
3.45 (1H, dd, J = 14Hz and 9Hz), 3.60 (1H,
m), 4.31 (2H, d, J=5Hz), 4.47 (1H, dd,
J=9 and 4Hz), 4.55 (2H, d, J=5Hz),
6.80 (2H, d, J=9Hz), 7.10 (2H, d, J=9
Hz), 7.20 (1H, d, J=8Hz), 7.48 (1H, dd,
Examples 7 to 9 The following compounds were obtained in the same manner as in Example 1.

[ka]

[Table] Example 10 5-{4-[2-(4,2
The sodium salt of -dimethyl-2-pyridyl)-2-hydroxyethoxy]benzyl}-2,4-thiazolidinedione was obtained. Yield 72.7%. Recrystallized from ethanol-ether to give colorless crystals. Melting point 228−
229℃ Elemental analysis value C ₁₉ H ₁₉ N ₂ O ₄ As S・Na Calculated value: C, 57.86; H, 4.86; N, 7.10 Experimental value: C, 57.38; H, 4.69; N, 6.96 Example 11 5- {4-[2-ethyl-2-pyridyl)-2-
A mixed solution of hydroxypropoxy]benzyl}-2,4-thiazolidinedione (500 mg), pyridine (5 ml) and propionic anhydride (0.3 ml) was left at room temperature overnight, then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and then the solvent was distilled off. The residue was subjected to column chromatography using silica gel (30 g). 5-{4-[2-(5-ethyl-2-pyridyl)-2-propionyloxyethoxy]benzyl}-2,4-thiazolidinedione by elution with benzene-acetone (15:1, V/V) was obtained as an oil. Yield 515 mg (89.7%). IR (Neat): 1745, 1700, 1170cm ^-1 . NMR
(CDCl ₃ ) δ: 1.13 (3H, t, J = 7Hz), 1.23
(3H, t, J=7Hz), 2.40 (2H, q, J=7
Hz), 2.31 (2H, q, J = 7Hz), 3.02 (1H, dd,
J = 14Hz and 10Hz), 3.4 (1H, m), 4.38 (2H,
d, J = 5Hz), 4.40 (1H, dd, J = 10 and 4
Hz), 6.18 (1H, t, J=5Hz), 6.81 (2H, d,
J=9Hz), 7.10 (2H, d, J=9Hz), 7.3-7.6
(2H, m), 8.43 (1H, d, J=2Hz), 9.2 (1H,
broad). Example 12 (1) 5-{4-[2-(5-ethyl-2-pyridyl)
-2-hydroxyethoxy]benzyl}-2,
4-thiazolidinedione 100g (2) Lactose 50g (3) Corn starch 15g (4) Carboxymethyl cellulose calcium 44g (5) Magnesium stearate 1g 1000 tablets 210g (1), (2), (3) total amount and 30g ( Mix 4) with water,
After vacuum drying, granulation is performed. 14g (4) of this granulated powder
and 1 g of (5) are mixed and made into tablets using a tablet machine to produce 1000 tablets with a diameter of 8 mm each containing 100 mg of (1). Reference example 1 (1) 2-bromo-3-{4-[2-(6-methyl-
To a solution of methyl 2-pyridyl)ethoxyphenylpropionate (10.0 g) in methanol (100 ml) was added m-chloroperbenzoic acid (70% content, 7.1 g), and the mixture was heated under reflux for 30 minutes. After adding an aqueous sodium thiosulfate solution to decompose the excess oxidizing agent, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer is water,
After washing successively with 2N-potassium hydroxide and water and drying (MgSO ₄ ), the solvent was distilled off to give 2-bromo-3-
A crude oil of methyl {4-[2-(6-methyl-2-pyridyl)ethoxy]phenyl}propionate N-oxide was obtained. Yield 10.1g.IR
(Neat): 1740, 1250cm ^-1 (2) 2-Brom-3-{4-[2-(6-
Methyl-2-pyridyl)ethoxy]phenyl}
Methyl propionate N-oxide (10.1g),
A mixture of acetic anhydride (50 ml) was heated at 110° C. for 1 hour, concentrated under reduced pressure, and the residue was subjected to column chromatography using silica gel (200 g). Benzene-acetone (50:1, V/
V), 3-{4-[2-acetoxy-2-(6-methyl-2-pyridyl)
Methyl ethoxy]phenyl}-2-bromopropionate was obtained as an oil. Yield 3.3g.IR
(Neat): 1740cm ^-1 (broad). NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.53 (3H,
s), 3.14 (1H, dd, J=14 and 7Hz), 3.40
(1H, dd, J=14 and 7Hz), 3.70 (3H, s),
4.2−4.5 (3H, m), 6.15 (1H, t, J=6Hz),
6.8-7.6 (7H, m) Reference Example 2 (1) 2(3-Methyl-2-pyridyl)-1,3-propylene glycol (10.0g) p-fluoronitrobenzene (8.45g) in dimethylformamide (100ml) solution 60 minutes while stirring under ice-cooling.
% oily sodium hydride (2.8g) was added portionwise. After stirring for 1 hour under ice cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (200 g). 4-[3-hydroxy-2-(3-
Methyl-2-pyridyl)propoxy]nitrobenzene was obtained as crystals. The yield was 9.6 g, and colorless prism crystals were obtained by recrystallization from ethyl acetate-hexane. Melting point 135-136℃ Elemental analysis value as C ₁₅ H ₁₆ N ₂ O ₄ Calculated value: C, 62.49; H, 5.59; N, 9.72 Experimental value: C, 62.60; H, 5.69; N, 9.93 (2) (1 4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]nitrobenzene (9.0 g) obtained in ) was dissolved in methanol (100 ml),
Catalytic reduction was performed using 10% palladium on carbon at room temperature and pressure. After the catalyst was filtered off, the solvent was distilled off. Next, the residue was mixed with methanol (80 ml) and acetone (20 ml).
ml) and a 47% aqueous hydrobromic acid solution (21.5 g), and a solution of sodium nitrite (2.4 g) in water (5 ml) was added dropwise at a temperature below 5°C under ice-cooling, followed by further dilution at 5°C. Stir for 30 minutes. Add methyl acrylate (15.9g) to this, heat to about 40℃, and add cuprous oxide (7.0g) while stirring vigorously.
was added little by little. Keep the reaction temperature below 45℃ for approx.
Stir for an hour until nitrogen evolution ceases. The reaction solution was concentrated under reduced pressure, made alkaline with concentrated aqueous ammonia, and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), the solvent was distilled off, and the residue was subjected to column chromatography using silica gel (230 g). Ethyl ether-hexane-triethylamine (75:25:
1, V/V) to obtain methyl 2-bromo-3-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]phenyl}propionate as an oil. yield
4.8g.IR (Neat): 3370, 1735 NMR (CDCl ₃ ) δ2.35 (3H, s), 2.9−3.4 (2H,
m), 3.3-3.7 (1H, m), 3.63 (3H, s), 3.9
(1H, broad), 4.07 (2H, d, J=3Hz), 4.1
-4.6 (3H, m), 6.76 (2H, d, J=9Hz),
7.04 (2H, d, J = 9Hz), 7.3-7.6 (2H, m),
8.30 (1H, dd, J=5 and 2Hz) Reference example 3 (1) 2-bromo-3-{4-[2-(5-ethyl-
Methyl 2-pyridyl)ethoxyphenylpropionate (18.5 g) was oxidized with m-chromium perbenzoic acid in the same manner as in Reference Example 1-(1) to give 2-bromo-
3-{4-[2-(5-ethyl-2-pyridyl)
Methyl ethoxyphenylpropionate
The N-oxide was made into an oil. Yield: 19.2g. (2) 2-bromo-3-{4-[2-(5-
Ethyl-2-pyridyl)ethoxy[phenyl]methyl propionate N-oxide (19.0 g) was reacted with acetic anhydride in the same manner as in Reference Example 1-(2), and the product was purified by silica gel column chromatography. , 3-{4-[2
Methyl -acetoxy-2-(5-ethyl-2-pyridyl)ethoxy]phenyl}-2-bromopropionate was obtained as an oil. yield
10.2g. IR (Neat): 1730cm ^-1 NMR (CDCl ₃ ) δ1.23 (3H, t, J = 7Hz),
2.13 (3H, s), 2.66 (2H, q, J=7Hz),
3.12 (1H, dd, J = 14 and 7Hz), 3.40 (1H,
dd, J=14 and 3Hz), 3.70 (3H, s), 4.33
(1H, t, J = 7Hz), 4.40 (2H, d, J = 5
Hz), 6.17 (1H, t, J = 5Hz), 6.83 (2H, d,
J=9Hz), 7.11 (2H, d, J=9Hz), 7.33
(1H, d, J=8Hz), 7.54 (1H, dd, J=8
Reference Example 4 The following compound was obtained in the same manner as Reference Example 2. (1) 4-[2-(5-ethyl-2-pyridyl)-3
-Hydroxypropoxy]nitrobenzene: Oil, IR (Neat): 3250, 1330cm ^-1 . NMR (CDCl ₃ ) δ1.23 (3H, t, J = 7Hz),
2.63 (2H, q, J=7Hz), 3.35 (1H, m),
4.10 (2H, d, J = 4Hz), 4.50 (3H, m),
6.93 (2H, d, J = 9Hz), 7.19 (1H, d, J =
8Hz), 7.51 (1H, dd, J=8 and 2Hz), 8.13
(2H, d, J=9Hz), 8.35 (1H, d, J=2
Hz) (2) 2-bromo-3-{4-[2-(5-ethyl-
2-pyridyl)-3-hydroxypropoxy]
Methyl phenylpropionate: Oil. IR (Neat): 3300, 1730cm ^-1 . NMR (CDCl ₃ ) δ1.23 (3H, t, J = 7Hz),
2.62 (2H, q, J=7Hz), 3.0~3.5 (3H, m),
3.63 (3H, s), 4.09 (2H, d, J=7Hz), 4.2
~4.6 (3H, m), 6.7 ~ 7.6 (6H, m), 8.35 (1H,
d, J=2Hz) Reference Example 5 The following raw material compound was obtained in the same manner as in Reference Example 1. ○ Methyl 3-{4-[2-acetoxy-2-(2-pyridyl)ethoxy]phenyl}-2-bromopropionate. Oily substance. Yield 54.4%. IR (Neat): 1740cm ^-1 . NMR (CDCl ₃ ) δ2.14 (3H, s), 3.11 (1H, dd,
J = 14 and 7Hz), 3.38 (1H, dd, J = 14 and 7Hz), 3.69 (3H, s), 4.33 (1H, t, J = 7
Hz), 4.40 (2H, d, J = 5Hz), 6.17 (1H, t,
J=5Hz), 6.80 (2H, d, J=9Hz), 8.08
(2H, d, J=9Hz), 7.2~7.8 (3H, m),
8.25 (1H, dd, J=5 and 2Hz) ○ 3-{4-[2-acetoxy-2-(3-methyl-2-pyridyl)ethoxy]phenyl}-2
-Methyl bromopropionate. Oily substance. yield
30.1%. IR (Neat): 1730cm ^-1 . NMR (CDCl ₃ ) δ2.09 (3H, s), 2.49 (3H, s),
3.12 (1H, dd, J=14 and 7Hz), 3.40 (1H, dd,
J=14 and 7Hz), 3.70 (3H, s), 4.1~4.6 (3H,
m), 6.33 (1H, dd, J=8 and 5Hz), 6.81 (2H,
d, J=9Hz), 8.08 (2H, d, J=9Hz), 7.2~
7.8 (2H, m), 8.44 (1H, dd, J=5 and 2Hz). ○ 3-{4-[2-acetoxy-2-(5-methyl-2-pyridyl)ethoxy]phenyl}-2
-Methyl bromopropionate. Oily substance. yield
61.0%. IR (Neat): 1740cm ^-1 . NMR (CDCl ₃ ) δ2.19 (3H, s), 2.30 (3H,
s), 3.10 (1H, dd, J=14 and 7Hz), 3.37
(1H, dd, J = 14 and 7Hz), 4.30 (1H, t,
J=7Hz), 4.37 (2H, d, J=5Hz), 6.12
(1H, t, J = 5Hz), 6.79 (2H, d, J = 9
Hz), 8.06 (2H, d, J=9Hz), 7.2~7.6 (2H,
m), 8.37 (2H, d, J = 2Hz). ○ 3-{4-[2-acetoxy-2-(4,6-
Methyl dimethyl-2-pyridyl)ethoxyphenyl}-2-bromopropionate. Oily substance.
Yield 5.12%. IR (Neat): 1740cm ^-1 . NMR (CDCl ₃ ) δ2.13 (3H, s), 2.28 (3H,
s), 2.47 (3H, s), 3.12 (1H, dd, J = 14 and 7Hz), 3.38 (1H, dd, J = 14 and 7Hz),
3.69 (3H, s), 4.31 (1H, t, J=7Hz),
4.37 (2H, d, J = 5Hz), 6.10 (1H, d, J =
5Hz), 6.7~7.2 (6H, m)

Claims (1)

[Claims] 1 General formula [Formula] [In the formula, R ¹ and R ² are the same or different and represent hydrogen or a lower alkyl group, R ³ represents hydrogen or an acyl group, and n represents 0 or 1. ] A thiazolidinedione derivative or a salt thereof. 2 General formula [Formula] [In the formula, R ¹ and R ² are the same or different and represent hydrogen or a lower alkyl group, R ⁴ represents hydrogen or an acyl group, R ⁵ represents hydrogen or a lower alkyl group, and X represents a halogen atom. , n represents 0 or 1, respectively. ] A compound represented by the formula [Formula] is reacted with thiourea to form a compound represented by the general formula [Formula] [Each symbol in the formula has the same meaning as above. ] is obtained, and then hydrolyzed,
A general formula characterized by further acylation if necessary: [Formula, R ¹ , R ² and n have the same meanings as above, and R ³ represents hydrogen or an acyl group. ] A method for producing a thiazolidinedione derivative represented by: 3 General Formula [Formula] [In the formula, R ¹ and R ² are the same or different and represent hydrogen or a lower alkyl group, R ³ represents hydrogen or an acyl group, and n represents 0 or 1. ] A therapeutic agent for diabetes or hyperlipidemia, comprising a thiazolidinedione derivative or a salt thereof.