JPH0135831B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an aldose reductase inhibitor and a thiazolidine derivative having an aldose reductase inhibitory effect. More specifically, the present invention comprises 1 general formula [In the formula, R is a lower alkyl group, a hydroxyl group, an alkoxy group having 2 to 10 carbon atoms, a nitro group, an amino group,
Indicates a lower acylamino group, a fluorine atom, and a trifluoromethyl group. The present invention relates to an aldose reductase inhibitor containing a thiazolidine derivative represented by the formula (2) and a thiazolidine derivative represented by the general formula (2). In the above formula, examples of the lower alkyl group represented by R include methyl, ethyl, n-propyl, i-
Examples include straight-chain or branched carbon atoms having 1 to 6 carbon atoms, such as propyl, n-butyl, and i-butyl. Examples of the lower alkoxy group having 2 to 10 carbon atoms represented by R include ethoxy, n-propoxy, i
-propoxy, n-butoxy, i-butoxy, n
- Bentyloxy, n-hexyloxy, n-octyloxy, etc. Furthermore, examples of the lower acylamino group represented by R include those having 1 to 4 carbon atoms, such as acetylamino and propionylamino groups. These substituents can be substituted at any position on the benzene ring. 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. It is known that certain aldose reductase inhibitors are useful as drugs for preventing or alleviating chronic symptoms of diabetes such as diabetic cataracts, neurological diseases, and retinopathy, and thiazolidine derivatives represented by the general formula () also has the effect of inhibiting the activity of aldose reductase in vivo, so it suppresses the reduction of glucose to sorbitol in vivo, and prevents the accumulation of sorbitol in the crystalline lens, peripheral nerve cords, and kidneys of diabetic patients, for example. or reduce, thereby suppressing the cumulative complications of chronic diabetes. The aldose reductase inhibitor of the present invention is specifically useful for the prevention and treatment of chronic conditions such as diabetic cataracts, neurological diseases, and retinopathy in mammals including humans. The aldose reductase inhibitor of the present invention may be used as the compound () as it is, but it can also be used orally in the form of tablets, granules, powders, hard capsules, soft capsules, etc., as well as injections and pellets. It can be administered parenterally or topically as an ophthalmic solution. Tablets, granules, powders or capsules can be prepared by conventional methods, in which case starch, lactose and the like can be used as excipients. As excipients for preparing soft capsules, pharmaceutically acceptable harmless oils and fats of animal, vegetable or mineral origin can be used. The main drug is usually dissolved in these oils and fats and filled into soft capsules. Injections and eye drops can be prepared in the form of solutions or suspensions. The compound () of the present invention is oil-soluble,
Moreover, since it is poorly soluble in water, an aqueous injection solution can be prepared by using a water-solubilizing agent if desired.
As such a water-solubilizing agent, an appropriate nonionic surfactant commonly used in the preparation of injection solutions may be used.
Those having HLB can be selected and used. The dosage is usually 0.2mg to 1000 per adult per day.
It is appropriate to administer 1 to 4 mg orally or parenterally in 1 to 4 divided doses. Also, for eye drops
As a 0.001-1% eye drop solution 3-5 times a day,
It is recommended to instill one to several drops into the eye. The thiazolidine derivative () of the present invention can be expressed, for example, by the general formula [In the formula, R has the same meaning as above, X represents a halogen atom, and Z represents a nitrile group, a carboxyl group, or an alkoxycarbonyl group. ] By reacting the compound represented by thiourea with the general formula [In the formula, R has the same meaning as above, and Y represents an oxygen atom or an imino group. ] and then hydrolyzing it. Note that the compound () may have tautomers as shown in the following formula, but 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 methanol, ethanol, propanol, butanol,
Examples include alcohols such as ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, as well as acetone, dimethyl sulfoxide, sulfolane, and dimethyl formamide. The contact ratio between compound () and thiourea is not particularly limited, but 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. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, but the reaction usually takes place at the boiling point of the solvent or at 100 to 130°C for 10 minutes or more.
It will be held for 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. 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. Example 1 12.0 g of α-chloro-α-(3-fluorophenyl)acetonitrile and 8.1 g of thiourea are stirred in 100 ml of ethanol under reflux for 1 hour. 2N-hydrochloric acid
After adding 80 ml and heating under reflux for a further 24 hours,
Cool, add water and extract with chloroform. After washing with water and drying (MgSO ₄ ), chloroform is distilled off to obtain 6.1 g (40.7%) of crystals of 5-(3-fluorophenyl)thiazolidine-2,4-dione. Recrystallize from ether-n-hexane. Pale yellow prismatic crystal. mp129-130℃. Example 2 2.0 g of α-chloro-α-(4-fluorophenyl)acetic acid ethyl ester and 1.0 g of thiourea are stirred in 30 ml of ethanol under reflux for 1 hour. Add 20 ml of 2N hydrochloric acid, heat under reflux for an additional 15 hours, cool, add water, and extract with chloroform. After washing with water and drying (MgSO ₄ ), chloroform was distilled off, yielding 900 mg (46.1%) of crystals of 5-(4-fluorophenyl)thiazolidine-2,4-dione.
is obtained. Recrystallize from ether-n-hexane. Colorless prismatic crystal. mp145-146℃. Example 3 (a) 7.0 g of α-bromo-α-(3-trifluoromethylphenyl)acetic acid methyl ester and 2.7 g of thiourea are heated under reflux for 2 hours in 70 ml of ethanol. After cooling, ethanol is distilled off under reduced pressure, and a saturated aqueous sodium bicarbonate solution is added to collect the precipitated crystals. After washing with water and drying, 2-imino-5-(3-trifluoromethylphenyl)thiazolidin-4-one 4.9g (79.0%)
get. mp245-246℃ (dec.) (b) 4.5 g of 2-imino-5-(3-trifluoromethylphenyl)thiazolidin-4-one obtained above was refluxed in 50 ml of ethanol and 50 ml of 2N-hydrochloric acid. Cook for 6 hours. After cooling, water is added to remove the precipitated crystals. After washing with water and drying,
4.2 g (93.3%) of (3-trifluoromethylphenyl)thiazolidine-2,4-dione are obtained.
Recrystallize from ether-n-hexane. Colorless plate crystals. mp139-140℃. Example 4 Compounds Nos. 1 to 13 were contained in the same manner.

[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】

[Table] Experimental Example 2 The effectiveness of the main compound in suppressing water influx 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 the main compounds are shown in Table 3 as percentage inhibition of water inflow into the lens at a concentration of 10 ^-6 molar.

[Table] Experimental Example 3 Six 7-week-old male ICR mice were given 1000 mg of 5-(4-ethoxyphenyl)thiazolidine-2,4-dione suspended in a 5% gum arabic solution.
Kg//20ml was orally administered, and the animals were kept and observed for 7 days after administration. [Results] There were no cases of death. Therefore, the acute toxicity of this compound when administered orally to mice is 1000 mg/Kg.
That is all. Example 5 A prescription example is shown when the compound of the present invention is used as an eye drop. Eye drops ● Polyvinyl alcohol 500 500mg ● Monosodium phosphate dihydrate 200mg ● Disodium phosphate dodecahydrate 500mg ● Sodium chloride 750mg ● Edetate. Disodium salt 20mg ●5-(3-fluorophenyl)thiazolidine-
2,4-dione 10mg ●Benzalkonium chloride 7mg Make a total solution of 100ml with purified water. Example 6 A formulation example is shown when the compound of the present invention is used as a tablet. 5-(4-ethoxyphenyl)thiazolidine 2,4-dione 30 mg Lactose 35 mg Starch 170 mg Microcrystalline cellulose 30 mg Magnesium stearate 5 mg Total amount 270 mg After mixing in a conventional manner, tablets were made.

Claims (1)

[Claims] 1. General formula [In the formula, R is a lower alkyl group, a hydroxyl group, and a carbon number of 2
-10 alkoxy groups, nitro groups, amino groups, lower acylamino groups, fluorine atoms, and trifluoromethyl groups. ]A thiazolidine derivative represented by 2 General formula [In the formula, R is a lower alkyl group, a hydroxyl group, and a carbon number of 2
-10 alkoxy groups, nitro groups, amino groups, lower acylamino groups, fluorine atoms, and trifluoromethyl groups. ] An aldose reductase inhibitor comprising a thiazolidine derivative represented by: