JPH0114230B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing novel thiazolidine derivatives that have the effect of suppressing certain chronic symptoms resulting from diabetes, such as diabetic cataracts and diabetic neurological diseases. More specifically, the present invention provides that under acidic conditions, the general formula [In the formula, R represents a phenyl group having two substituents selected from the group consisting of an alkoxy group and a hydroxyl group on the ring or a methylenedioxy group at an adjacent position on the ring] A general formula characterized by reacting with thiourea and then subjecting it to a hydrolysis reaction. The present invention relates to a method for producing a thiazolidine derivative represented by [the symbols in the formula have the same meanings as above]. 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,
Examples include those having 1 to 7 carbon atoms such as i-hexyloxy. These substituents for R may be substituted at any position on the benzene ring, but those substituted at the 3- and 4-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 preferably has 4 to 6 carbon atoms, such as n-butoxy and n-pentyloxy. In the present invention, first, a compound represented by the general formula () is reacted with thiourea in the presence of an acid. This reaction is usually carried out in a solvent, such as alcohols (e.g. methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether), ethers (e.g. tetrahydrofuran, dioxane),
Examples include dimethyl sulfoxide, sulfolane, and dimethylformamide. As the above acid,
Examples include acetic acid, hydrochloric acid, phosphoric acid, and sulfuric acid. These acids are usually used for compounds ()
0.5 to 3 equivalents are used. The contact ratio between the compound () and thiourea is not particularly limited, but it is usually preferable to use thiourea in a slight excess (molar ratio), preferably 1 to 2 times the mole of thiourea. reaction temperature,
Reaction conditions such as reaction time vary depending on the type of raw material compound, type of solvent, type and amount of acid, etc., but are usually 50 to 60°C for 20 minutes or more, preferably 30 minutes to more than ten hours. This reaction gives the general formula A compound represented by the formula [wherein R has the same meaning as above] is obtained. Compound () may have tautomers as shown in the following formula, but for convenience, these are simply expressed as compound (). In the reaction of the present invention, the compound () obtained in the above step is subjected to a hydrolysis reaction after or without isolation. The hydrolysis reaction is carried out by heating in a suitable solvent (such as sulfolane) in the presence of water and a mineral acid. The amount of acid added is usually the compound ()
The amount added is usually 0.1 to 10 mol per mol, preferably 0.2 to 3 mol, in large excess per mol of compound (). The heating time is usually several hours to more than ten hours. In this hydrolysis reaction process, the compound () has the general formula

[Formula] Ma Taha

[Formula] [In the formula, R has the same meaning as above] It is thought that the target compound represented by the general formula () is obtained. Note that the compound (
Although a) and (b) may have tautomers represented by the following formulas, for convenience, these compounds are simply represented as compounds (a) and (b), respectively. [In the formula, R has the same meaning as defined above] The object compound () of the present invention can be formed into a salt with various cations such as sodium, potassium, calcium, and ammonium by a conventional method. 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. The target compound of the present invention, a thiazolidine derivative (), 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. It is also expected to be useful for diabetic cataracts, neurological diseases, retinopathy, etc. in mammals. 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 in the form of ophthalmic solutions for eye drops. Dosage is usually 1 day per adult
It is appropriate to administer 0.2 mg to 1000 mg, preferably 10 to 100 mg, orally or parenterally in 1 to 4 divided doses. For eye drops, it is desirable to instill one to several drops of the solution as a 0.01 to 1% eye drop solution three to five times a day. The starting compound () in the reaction of the present invention is, for example, a compound represented by the general formula R-CHO () [wherein R has the same meaning as above] in the presence of an acid and a compound represented by the general formula MCN () [wherein M is, for example, It can be obtained by reacting a compound represented by [representing an alkali metal atom such as sodium or potassium]. This reaction is usually carried out using e.g. methanol, ethanol,
Examples include alcohols such as propanol and ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, dimethyl sulfoxide, sulfolane, and dimethyl formamide. Although the contact ratio between compound () and compound () is not particularly limited, it is preferable to use a slightly excess molar amount of compound (). Examples of the acid present in the reaction system include acidic sodium sulfite, acetic acid, hydrochloric acid, phosphoric acid, and sulfuric acid. The amount of acid used is preferably 1 to 3 equivalents based on compound (). Reaction conditions such as reaction temperature and reaction time vary depending on the type and amount of raw materials, acids, and solvents used, but are usually -20°C to 50°C for several minutes to several hours, preferably 0°C to 30°C for 10 to 30 minutes. It is 30 minutes. The compound () thus obtained can be subjected to the reaction of the present invention as a starting compound of the present invention after being isolated by a conventional method or without being isolated. The target compound () of the present invention can be obtained by the following reaction in addition to the reaction of the present invention. According to the method of the present invention, compound () can be obtained in a better yield than the methods 1) and 2) above. EXAMPLES The present invention will be explained in more detail by describing Examples and Experimental Examples below. Reference example 1 Dissolve 11.8 g of 3-ethoxy-4-pentyloxybenzaldehyde in 45 ml of methanol and add 4.1 ml of concentrated hydrochloric acid while stirring to prevent the temperature from rising above 15°C.
and then add 2.81 g of sodium cyanide and 7 ml of water.
Add the solution quickly. Add to 300 ml of cold water, stir for 0.5 hours at room temperature. Hexane-ether (2:1)
Add 300ml of mixed solvent, shake well, and separate the liquids. The upper layer was washed three times with 100 ml of water, dried over MgSO ₄ and the solvent was distilled off under reduced pressure to obtain 12.9 g of a pale yellow oil. The obtained crude oil was purified by column chromatography (chloroform elution),
2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetonitrile is obtained as a pale yellow oil. Reference Example 2 25 g of 3,4-diethoxybenzaldehyde was dissolved in 200 ml of ethyl acetate, and while cooling in an ice-salt bath, a solution of 67 g of sodium bisulfite in 100 ml of water was added dropwise, followed by a solution of 42 g of potassium cyanide in 60 ml of water, and the mixture was cooled with ice. Stir for 7 hours. Separate the organic layer,
After washing with water and drying (MgSO ₄ ), the solvent was distilled off under reduced pressure, and 2-(3,4-diethoxyphenyl)-
2-hydroxyacetonitrile crystals 23.0g
(81.3%) is obtained. Recrystallize from ether-n-hexane. Colorless plate crystals. mp71-72℃ Example 1 Dissolve 2.36g of 3-ethoxy-4-pentyloxybenzaldehyde in 7.5ml of 2-methoxyethanol, add 0.83ml of concentrated hydrochloric acid while stirring to prevent the temperature from rising above 25℃, and then dissolve 0.56g of sodium cyanide. Add a solution of 1.5ml of water. 1
After stirring for an hour, thiourea 1.14g, concentrated hydrochloric acid 3.6g.
ml, stirred at 60-65°C for 2.5 hours, and then refluxed for 4 hours. After cooling, hexane-ethyl acetate (25:
3) Add 22ml and 15ml of water and stir for 0.5 hour.
The precipitated crystals are collected and dried to obtain 2.2 g of colorless, scaly crystals of 5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione. Recrystallize from dilute ethanol. Melting point 104~105
℃. Example 2 2-(3-ethoxy-4-pentyloxyphenyl)-2-hydroxyacetonitrile 2g
- Thiourea 866 dissolved in 4 ml of methoxyethanol
mg, and 2.75 ml of concentrated hydrochloric acid, and stir at 57 to 65°C for 2 hours. Add 1 ml of water and reflux for 5 hours. Add 15 ml of a 25:3 mixture of hexane and ethyl acetate, and then add 15 ml of water. The precipitated crystals were collected to obtain 2.1 g of colorless scaly crystals of 5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine-2,4-dione. Example 3 23.6 g of 3-ethoxy-4-pentyloxybenzaldehyde in 50 ml of 2-methoxyethanol
While stirring at °C, add 6.9 g of acetic acid, followed by a solution of 5.64 g of sodium cyanide dissolved in 110 ml of water. Thiourea after stirring at room temperature for 0.5 hours
Add 11.4 g and 36 ml of concentrated hydrochloric acid, stir at 57-64°C for 2 hours, and then reflux for 4 hours. After cooling, add 224 ml of hexane-ethyl acetate (25:3) and 150 ml of water, and stir in an ice bath for 0.5 hour. The precipitated crystals are collected and dried to give colorless scaly crystals of 5-(3-ethoxy-4-pentyloxyphenyl)thiazolidine.
Obtain 25.0 g of 2,4-dione. Recrystallize from dilute ethanol. Melting point 104-105℃. Reference Example 3 4.8 g of 2-chloro-2-(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. washing with water,
After drying (MgSO ₄ ), chloroform is distilled off.
5-(3,4-diethoxyphenyl)-2,4-
3.9 g (69.6%) of diiminothiazolidine are obtained. mp185-190℃ Reference example 4 5-(3,4-diethoxyphenyl)-2,4
- 2.8g of diiminothiazolidine and 40ml of ethanol
- Dissolve in 40ml of 2N hydrochloric acid and heat under reflux for 8 hours. After cooling, add water and extract with chloroform.
After washing with water and drying (MgSO ₄ ), chloroform was distilled off and 2.6 g (92.9 g) of crystals of 5-(3,4-diethoxyphenyl)thiazolidine-2,4-dione were obtained.
%) is obtained. Recrystallize from methanol. Colorless prismatic crystal. mp139-140℃. Reference Example 5 1.0 g of 2-chloro-2-(3,4-diethoxyphenyl)acetonitrile and 477 mg of thiourea are stirred in 20 ml of ethanol under reflux for 1 hour. 2N―
After adding 20 ml of hydrochloric acid and heating under reflux for an additional 10 hours, the mixture is cooled, water is added, and the mixture is extracted with chloroform. After washing with water and drying (MgSO ₄ ), chloroform is distilled off to produce 5-(3,4-diethoxyphenyl).
Thiazolidine-2,4-dione crystals 870mg
(73.7%) is obtained. Reference Example 6 24.6 g of 2-chloro-2-(3-ethoxy-4-pentyloxyphenyl)acetonitrile and 10.2 g of thiourea are stirred in 100 ml of ethylene glycol monomethyl ether at 90 to 100°C for 10 minutes.
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 platelets. mp104.5~106
C. Example 4 Compounds Nos. 1 to 18 were synthesized in the same manner as in Examples 1 and 2 and Reference Examples 1 to 6.

【table】

【table】

[Table] * "Actual" means an example, and "Reference" means a "reference example."
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, Mr. 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】

Claims (1)

[Claims] 1. General formula under acidic conditions A compound represented by the formula [wherein R represents a phenyl group having two substituents selected from the group consisting of an alkoxy group and a hydroxyl group on the ring or a methylenedioxy group at an adjacent position on the ring] General formula characterized by reacting with thiourea and then subjecting to a hydrolysis reaction A method for producing a thiazolidine derivative represented by [wherein R has the same meaning as above].