JP2558473B2 - Thiazolidine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a thiazolidine derivative and a salt thereof having an aldose reductase (hereinafter abbreviated as AR) inhibitory action.

Prior Art Bull.Soc.Chim.Belg., 72 , 87-90 (1962) describes that a compound similar to the compound of the present invention was synthesized in anticipation of antibacterial action and growth regulating action. However, there is no disclosure or suggestion that these compounds have an AR inhibitory action.

In addition, JP-A-57-28074, 57-40478, 60-136575, and 6
0-156387, 61-27984, 61-53271 and 61-56175 disclose compounds having an AR inhibitory action.

However, the compounds of the present invention are structurally totally different from the compounds disclosed in these applications in that they have carboxy lower alkoxy as a substituent on the aromatic ring.

Content of the invention AR is an enzyme that reduces aldoses such as glucose and galactose to polyols such as sorbitol and galactitol in vivo. On the other hand, the onset and progression of diabetic complications (diabetic cataract, retinopathy, neuropathy, nephropathy, etc.)
It is known that accumulation of sorbitol, galactitol and other tissues and organs caused by AR is involved.

The compound of the present invention has a strong AR inhibitory action and is useful for the prevention and treatment of diabetic complications.

The present invention is a thiazolidine derivative represented by the following formula and salts thereof. (In the formula, R ₁ represents a hydrogen atom, C _1-15 alkyl optionally substituted with carboxyl or lower alkoxycarbonyl, or amino optionally substituted with acyl, and R ₂ represents a hydrogen atom or lower alkyl. X represents a sulfur atom or an oxygen atom, and R ₃ represents the following formula [a],
It means a group represented by [b], [c] or [d].

Here, R ₄ represents a hydrogen atom, lower alkyl or aralkyl, R _{5 to} R ₈ are the same or different and are a hydrogen atom,
Hydroxy, halogen atom, lower alkyl, lower alkoxy, nitrile, trifluoromethyl or amino, A represents lower alkylene or lower alkenylene, R ₅ and R ₈ are both hydrogen atoms, R ₁ is hydrogen atom,
When it is ethyl or carboxymethyl, A represents C ₂ or higher lower alkylene or C ₃ or higher lower alkenylene. ) Concerning.

In the present specification, alkyl, alkoxy, alkylene and alkenylene may be linear or branched.

The lower alkyl means one having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl and the like.

The lower alkoxy means one having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxin, isopropoxy and the like.

The lower alkylene means one having 1 to 10 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and heptamethylene.

The lower alkenylene means one having 3 to 6 carbon atoms having a double bond at a position other than the 1-2 position, for example, 2
-Propylene, 2-butenylene, 3-methyl-2-butenylene, 3-methyl-2-butenylene, 3- or 4-pentenylene, 2-, 3-, 4- or 5-hexenylene.

Acyl means an aliphatic or aromatic carboxylic acid residue having 1 to 7 carbon atoms, for example, formyl, acetyl,
Examples include propionyl, butyryl, benzoyl and the like.

Aralkyl means 1 carbon atom substituted with an aromatic ring.
~ 4 alkyl means, for example, benzyl, phenethyl, naphthylmethyl and the like.

The halogen atom means fluorine, chlorine, bromine and iodine, but fluorine, chlorine and bromine are preferable.

The salt of the compound (I) of the present invention is a physiologically acceptable non-toxic salt, for example, an inorganic base such as sodium salt, potassium salt, calcium salt, ammonium salt or ethylamine salt, or an organic base. Examples include salt.

Since the compound (I) of the present invention and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the scope of the present invention.

The compound (I) of the present invention has one or more carbon-carbon double bond and optionally one or more asymmetric carbon atom, and stereoisomers based on these may exist. These stereoisomers and their mixtures are also included in the scope of the present invention.

The compound (I) of the present invention can be prepared, for example, by the following (a),
It can be produced by the method (b).

(A) General formula (II) (In the formula, R ₂ and R ₃ are the same as the above), and a compound represented by the general formula (III) The compound (I) of the present invention can be obtained by reacting with a compound represented by the formula (wherein R ₁ and X are the same as the above). This reaction is usually carried out in a suitable solvent, and specific examples of the solvent include acetic acid,
Water or alcohols such as methanol, ethanol, isopropyl alcohol, dimethylformamide,
Aromatic hydrocarbons such as chloroform, pyridine, cyclohexane and benzene, toluene, xylene are mentioned. These solvents can be used alone or in admixture of two or more.

This reaction is preferably carried out in the presence of an organic acid salt, an alkali metal alkoxide, an inorganic base, or an organic base,
Specific examples of the organic acid salt include sodium acetate, potassium acetate, ammonium acetate, piperidine chain acid salt, piperidine benzoate and diethylamine organic acid salt, and specific examples of the alkali metal alkoxide include sodium methoxide and sodium. Ethoxide, potassium
Examples of the inorganic base include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, and the like. Specific examples of the organic base include triethylamine, morpholine, piperidine, and the like.
Examples thereof include 1,8-diazabicyclo [5.4.0] undec-5-ene (hereinafter abbreviated as DBU) and 1,5-diazabicyclo [4.3.0] nonane-5-ene (hereinafter abbreviated as DBN). In some cases, acetic anhydride, zinc chloride or the like may be added in addition to the above-mentioned salts and bases. The reaction temperature is usually 0 ° C
200 ° C, preferably 0 ° C to 120 ° C.

In the formula (I), the compound in which R ₄ represents a hydrogen atom can be obtained in the form of a free carboxylic acid or a salt thereof depending on the post-treatment conditions of the reaction and the like. Free carboxylic acids can also be obtained by treating the corresponding salts with an acid such as hydrochloric acid.

The compound in which R ₄ represents a hydrogen atom in the formula (1) is
In the formula (1), a compound in which R ₄ represents lower alkyl or aralkyl is water, a mixed liquid of water and alcohols such as ethanol and methanol, a mixed liquid of water and dioxane, cyclic ethers such as tetrahydrofuran, or a mixture thereof. It can also be obtained by hydrolyzing sodium bicarbonate or potassium bicarbonate to a catalyst in a mixed solution.

In the formula (I), compounds wherein R ₄ means a lower alkyl group, an alcohol and a non-catalyst R ₄ corresponds with a compound that a hydrogen atom in formula (I) or the presence of an acid catalyst, at room temperature Alternatively, it can be obtained by heating.

(B) In the case where R ₁ is C _1-15 alkyl optionally substituted with lower alkoxycarbonyl, general formula (IV) (Wherein R ₂ and R ₃ are the same as above), and a compound of the general formula (V) R ₁ ′ -Y (V) (wherein R ₁ ′ may be substituted with a lower alkoxycarbonyl) A good C _1-15 alkyl, and Y means a halogen atom.) Is also reacted with a compound represented by
The compound (I) of the present invention can be obtained. This reaction is
Basic catalysts such as sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, potassium hydroxide, DBU, D
It is preferably carried out in the presence of BN or the like in a solvent such as dimethylformamide (hereinafter abbreviated as DMF), alcohols such as methanol, ethanol and propanol.

Compound (I) of the present invention produced as described above
Can be changed to a salt as described above, if necessary, by a conventional method.

The compound (I) of the present invention or a salt thereof can be prepared by appropriately combining known purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, high performance liquid chromatography or ion exchange resin. It can be isolated and purified.

The compound (I) and salts thereof of the present invention have excellent AR inhibitory action and hypoglycemic action, and are useful for prevention and treatment of diabetic complications and the like.

 The pharmacological action of the present invention will be described below.

Test example AR inhibitory effect This test is based on the method of S. Hyman and JH Kinoshita (J. Bioc
hem. 242 877-882 (1965)).

(Preparation of Crude Enzyme Solution) The lens isolated from Wistar rats was homogenized with 5 mM phosphate buffer (pH 7.4, containing 1 mM mercaptoethanol), and then centrifuged at 18,000 xg for 20 minutes. Then, solid ammonium sulfate was added to the supernatant for salting out, and a 40% to 75% saturated ammonium sulfate fraction was used as a crude enzyme solution.

(Measurement of enzyme activity) 0.08 M phosphate buffer, 0.47 M lithium sulfate, 1.76x10 ^-4 M NADPH and 1.76x10 ^-3 glyceraldehyde solution (pH 6.2, 1.7 ml of test compound solutions of various concentrations) (0.2 ml) was added and incubated at 30 ° C., and then the crude enzyme solution (0.1 ml) was added to start the reaction.The absorbance at 340 nm after the addition of the crude enzyme solution was measured by Hitachi Double Beam Spectrophotometer 20 type) and the enzyme activity was determined from the decrease in the absorbance.
It was expressed as a% inhibitory concentration (IC ₅₀ ). The results are shown in Table 1.

The route of administration of the compound (I) of the present invention and physiologically acceptable salts thereof may be any of oral administration, parenteral administration, rectal administration and eye drop administration. The dose is
The amount is usually 0.1 mg to 10 mg / kg / day, varying depending on the type of compound, administration method, patient's symptoms, age and the like. Compound (I) or a salt thereof of the present invention is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and which does not react with the compound (I) of the present invention or a salt thereof is used. Specifically, for example, lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, Arabic. Rubber, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, carboxyvinyl polymer, titanium oxide, sorbitan Fatty acid ester, sodium lauryl sulfate, cacao butter, glycerin, fatty acid glycerin ester, purified lanolin, glyce Rozerachin, polysorbate, macrogol, vegetable oils, waxes, propylene glycol, water and the like.
Examples of the dosage form include tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections and eye drops. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. Also tablets,
Granules and fine granules may be coated by a known method.

These formulations can contain the compound (I) of the present invention or a physiologically acceptable salt thereof in a proportion of 0.5% or more, preferably 1 to 70%. These formulations may also contain therapeutically valuable values of the ingredients.

In order to explain the present invention in more detail, reference examples and examples will be given below, but the present invention is not limited thereto.

Reference Example 1 4- (1-formyl-2-naphthyloxy) butyric acid ethyl ethanol (200 ml) was dissolved in metallic sodium (2.4 g), and then 2-hydroxynaphthaldehyde (17.2
g) was added and the mixture was refluxed for 1 hour, then ethanol was distilled off.
The residue was dissolved in dry DMF (110 ml), ethyl 4-bromobutyrate (12.5 g) was added, and the mixture was heated with stirring at 60 ° C. for 4 hr.
The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform, and acid-base treatment was performed according to a conventional method to obtain 8.8 g of the desired product as an oil.

Reference Examples 2 to 4 Instead of 2-hydroxynaphthaldehyde in Reference Example 1, a corresponding hydroxybenzaldehyde derivative or hydroxynaphthaldehyde derivative was used, and reacted and treated in the same manner as in Reference Example 1 to obtain the compounds shown below. .

Reference Example 2: 4- (2-formyl-4-chlorophenoxy)
Ethyl butyrate Reference Example 3: 4- (2-formyl-4-bromophenoxy)
Ethyl butyrate Reference Example 4: Ethyl 4- (1-formyl-6,7-dimethoxy-2-naphthyloxy) butyrate Reference Example 5 Ethyl (5-bromo-1-formyl-6-methoxy-2-naphthyloxy) butyrate Ethanol After dissolving metallic sodium (0.44 g) in (100 ml), 5-bromo-2-hydroxy-6-methoxy-2-naphthaldehyde (4.9 g) was added and the mixture was heated and ethanol was distilled off. Dimethylformamide (100 ml) and methyl α-bromoacetate (2.2 ml) were added to the residue.
The mixture was stirred at 80 ° C for 17 hours. After cooling, the reaction solution was added to ice water, extracted with toluene, washed with water, dried with sodium sulfate, and concentrated under reduced pressure.
The residue was recrystallized from ethanol to obtain 4.2 g of the desired product. mp15
4-157 ° C. Reference Examples 6 to 9 5-Bromo-2-hydroxy-6 in Reference Example 5
The corresponding hydroxybenzaldehyde derivative or hydroxynaphthaldehyde derivative was used in place of -methoxy-2-naphthaldehyde and reacted and treated in the same manner as in Reference Example 5 to obtain the compound shown below.

Reference Example 6: Methyl (2-bromo-4-formyl-6-methoxyphenoxy) acetate Reference Example 7: Methyl (2-chloro-4-formyl-6-methoxyphenoxy) acetate Reference Example 8: (2-Chloro-4) -Formyl-1-naphthyloxy) methyl acetate Reference Example 9: (1-formyl-6,7-dimethoxy-2-naphthyloxy) methyl acetate Reference Example 10 2- (1-formyl-2-naphthyloxy) ethyl acetate Reference 2 instead of ethyl 4-bromobutyrate in Example 1
By using ethyl bromobutyrate and reacting and treating in the same manner as in Reference Example 1, an oily target compound was obtained.

Mass spectrum m / z: 286 (M +) Reference Example 11 4- (4-formyl-6-methoxyphenoxy) crotonate ethyl 4-hydroxy-3-methoxybenzaldehyde and ethyl 4-bromocrotonate were used as Reference Example 1. The same reaction and treatment was carried out to obtain an oily target product.

Mass spectrum m / z: 264 (M ⁺ ) Reference Example 12 4- (1-formyl-2-naphthyloxy) butyric acid Ethyl 4- (1-formyl-2-naphthyloxy) butyrate (8 g) was added to sodium hydroxide (1.5 g). The mixture is heated under reflux for 1 hour in a mixed solution of g) of water (30 ml) -ethanol (40 ml). After post-treatment according to a conventional method, the product was reconstituted with water to obtain 5.5 g of the desired product. mp179-181 ° C. Reference Examples 13 to 20 The following ester compounds were used in the same manner as in Reference Example 12 except that the corresponding ester compound was used instead of ethyl 4- (1-formyl-2-naphthyloxy) butyrate in Reference Example 12. The compound was obtained.

Reference Example 13: 2-Bromo-4-formyl-6-methoxyphenoxyacetic acid mp 118-120 ° C Reference Example 14: 2-chloro-4-formyl-6-methoxyphenoxyacetic acid mp 118-121 ° C Reference Example 15: 4- (4 -Chloro-2-formylphenoxy)
Butyric acid mp 95-96 ° C Reference Example 16: 4- (4-Bromo-2-formylphenoxy)
Butyric acid mp100-103 ° C mp176-179 ° C Reference example 17: 1-formyl-2-naphthyloxyacetic acid Reference example 18: 4-Chloro-2-formyl-1-naphthyloxyacetic acid mp180-182 ° C Reference example 19: 5-Bromo -1-formyl-6-methoxy-2
-Naphthyloxyacetic acid mp224-228 ° C Reference Example 20: 1-formyl-6,7-dimethoxy-2-naphthyloxyacetic acid mp213-219 ° C Reference Example 21 2-formyl-5-methoxycarbonylmethoxypyridine 3-hydroxy-6- Hydroxymethylpyridine (4 g) was dissolved in a freshly prepared sodium ethoxide (sodium metal 1.15 g, ethanol 100 ml) solution, heated under reflux for 1 hour, and ethanol was distilled off. Dissolve the residue in dimethylformamide (80 ml), add methyl bromoacetate,
After heating at ℃ for 3 hours, dimethylformamide was distilled off. The residue was extracted with ethyl acetate, dried over sodium sulfate, and concentrated to give an oily substance, which was purified by silica gel column chromatography (developing solvent: chloroform-methanol) to give 2-hydroxymethyl-.
5-Methoxycarbonylmethoxypyridine (1.8 g) was obtained. This product (0.85 g) was dissolved in chloroform (40 ml), manganese dioxide (2.4 g) was added, and the mixture was heated under reflux for 3 hours. The precipitate was filtered off, washed with hot chloroform, and the filtrate was dried over sodium sulfate and concentrated ( 0.63 g) was obtained.

mp50-55 ° C Reference Example 22 4-oxo-2-thioxothiazolidine-3-undecanoic acid 11-aminoundecanoic acid (30.1 g) aqueous solution (90 ml)
An aqueous solution (50 ml) of potassium hydroxide (85%, 19.8 g) was added to the mixture under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Carbon dioxide (1
(0 ml) was added and the mixture was stirred at room temperature for 0.5 hours and washed with ether. Separately prepared aqueous solution of monochloroacetic acid (14.6 g) of potassium carbonate (20.7 g) (120 ml) was added and left overnight at room temperature. The mixture was acidified with diluted hydrochloric acid and stirred at room temperature for 1 hour. The precipitate was filtered and stirred in 6N hydrochloric acid at 100 ° C for 3 hours. After ice-cooling, the deposited precipitate was filtered, dissolved in ethyl acetate, n-hexane was added, and the precipitated crystal was filtered off. The filtrate was concentrated and the residue was recrystallized from ethyl acetate-n-hexane repeatedly to obtain 16.7 g of the desired product. mp72-74 ° C Example 1 5- (3-Carboxymethoxy-4-methoxybenzylidene) -4-oxo-2-thioxoazolidine-3-
Acetic acid 4-oxo-2-thioxothiazolidine-3-acetic acid (0.70 g), 3-formyl-6-methoxyphenoxyacetic acid (0.78 g) and anhydrous sodium acetate (0.61 g) were dissolved in glacial acetic acid (12 ml), The mixture was heated and stirred at 110 ° C for 48 hours. After cooling, glacial acetic acid was distilled off, diluted hydrochloric acid was added to the residue, and the mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water, and recrystallized from hydrous ethanol to obtain 0.2 g of the desired product. mp250 ° C. or higher Example 2 5- [2- (3-Carboxypropoxy) benzylidene] -4-oxo-2-thioxothiazolidine-3-acetic acid monosodium salt 4-oxo-2-thioxothiazolidine-3-acetic acid ( 0.48g), 4- (2-formyl-phenoxy) butyric acid (0.5
2g) and anhydrous sodium acetate (0.41g) to glacial acetic acid (10m
l), and heated and stirred at 100 ° C for 56 hours. After cooling, the glacial acetic acid was distilled off, the residue was washed with water, and reconstituted from methanol
0.45 g was obtained. mp250 ° C. or higher Example 3 5- (3-Bromo-6-carboxymethoxybenzylidene) -4-oxo-2-thioxothiaziridine 4-oxo-2-thioxothiazolidine (0.42 g), 4
-Bromo-2-formylphenoxyacetic acid (0.80 g) and anhydrous sodium acetate (0.51 g) were dissolved in glacial acetic acid (15 ml), and the mixture was heated under reflux for 4.5 hours. After cooling, water was added and the mixture was stirred for 1 hour, the precipitate was collected by filtration, diluted hydrochloric acid was added thereto, and the mixture was stirred for 1 hour. mp252-254 ° C Example 4 5- (2-Carboxymethoxy-1-naphthylmethylene) -3-methyl-4-oxo-2-thioxothiazolidine 1-formyl-2-naphthoxyacetic acid (4.72 g), 3-methyl -4-oxo-2-thioxothiazolidine (3.2g)
And anhydrous sodium acetate (3.28 g) was dissolved in acetic acid (50 ml) and heated under reflux for 4 hours. After cooling, water was added and the mixture was stirred for 1 hour, then the deposited precipitate was collected by filtration, diluted hydrochloric acid was added to the obtained crude crystals and stirred for 1 hour, and the crystals were collected by filtration. It was treated with activated carbon and reconstituted from a mixed solution of acetone-water to obtain 4.3 g of the desired product. mp206
-209 [deg.] C. Examples 5 to 96 Using the corresponding starting compounds, the same reaction as in Example 1,
Treatment gave the compound shown below.

Example 5 5- (2-Carboxymethoxy-1-naphthylmethylene) -4-oxo-2-thioxothiazolidine (mp 231-234 ° C./recrystallization solvent: acetic acid-water) Example 6 5- (2-carboxymethoxy) -1-Naphthylmethylene) -4-oxo-2-thioxothiazolidine-3-acetic acid (mass spectrum m / z: 403 (M ⁺ )) Example 7 5- (1-Carboxymethoxy-4-chloro-2- Naphthylmethylene) -4-oxo-2-thioxothiazolidine (mp 250 ° C. or higher / recrystallization solvent: acetic acid-water) Example 8 5- (1-carboxymethoxy-4-chloro-2-naphthylmethylene) -3-methyl -4-oxo-2-thioxothiazolidine (mp224-226 ° C / recrystallization solvent: acetone-water) Example 9 5- (1-carboxymethoxy-4-chloro-2-naphthylmethylene) -4-o So-2-thioxothiazolidine-3-acetic acid (mp 250 ° C. or higher / recrystallization solvent: acetonitrile-water) Example 10 5- (4-chloro-1-methoxycarbonylmethoxy-2-naphthylmethylene) -3-methyl- 4-oxo-
2-Thioxothiazolidine (mp181-183 ° C / recrystallization solvent: ethanol-water) Example 11 5- (5-Bromo-2-carboxymethoxy-6-methoxy-1-naphthylmethylene) -3-methyl-4- Oxo-2-thioxothiazolidine (mp 215-220 ° C./recrystallization solvent: acetone-water) Example 12 5- (5-bromo-2-carboxymethoxy-6-methoxy-1-naphthylmethylene) -4-oxo- 2-Thioxothiazolidine-3-acetic acid (mp 135 to 143 ° C./recrystallization solvent: acetone-water) Example 13 5- [6- (3-ethoxycarbonylpropoxy)-
2-Hydroxy-1-naphthylmethylene] -3-methyl-4-oxo-2-thioxothiazolidine (mp137-142 ° C./recrystallization solvent: chloroform-n-hexane) Example 14 5- [2- (3- Ethoxycarbonylpropoxy)-
6-Hydroxy-1-naphthylmethylene] -3-methyl-4-oxo-2-thioxothiazolidine (mp124-129 ° C./recrystallization solvent: chloroform-n-hexane) Example 15 5- [2- (3- Carboxypropoxy) -1-naphthylmethylene] -4-oxo-2-thioxothiazolidine-3-acetic acid (mp 159 to 161 ° C./recrystallization solvent: ethyl acetate-n-hexane) Example 16 5- [2- (3 -Carboxypropoxy) -1-naphthylmethylene] -3-methyl-4-oxo-2-thioxothiazolidine (mp93-95 ° C / recrystallization solvent: ethyl acetate-n-hexane) Example 17 5- [2-carboxy -1-Methylethoxy) -1-
Naphthylmethylene] -3-methyl-4-oxo-2-thioxothiazolidine (mp157-164 ° C / recrystallization solvent: acetone-water) Example 18 5- (6-Bromo-2-carboxymethoxy-1-naphthylmethylene) ) -4-Oxo-2-thioxothiazolidine-3-acetic acid (mass spectrum m / z: 481,483 (M ⁺ )) Example 19 5- [6-Bromo-2- (3-carboxypropoxy-1-naphthylmethylene) ] -4-Oxo-2-thioxothiazolidine (mp181 to 188 ° C./recrystallization solvent: acetone-water) Example 20 5- [6-Bromo-2- (3-carboxypropoxy-1-naphthylmethylene] -3 -Methyl-4-oxo-
2-Thioxothiazolidine (mp 100 to 103 ° C / recrystallization solvent: acetone-water) Example 21 5- [6-Bromo-2- (3-carboxypropoxy-1-naphthylmethylene] -4-oxo-2-thiol Oxothiazolidine-3-acetic acid (mp129-134 ° C./recrystallization solvent: acetone-water) Example 22 5- [2- (2-carboxyethoxy) -1-naphthylmethylene] -4-oxo-2-thioxothiazolidine (Mp175-185 ° C./recrystallization solvent: acetone-water) Example 23 5- [2- (2-carboxyethoxy) -1-naphthylmethylene] -3-methyl-4-oxo-2-thioxothiazolidine (mp152 ˜157 ° C./recrystallization solvent: acetone-water) Example 24 5- [2- (2-carboxyethoxy) -1-naphthylmethylene] -4-oxo-2-thioxothiazolidine-3-acetic acid (mp117-123) ℃ / Recrystallization solvent: acetic acid-water) Example 25 5- (5-Bromo-2-carboxymethoxy-6-methoxy-1-naphthylmethylene-4-oxo-2-thioxothiazolidine (mass spectrum m / z: 453,455 (M ⁺ )) Example 26 5- (2-Carboxymethoxy-6,7-dimethoxy-
1-naphthylmethylene) -4-oxo-2-thioxothiazolidine (mp 250 ° C. or higher / recrystallization solvent: acetone-water) Example 27 5- (2-carboxymethoxy-6,7-dimethoxy-)
1-naphthylmethylene) -3-methyl-4-oxo-2
-Thioxothiazolidine (mp 250-255 ° C / recrystallization solvent: acetone-water) Example 28 5- (2-Carboxymethoxy-6,7-dimethoxy-)
1-naphthylmethylene) -4-oxo-2-thioxothiazolidine-3-acetic acid (mp246-248 ° C./recrystallization solvent: acetone-water) Example 29 5- [2- (3-carboxypropoxy) -6, 7-Dimethoxy-1-naphthylmethylene] -4-oxo-2-
Thioxothiazolidine (mp201 to 206 ° C./recrystallization solvent: acetone-water) Example 30 5- [2- (3-Carboxypropoxy) -6,7-dimethoxy-1-naphthylmethylene] -3-methyl-4 −
Oxo-2-thioxothiazolidine (mp175-180 ° C./recrystallization solvent: acetone-water) Example 31 5- [2- (3-Carboxypropoxy) -6,7-dimethoxy-1-naphthylmethylene] -4 -Oxo-2-
Thioxothiazolidine-3-acetic acid (mp203-206 ° C / recrystallization solvent: acetone-water) Example 32 5- (6-Bromo-2-carboxymethoxy-1-naphthylmethylene) -4-oxo-2-thioxo Thiazolidine (mp 253-257 ° C./recrystallization solvent: acetone-water) Example 33 5- (6-Bromo-2-carboxymethoxy-1-naphthylmethylene) -3-methyl-4-oxo-2-thioxothiazolidine ( mp210 to 215 ° C / recrystallization solvent: acetone-water) Example 34 5- [2- (3-ethoxycarbonylpropoxy) benzylidene] -4-oxo-2-thioxothiazolidine-3-acetic acid (mp225 to 257 ° C ( Decomposition / recrystallization solvent: methanol) Example 35 5- [2- (3-Carboxypropoxy) benzylidene] -3-methyl-4-oxo-2-thioxothiazolidine (mp 250 ° C. or higher) Top / recrystallization solvent: acetic acid-ethanol) Example 36 5- [2- (3-Carboxypropoxy) benzylidene] -4-oxo-2-thioxothiazolidine (mp237-241 ° C / recrystallization solvent: acetone-water) Example 37 5- [2- (3-Carboxypropoxy) -5-chlorobenzylidene] -4-oxo-2-thioxothiazolidine (mp 197 to 203 ° C./recrystallization solvent: acetone-water) Example 38 5- [ 2- (3-Carboxypropoxy) -5-chlorobenzylidene] -3-methyl-4-oxo-2-thioxothiazolidine (mp157-162 ° C / recrystallization solvent: acetone-water) Example 39 5- [2- (3-Carboxypropoxy) -5-chlorobenzylidene] -4-oxo-2-thioxothiazolidine-3-acetic acid (mp203-206 ° C / recrystallization solvent: acetone-water) Example 40 5- [5- Lomo-2- (3-carxylpropoxy) benzylidene] -4-oxo-2-thioxothiazolidine-3-acetic acid (mp212 to 220 ° C / recrystallization solvent: acetone-water) Example 41 5- [5-bromo 2- (3-Carboxypropoxy) benzylidene] -3-methyl-4-oxo-2-thioxothiazolidine (mp167-170 ° C / recrystallization solvent: acetone-water) Example 42 5- [5-Bromo-2 -(3-Carboxypropoxy) benzylidene] -4-oxo-2-thioxothiazolidine (mp209-217 ° C / recrystallization solvent: acetone-water) Example 43 5- [4- (2-carboxethoxy) benzylidene]
-4-oxo-2-thioxothiazolidine (mp244-250 ° C / recrystallization solvent: acetone-water) Example 44 5- [4- (2-carboxethoxy) benzylidene]
-3-Methyl-4-oxo-2-thioxothiazolidine mp 215-219 ° C. (decomposition) / recrystallization solvent: methanol) Example 45 5- [4- (2-carboxethoxy) benzylidene]
-4-oxo-2-thioxothiazolidine-3-acetic acid (mp 241-246 ° C./recrystallization solvent: ethanol-water) Example 46 5- [4- (2-carboxethoxy) benzylidene]
-4-Oxo-2-thioxothiazolidine-3-propionic acid (mp207-208 ° C / recrystallization solvent: ethanol-water) Example 47 5- [4- (2-Carboxyethoxy) -3-methoxybenzylidene]- 4-oxo-2-thioxothiazolidine-3-acetic acid (mp232-236 ° C / recrystallization solvent: ethanol-water) Example 48 5- (2-Carboxymethoxy-5-chlorobenzylidene) -4-oxo-2- Thioxothiazolidine (mp 253-255 ° C./recrystallization solvent: acetone-water) Example 49 5- (2-carboxymethoxy-5-chlorobenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine (mp235- 240 ° C./recrystallization solvent: acetone-water) Example 50 5- (2-Carboxymethoxy-5-chlorobenzylidene) -4-oxo-2-thioxothiazolidine-3-
Acetic acid (mp208-212 ° C / recrystallization solvent: acetic acid-water) Example 51 5- (5-Bromo-2-carboxymethoxybenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine (mp239-243 ° C) / Recrystallization solvent: acetone-water) Example 52 5- (5-Bromo-2-carboxymethoxybenzylidene) -4-oxo-2-thioxothiazolidine-3-
Acetic acid (mp200-204 ° C / recrystallization solvent: acetone-water) Example 53 5- (4-carboxymethoxy-3-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3
-Acetic acid monosodium salt (mp260 ° C or higher / recrystallization solvent: acetic acid-water) Example 54 5- (2-Carboxymethoxy-3-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3
-Acetic acid (mp250 ° C or higher / recrystallization solvent: acetic acid-water) Example 55 5- (2-carboxymethoxy-5-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3
-Acetic acid (mp208-212 ° C / recrystallization solvent: acetic acid-water) Example 56 5- (4-methoxycarbonylmethoxy-3-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3-acetic acid (mp260 ° C) Above / recrystallization solvent: ethanol-water) Example 57 5- (4-Carboxymethoxy-3-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3
-Propionic acid (mp213-218 ° C / recrystallization solvent: ethanol-water) Example 58 5- (2-Carboxymethoxy-3-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3
-Propionic acid (mp212-214 ° C / recrystallization solvent: ethanol-water) Example 59 5- (4-Carboxymethoxy-3-methoxybenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine (mp203- 208 ° C / recrystallization solvent: acetic acid-water) Example 60 5- (2-Carboxymethoxy-3-methoxybenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine (mp 163-165 ° C / recrystallization solvent) : Acetic acid-water) Example 61 5- (3-Carboxymethoxy-3-methoxybenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine monosodium salt (mp 260 ° C or higher / recrystallization solvent: acetic acid-methanol) ) Example 62 5- [3- (3-Ethoxycarbonyl-2-propylenyloxy) -4-methoxybenzylidene] -3-methyl-4-oxo-2-thioxo Thiazolidine (mp160-163 ° C / recrystallization solvent: methanol) Example 63 5- (2-Carboxymethoxy-5-methoxybenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine (mp207-212 ° C / re-) Crystal solvent: acetone-water) Example 64 5- (2-Carboxymethoxy-5-methoxybenzylidene) -4-oxo-2-thioxothiazolidine (mp 224 to 229 ° C / recrystallization solvent: methanol-water) Example 65 5- (3-Bromo-4-carboxymethoxy-5-methoxybenzylidene) -4-oxo-2-thioxothiazolidine (mp 261-268 ° C./recrystallization solvent: acetone-water) Example 66 5- (3-bromo -4-Carboxymethoxy-5-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3-acetic acid (mp 221-224 ° C / recrystallization solvent: acetone-water ) Example 67 5- (3-Bromo-4-carboxymethoxy-5-methoxybenzylidene) -3-methyl-4-oxo-2-
Thioxothiazolidine (mp217-225 ° C./recrystallization solvent: acetone-water) Example 68 5- (4-Carboxymethoxy-3-chloro-5-methoxybenzylidene) -4-oxo-2-thioxothiazolidine-3- Acetic acid (mp 229 to 235 ° C./recrystallization solvent: acetone-water) Example 69 5- (4-carboxymethoxy-3-chloro-5-methoxybenzylidene) -3-methyl-4-oxo-2-
Thioxothiazolidine (mp224-246 ° C / recrystallization solvent: acetic acid-water) Example 70 5- (3,5-dibromo-5-carboxymethoxybenzylidene) -4-oxo-2-thioxothiazolidine-
3-Acetic acid (mp 241-247 ° C./recrystallization solvent: acetone-water) Example 71 5- (3,5-dibromo-5-carboxymethoxybenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine ( mp250 ° C or higher / recrystallization solvent: acetone-water) Example 72 5- (2-carboxymethoxy-3,5-dichlorobenzylidene) 4-oxo-2-thioxothiazolidine (mp255-259 ° C / recrystallization solvent: acetic acid -Water) Example 73 5- (2-Carboxymethoxy-3,5-dichlorobenzylidene) -3-methyl-4-oxo-2-thioxothiazolidine (mp 233-239 ° C / recrystallization solvent: acetone-water) Example 74 5- (2-Carboxymethoxy-3,5-dichlorobenzylidene) -4-oxo-2-thioxothiazolidine-
3-Acetic acid (mp238 to 243 ° C / recrystallization solvent: acetone-water) Example 75 5- (3,5-dibromo-5-carboxymethoxybenzylidene) -4-oxo-2-thioxothiazolidine (mp250 ° C or higher / Recrystallization solvent: acetone-water) Example 76 5- (2-carboxymethoxybenzylidene) thiazolidine-2,4-dione (mp209 to 211 ° C / recrystallization solvent: methanol) Example 77 5- (2-carboxymethoxy- 3-Methoxybenzylidene) thiazolidine-2,4-dione (mp 230 to 232 ° C./recrystallization solvent: acetic acid-water) Example 78 5- (4-carboxymethoxy-3-methoxybenzylidene) thiazolidine-2,4-dione ( mp250 ° C or higher / recrystallization solvent: methanol) Example 79 5- (4-carboxymethoxybenzylidene) thiazolidine-2,4-dione (mp260 to 262 ° C / recrystallization solvent: methanol) Example 80 5- (2-Carboxymethoxybenzylidene) thiazolidine-2,4-dione-3-acetate methyl mp64-67 ° C./recrystallization solvent: acetone-n-hexane Example 81 5- (4-carboxymethoxybenzylidene) -3-
Methyl-4-oxo-2-thioxothiazolidine (mp 253-255 ° C./recrystallization solvent: acetic acid-water) Example 82 5- (4-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-propionic acid (mp 236 to 238 ° C./recrystallization solvent: ethanol-water Example 83 5- (4-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-butyric acid (mp 250 ° C. or higher / recrystallization solvent: ethanol-water) Example 84 5- (4-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-hexanoic acid (mp 190 to 193 ° C./recrystallization solvent: ethanol-water Example 85 5- (4-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-undecanoic acid (mp 183-187 ° C./recrystallization solvent: ethanol-water) Example 86 3-amino-5- (4-carboxymethoxybenzylidene) -4-oxo-2-thio Oxothiazolidine (mp223 to 226 ° C./recrystallization solvent: ethanol-water) Example 87 5- (2-carboxymethoxybenzylidene) -3-
Methyl-4-oxo-2-thioxothiazolidine (mp 220-221 ° C./recrystallization solvent: acetic acid-water) Example 88 3-Amino-5- (2-carboxymethoxybenzylidene) -4-oxo-2-thioxo Thiazolidine (mp203-210 ° C / recrystallization solvent: ethanol-water) Example 89 5- (2-Carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-propionic acid (mp 166-169 ° C./recrystallization solvent: ethanol-water) Example 90 5- (2-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-butyric acid (mp 168 to 172 ° C./recrystallization solvent: ethanol-water) Example 91 5- (2-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-hexanoic acid (mp 176 to 178 ° C./recrystallization solvent: ethanol-water) Example 92 5- (2-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-undecanoic acid (mp137-140 ° C./recrystallization solvent: ethanol-water) Example 93 5- (3-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-propionic acid (mp 210 to 212 ° C./recrystallization solvent: ethanol-water) Example 94 5- (3-carboxymethoxybenzylidene) -4-
Oxo-2-thioxothiazolidine-3-undecanoic acid (mp 145-146 ° C./recrystallization solvent: ethanol-water) Example 95 3-amino-5- (3-carboxymethoxybenzylidene) -4-oxo-2-thio Oxothiazolidine (mp 240 to 242 ° C./recrystallization solvent: ethanol-water) Example 96 3-benzoylamino-5- (2-carboxymethoxy-5-methoxybenzylidene) -4-oxo-2-thioxothiazolidine (mp130- 132 ° C./recrystallization solvent: acetone-water) Example 97 5- (5-methoxycarbonylmethoxy-2-pyridylmethylene) -4-oxo-2-thioxothiazolidine-3-acetic acid 2-methoxy-5-methoxycarbonyl Methoxypyridine (2.1g), 4-oxo-2-thioxothiazolidine-
A mixture of 3-acetic acid (2.1 g), anhydrous sodium acetate (1.78 g) and glacial acetic acid (20 ml) was stirred at 110 ° C for 48 hours.
After completion of the reaction, acetic acid was distilled off under reduced pressure, diluted hydrochloric acid was added, the resulting precipitate was collected by filtration, dissolved in acetic acid-water mixture and treated with activated carbon, and then recrystallized from ethanol-water mixture. , 5-((5-methoxycarbonylmethoxy-2-pyridinylmethylene) -4-oxo-2-thioxothiazolidineacetic acid (1.4 g) was obtained.

Example 98 5- (5-cicarboxymethoxy-2-pyridylmethylene) -4-oxo-2-thioxothiazolidine-3-
Acetic acid 5- (5-methoxycarbonylmethoxy-2-pyridylmethylene) -4-oxo-2-thioxothiazolidine-3-acetic acid (0.7 g) obtained in Example 97 was added to sodium bicarbonate (0.36 g), water ( The mixture was heated under reflux for 2.5 hours in a mixed solution of 30 ml) and ethanol (80 ml). After cooling, ethanol was distilled off, diluted hydrochloric acid was added, and the deposited precipitate was collected by filtration, and acetone-
The product was recrystallized from water to obtain the desired product (0.2 g). mp241 ~ 244 ℃

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Claims (1)

(57) [Claims] 1. A thiazolidine derivative represented by the following formula and salts thereof. (In the formula, R ₁ represents a hydrogen atom, C _1-15 alkyl optionally substituted with carboxyl or lower alkoxycarbonyl, or amino optionally substituted with acyl, and R ₂ represents a hydrogen atom or lower alkyl. X represents a sulfur atom or an oxygen atom, and R ₃ represents the following formula [a],
It means a group represented by [b], [c] or [d]. Here, R ₄ represents a hydrogen atom, lower alkyl or aralkyl, R _{5 to} R ₈ are the same or different and are a hydrogen atom,
Hydroxy, halogen atom, lower alkyl, lower alkoxy, nitrile, trifluoromethyl or amino, A represents lower alkylene or lower alkenylene, X is a sulfur atom, and R ₅ and R ₈ are both hydrogen atoms. , R ₁ is a hydrogen atom, ethyl or carboxymethyl, A represents C ₂ or higher lower alkylene or C ₃ or higher lower alkenylene. )