JPH0118905B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel thiazolidine derivatives that have the ability to suppress certain chronic conditions resulting from diabetes, such as diabetic cataracts and diabetic neurological diseases. More specifically, the present invention relates to (1) general formula [In the formula, R is phenyl having two substituents selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyl group, a halogen, and an acyloxy group on the ring, or a methylenedioxy group at an adjacent position on the ring. group, and R ¹ represents a hydrogen atom or an alkyl group]. (2) General formula [In the formula, R and R ¹ have the same meanings as above, and
represents a halogen atom, Z represents a nitrile group, a carboxyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a group represented by the formula COOM' (M ¹ represents an alkali metal atom or NH ₄ ) and thio General formula by reacting urea [In the formula, R and R ¹ have the same meanings as above, and Y
represents an oxygen atom or an imino group. The present invention relates to a method for producing a thiazolidine derivative represented by the general formula (), which comprises obtaining a compound represented by the formula () and then hydrolyzing the same. Examples of the substituent for R and the alkyl group represented by R ¹ include linear or branched alkyl groups having 1 to 1 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, and i-butyl. Among them, lower alkyl groups having 1 to 4 carbon atoms are preferred. Examples of alkoxy groups that can be used as substituents for R include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, n- -hexyloxy, i-hexyloxy, and other groups having 1 to 7 carbon atoms; halogens include fluorine, chlorine, and the like; and acyloxy groups include those having 1 to 4 carbon atoms, such as acetyloxy and propionyloxy. These substituents for R can be substituted at any position on the benzene ring, but those substituted at the 3rd and 4th positions are particularly preferred. Among the compounds of the present invention, those substituted at the 3-position with lower alkoxy having 1 to 4 carbon atoms, particularly ethoxy, are preferred. When alkoxy is substituted at the 4-position,
The alkoxy is preferably one having 4 to 5 carbon atoms, such as n-butoxy and n-pentyloxy. The compound of the present invention represented by the general formula () can be formed into salts with various cations such as sodium, potassium, calcium, and ammonium by conventional methods. The thiazolidine derivative () of the present invention has the ability to inhibit the enzymatic activity of aldose reductase isolated from rat lenses or human placenta, and the ability to suppress water influx by the rat lens culture method, and It is expected to be useful for diabetic cataracts, neurological diseases, retinopathy, etc. For example, it can be administered orally in the form of tablets, capsules, powders, granules, etc., parenterally in the form of injections or pellets, or topically as an ophthalmic solution for eye drops. The dosage is usually 0.2 mg per day per adult.
It is appropriate to administer 1000 mg, preferably 10 to 100 mg, orally or parenterally in 1 to 4 divided doses. For eye drops, it is preferable to instill one to several drops as a 0.001 to 1% eye drop solution three to five times a day. The thiazolidine derivative () of the present invention can be obtained, for example, by reacting a compound represented by the general formula () with thiourea to obtain a compound represented by the general formula (), and then hydrolyzing this. Although the compound () may have tautomers as shown in the following formula, for convenience, these are simply expressed as the compound (). When Y is an oxygen atom When Y is an imino group The reaction between compound () and thiourea is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, as well as acetone, dimethyl sulfoxide, sulfolane, and dimethyl formamide. Although the contact ratio between compound () and thiourea is not particularly limited, it is preferable to use a slight excess of thiourea relative to the equivalent mole of compound (). Preferably 1 to 1 mole of compound ()
It is 2 moles. Although reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, the reaction is usually carried out at the boiling point of the solvent or at 100 to 130°C for 10 minutes or more, preferably 30 minutes to more than ten hours. In this way, a poorly soluble compound () can be obtained. This compound () is subjected to the next hydrolysis step after isolation or without isolation. The hydrolysis step is carried out by heating the compound () in a suitable solvent (such as sulfolane) in the presence of water and a mineral acid. The amount of acid added is usually 0.1 to 10 mol, preferably 0.2 to 3 mol, per 1 mol of compound (), and the amount of water added is based on 1 mol of compound ().
It is usually in large excess per mole. The heating time is usually several hours to more than ten hours. In addition, when trying to obtain a compound in which R ¹ is an alkyl group in the target compound (), for example, the general formula [In the formula, R has the same meaning as above and M ² represents an alkali metal atom such as sodium or potassium] is converted into a dianion in the presence of a strong base, and an alkylating agent such as an alkyl halide is added. It can be obtained by alkylation with As the strong base, lithium diisopropylamide is often used. This alkylation reaction is usually carried out in a solvent. Examples of the solvent include ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Regarding the contact ratio of the raw materials, equimolar amounts of the strong base alkylating agent to the compound () are used. Although the reaction temperature and reaction conditions vary depending on the raw material solvent used, etc., the reaction is usually carried out at 0°C to 50°C for 1 hour to more than ten hours. The thiazolidine derivative () thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution, chromatography, etc. Note that the compound () used as a raw material can be produced, for example, as follows. The present invention will be explained in more detail by referring to Reference Examples, Examples, and Experimental Examples below. Reference example 1 a Dissolve 25 g of 3,4-diethoxybenzaldehyde in 200 ml of ethyl acetate and cool in an ice-salt bath.
A solution of 67 g of sodium bisulfite in 100 ml of water and then a solution of 42 g of potassium cyanide in 60 ml of water were sequentially added dropwise and stirred under ice cooling for 7 hours. The organic layer was separated, washed with water, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure to obtain 23.0 g (81.3%) of crystals of α-(3,4-diethoxyphenyl)-α-hydroxyacetonitrile. is obtained. ether-
Recrystallize from n-hexane. Colorless plate crystals.
mp71−72℃ b α-(3,4-diethoxyphenyl)-α-
Dissolve 4.4 g of hydroxyacetonitrile in 60 ml of chloroform, add 1.5 ml of thionyl chloride, and heat under reflux for 15 minutes. After cooling, it is washed with saturated sodium bicarbonate and water in that order, and then dried (MgSO ₄ ). When the solvent was distilled off, 4.8 g (quantitative) of a crude oil of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile was obtained. The obtained crude oil can be used as it is for the next reaction, but it is purified by column chromatography (ether-n-hexane 1:5).
(elution) to form crystals. Recrystallize from n-hexane. Colorless needles. mp61−62℃. Example 1 a 4.8 g of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile and 2.3 g of thiourea are stirred in 70 ml of ethanol under reflux for 1 hour.
After cooling, pour into 200 ml of water, neutralize with saturated aqueous sodium bicarbonate solution, and extract with chloroform. After washing with water and drying (MgSO ₄ ), chloroform was distilled off, resulting in 3.9 g of 5-(3,4-diethoxyphenyl)-2,4-diiminothiazolidine.
(69.6%) is obtained. mp185−190℃ b 5-(3,4-diethoxyphenyl)-2,
2.8g of 4-diiminothiazolidine in ethanol
Dissolve in 40ml of 2N hydrochloric acid and heat under reflux for 8 hours. After cooling, water was added and extracted with chloroform. After washing with water and drying (MgSO ₄ ), chloroform was distilled off to obtain 2.6 g of crystals of 5-(3,4-diethoxyphenyl)thiazolidine-2,4-dione. (92.9%) is obtained. Recrystallize from methanol. Colorless prismatic crystal. mp139−140
℃. Example 2 a 1.0 g of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile and 477 mg of thiourea are stirred in 20 ml of ethanol under reflux for 1 hour.
Add 20 ml of 2N hydrochloric acid, heat under reflux for an additional 10 hours, cool, add water, and extract with chloroform. After washing with water and drying (MgSO ₄ ), chloroform is distilled off to obtain 870 mg (73.7%) of crystals of 5-(3,4-diethoxyphenyl)thiazolidine-2,4-dione. b 500 mg of 5-(3,4-diethoxyphenyl)thiazolidine-2,4-dione in methanol 50
ml and add 1 ml of 2N-sodium methylate methanol solution. The solvent was distilled off under reduced pressure and the remaining crystals were filtered with ether to give 5
-(3,4-diethoxyphenyl)thiazolidine-2,4-dione sodium salt 410 mg (76.1
%) is obtained. Recrystallize from ethanol-ether. mp254-255°C (dec.) Example 3 2.26 g of α-chloro-α-(3,4-dimethylphenyl)ethyl acetate and 910 mg of thiourea are stirred in 15 ml of ethylene glycol monoethyl ether under reflux for 2 hours. Next, add 1 ml of concentrated hydrochloric acid,
Heat under reflux for a further 3.5 hours. After cooling, water is added and extracted with ethyl acetate, washed with water and dried (MgSO ₄ ). The solvent was distilled off, and the remaining oil was subjected to column chromatography using 100 g of silica gel, and chloroform-ethyl acetate 5:
From the part eluted in 1, crystals of 5-(3,4-dimethylphenyl)thiazolidine-2,4-dione
Obtain 1.32g (60%). Recrystallize from cyclohexane-ethyl acetate. Colorless prismatic crystal. mp121
−122℃. Example 4 a 730 mg of ethyl α-chloro-α-(2,4-diethoxyphenyl)acetate and 380 mg of thiourea are stirred in 7 ml of ethanol under reflux for 1 hour. After cooling, pour into 30 ml of water, neutralize with saturated aqueous sodium hydrogen carbonate solution, and extract with ethyl acetate. washing with water,
After drying (MgSO ₄ ), ethyl acetate is distilled off.
510 mg (74.5%) of 5-(2,4-diethoxyphenyl)-2-iminothiazolidin-4-one
is obtained. mp179-181℃ (1/2 mole hydrate) b 5-(2,4-diethoxyphenyl)-2-
Dissolve 500 mg of iminothiazolidin-4-one in 5 ml of ethanol and 4 ml of 2N hydrochloric acid, and 8 ml of iminothiazolidin-4-one is dissolved under reflux.
Heat for an hour. After cooling, water was added and extracted with chloroform. After washing with water and drying (MgSO ₄ ), the chloroform was distilled off to give 420 mg (84 %) is obtained. ether-
Recrystallize from n-hexane. Colorless prismatic crystal. mp137-138℃ Example 5 Dissolve 1.0 g of diisopropylamine in 20 ml of anhydrous tetrahydrofuran, add 440 mg of 60% oily sodium hydride, and 5-(3,4-diethoxyphenyl).
Add 2.8g of thiazolidine-2,4-dione in sequence.
Stir for 30 minutes at 50℃. Cool to 0℃ and add 6.2 ml of n-butyllithium hexane standard solution (1.62N).
After adding dropwise at below 5℃, stir at 30℃ for 15 minutes. The mixture was cooled to 0° C. again and a solution of 1.6 g of ethyl iodide in 10 ml of tetrahydrofuran was added dropwise. After stirring at 35℃ for 1 hour, add 5ml of water and then 20ml of 2N hydrochloric acid.
Add dropwise at below 15°C and extract with ethyl acetate. After washing with water and drying (MgSO ₄ ), the solvent is distilled off, and the remaining oil is subjected to column chromatography using 50 g of silica gel. From the part eluted with cyclohexane-ethyl acetate 4:1, 5-(3,4-diethoxyphenyl)-5-ethylthiazolidine-
1.65 g (53.2%) of 2,4-dione crystals are obtained.
Recrystallize from ether-n-hexane. Colorless prismatic crystal. mp79-80℃ Example 6 24.6g of α-chloro-α-(3-ethoxy-4-pentyloxyphenyl)acetonitrile and 10.2g of thiourea are stirred at 90-100℃ for 10 minutes in 100ml of ethylene glycol monomethyl ether. .
Add 150 ml of 2N hydrochloric acid and stir at 110°C for an additional 15 hours. After cooling, add water and extract with ethyl acetate. After washing with water and drying (MgSO ₄ ), the solvent was distilled off to give 16 g of crystals of 5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione.
(56.2%) is obtained. Recrystallization from dilute ethanol gives colorless plate crystals. mp104.5~106
Example 7 Compounds Nos. 1 to 16 were synthesized in the same manner.

【table】

[Table] Experimental example 1 The inhibitory effect of thiazolidine derivatives () on aldose reductase activity was investigated by S. Haymen et al., Journal.
of Biological Chemistry, Vol.240, 877 (1965)
and Jin H. Kinoshita et al., Metabolism,
The test was conducted according to the method described in Vol. 28, Nr. 4, Suppl 1, 462 (1979), etc. The enzyme used in the test was partially purified aldose reductase from human placenta. The results obtained for each compound are 10% inhibition of enzyme activity at a concentration of ^-6 molar
It is shown in Table 2 as follows.

[Table] Experimental Example 2 The effect of each compound on water inflow inhibition using the rat lens culture method was evaluated by H.Obazawa et al., Invest.
Tested according to the method described in Ophthalmol Vol 13, Nr. 3, 204 (1974). The results obtained for each compound are shown in Table 3 as the inhibition rate (%) of water inflow into the lens at a concentration of 10 ^-6 molar.

【table】

[Table] Reference Example 2 A prescription example is shown when the compound of the present invention is used as an eye drop. B. Eye drops - Polyvinyl alcohol 500 500mg - Monosodium phosphate dihydrate 200mg - Disodium phosphate dodecahydrate 500mg - Sodium chloride 750mg - Edetate disodium salt 20mg - 5-(3 -Ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione
10mg ・Benzalkonium chloride 7mg Make a total solution of 100ml with purified water.

Claims (1)

[Claims] 1. General formula [In the formula, R is phenyl having two substituents selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyl group, a halogen, and an acyloxy group on the ring, or a methylenedioxy group at an adjacent position on the ring. group, and R ¹ represents a hydrogen atom or an alkyl group]. 2 General formula [In the formula, R is a phenyl group having two substituents selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyl group, a halogen, and an acyloxy group on the ring, or a methylenedioxy group at an adjacent position on the ring. group, and R ¹ represents a hydrogen atom or an alkyl group. Y represents an oxygen atom or an imino group. ] A general formula characterized by hydrolyzing a compound represented by A method for producing a thiazolidine derivative represented by [Each symbol in the formula has the same meaning as above]. 3 General formula [In the formula, R is phenyl having two substituents selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyl group, a halogen, and an acyloxy group on the ring, or a methylenedioxy group at an adjacent position on the ring. group, R ¹ is a hydrogen atom or an alkyl group, X is a halogen atom, Z is a nitrile group, carboxyl group, alkoxycarbonyl group, aminocarbonyl group or the formula COOM ¹ (M ¹ represents an alkali metal atom or NH ₄ ) and thiourea to form a compound represented by the general formula [In the formula, R and R ¹ have the same meanings as above, and Y represents an oxygen atom or an imino group. ] A general formula characterized by obtaining a compound represented by and then hydrolyzing it. A method for producing a thiazolidine derivative represented by [Each symbol in the formula has the same meaning as above].