JPH0114915B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 2-iminothiazolidin-4-one derivatives useful as synthetic intermediates for pharmaceuticals and the like, and a method for synthesizing the same. More specifically, the present invention comprises 1 general 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)
Iminothiazolidin-4-one derivative 2 Under acidic conditions, general formula (wherein, R has the same meaning as above, and R ¹ represents hydrogen or a lower alkyl group) is reacted with thiourea. A method for producing a thiazolidin-4-one derivative. In the above general formulas () and (), examples of the alkoxy group as a substituent for R include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, n-pentyloxy, i- Examples include those having 1 to 7 carbon atoms, such as pentyloxy, neopentyloxy, n-hexyloxy, and i-hexyloxy. These substituents for R can be substituted at any position on the benzene ring. The lower alkyl group represented by R ¹ is methyl, ethyl, n-propyl, i-propyl, n
-Butyl, i-butyl, t-butyl, etc. with 1 carbon number
~4 things can be mentioned. The 2-iminothiazolidin-4-one derivative represented by the general formula () is, for example, a derivative represented by the general formula ()
It can be obtained by reacting the compound represented by and thiourea under acidic conditions. This reaction is usually carried out in a solvent, and the solvent is
For example, alcohols (e.g. methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether), ethers (e.g.
(tetrahydrofuran, dioxane), dimethyl sulfoxide, sulfolane, dimethylformamide, etc. Acidic conditions can be created by the presence of an acid. Examples of the above acids include acetic acid, hydrochloric acid, phosphoric acid, and sulfuric acid. These acids are usually used in an amount of 0.5 to 5 equivalents based on the compound (). 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 conditions such as reaction temperature and reaction time vary depending on the type of raw material compound, type of solvent, type and amount of acid, etc., but are usually 70 to 100°C for 20 minutes or more, preferably 30 minutes to more than 10 hours. . In this way, a compound represented by the general formula () is obtained. Compound () may have tautomers as shown in the following formula, but for convenience, these are simply expressed as compound (). The object compound () of the present invention can be formed into a salt with various acids such as hydrochloric acid, sulfuric acid, acetic acid, and oxalic acid by conventional methods. According to the method of the present invention, the number of steps is shorter than the conventional method for producing 2-iminothiazolidin-4-one derivatives, and the yield of the target product is also good. The 2-imino-thiazolidin-4-one derivative () obtained in this manner is isolated and purified by known separation and purification means such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution, chromatography, etc. can do. The object compound of the present invention, a 2-iminothiazolidin-4-one derivative (2-iminothiazolidin-4-one derivative), has the ability to inhibit the enzymatic activity of aldose reductase isolated from rat lenses or human placenta, and has the ability to inhibit water influx by the rat lens culture method. Thiazolidine-2,4-dione derivatives () that have suppressive ability and are expected to be useful for diabetic cataracts, neurological diseases, retinopathy, etc. in humans and mammals. (wherein R has the same meaning as above). In order to derive compound () from compound (), compound () may be subjected to acid hydrolysis, for example. This acid hydrolysis reaction is carried out by heating in a suitable solvent (such as ethanol) in the presence of water and a mineral acid. The amount of acid added is usually 0.1 to 10 mol, preferably 0.2 mol, per 1 mol of compound ().
~3 mol, and the amount of water added is usually in large excess per 1 mol of compound (). Heating time is usually several hours.
It's more than ten hours. Further, the raw material compound () can be obtained, for example, by the following reaction. (R in the formula has the same meaning as above) The reaction (1) above is a reduction reaction following acylation by the well-known Friedel Crafts reaction, and the reaction (2) is a reduction reaction following acylation by the well-known Friedel Crafts reaction. This is the reaction described in the literature (J.Org.Chew, vol. 33, p. 2565, 1963). The present invention will be explained in more detail by describing Examples, Reference Examples, and Experimental Examples below. Reference Example 1 (a) 8.53 g of powdered aluminum chloride was suspended in 100 ml of dichloromethane, 8.8 g of ethyl oxalyl chloride was added under ice cooling, and then 10.9 g of orthodiethoxybenzene was added.
20 ml of dichloromethane solution was added dropwise and stirred at room temperature for 1 hour. After pouring into ice-water and separating the organic layer, it is washed with water and dried (MgSO ₄ ). When the solvent was distilled off, 10.7 g (62.9%) of crystals of 3,4-diethoxyphenylglyoxylic acid ethyl ester were obtained.
is obtained. Recrystallize from hexane. Colorless needle crystals. m.p40−41°. (b) Dissolve 6.0 g of 3,4-diethoxyphenylglyoxylic acid ethyl ester in 70 ml of ethanol, add 0.67 g of sodium borohydride, and heat at 5°C.
Stir for 30 minutes. After adding 4 ml of acetic acid, the mixture was poured into 300 ml of saturated aqueous sodium bicarbonate solution and extracted with ether. After washing with water and drying (MgSO ₄ ), the ether is distilled off to obtain 6.2 g (100%) of an oily product of 2-(3,4-diethoxyphenyl)-2-hydroxyethyl acetate. IR ν ^Neat _nax cm ^-1 : 3480, 1735 NMR δppm CDCl ₃ medium: 1.18 (3H, t, J=
7), 1.40 (6H, t, J=7), 3.73 (1H, d,
J=6), 4.04 (4H, q, J=7), 4.15 (2H,
q, J=7), 5.0 (1H, d, J=6), 6.7~
7.3 (3H, m) Reference Example 2 In the same manner as in Reference Example 1, an oily product of 2-(2,4-diethoxyphenyl)-2-hydroxyethyl acetate was synthesized. IR ν ^Neat _nax cm ^-1 : 3480, 1730 NMR δppm CDCl ₃ medium: 1.17 (3H, t, J=
7), 1.36 (6H, t, J=7), 3.61 (1H, d,
J=6), 3.95 (4H, q, J=7), 4.13 (2H,
q, J=7), 5.12 (1H, d, J=6), 6.2~
6.5 (2H, m), 7.05 (1H, d, J = 9) Reference example 3 Dissolve 21.5 g of potassium hydroxide and 8.14 g of lithium chloride in 80 ml of water, and add 24.3 g of bromoform under ice cooling.
A solution of 22.7 g of -ethoxy-4-n-pentyloxybenzaldehyde in 80 ml of dioxane is successively added. After stirring at 5°C for 24 hours and then at 35°C for 24 hours, it is poured into 300 ml of water and extracted with ether. The aqueous layer was acidified with 6N-HCl and extracted with ether.
This ether layer is washed with water and then dried (MgSO ₄ ).
When the ether is distilled off, 2-(3-ethoxy-4-
18.5 g (68.3%) of crystals of n-bentyloxyphenyl)-2-hydroxyacetic acid are obtained. Recrystallize from ethyl acetate/hexane. Colorless needle crystals.
m.p90−91℃. Reference Example 4 The compounds shown in Table 1 were synthesized in the same manner as in Reference Example 2.

[Table] Example 1 2.68 g of 2-(3,4-diethoxyphenyl)-2-hydroxyethyl acetate was dissolved in 30 ml of ethylene glycol monomethyl ether, 3.3 ml of concentrated hydrochloric acid,
Add 1.52g of thiourea and stir at 80℃ for 2 hours. After cooling, add 200 ml of saturated aqueous sodium bicarbonate solution.
ml and collect the crystals that precipitate. Recrystallization from ethanol gives 1.55 g (55.4%) of colorless platelets of 5-(3,4-diethoxyphenyl)-2-imino-thiazolidin-4-one. mp222−
223℃. Example 2 2.8 g of 2-(3-ethoxy-4-n-pentyloxyphenyl)-2-hydroxyacetic acid was dissolved in 30 ml of ethylene glycol monomethyl ether, 3.3 ml of concentrated hydrochloric acid and 1.52 g of thiourea were added, and the mixture was heated at 90°C. Stir the time. After cooling, pour into 200 ml of a saturated aqueous solution of sodium hydrogen carbonate to remove the precipitated crystals. Recrystallization from ethanol yields 5-(3-ethoxy-4
-n-pentyloxyphenyl)-2-imino-
1.85 g of colorless needles of thiazolidin-4-one
(57.5%) is obtained. mp220−222℃ (decomposition). Example 3 Compound No. 1 was prepared in the same manner as in Examples 1 and 2 above.
~6 was synthesized.

[Table] Reference Example 5 3.2 g of 5-(3-ethoxy-4-n-pentyloxyphenyl)-2-imino-thiazolidin-4-one was dissolved in 30 ml of ethanol and 30 ml of 2N HCl and heated under reflux for 12 hours. do. After cooling, 100ml of water
Add and collect the crystals that precipitate. Recrystallization from 80% ethanol yields 5-(3-ethoxy-4-n
-pentyloxyphenyl)-thiazolidine-2,
2.8 g (86.7%) of colorless platelet crystals of 4-dione are obtained. mp104−105℃. Reference Example 6 2.82g of 2-(3-ethoxy-4-n-pentyloxyphenyl)-2-hydroxyacetic acid was dissolved in 30ml of ethylene glycol monomethyl ether,
Add 3.3 ml of concentrated hydrochloric acid and 1.52 g of thiourea and stir at 90°C for 4 hours. Then add 15ml of 2N hydrochloric acid and
Heat under reflux for an hour. After cooling, pour into water to collect the precipitated crystals, and recrystallize from 80% ethanol to obtain 2.55 g of colorless plate crystals of 5-(3-ethoxy-4-n-pentyloxyphenyl)thiazolidine-2,4-dione. (78.9%) is obtained. mp104−
105℃. Reference Example 7 The compounds shown in Table 3 were synthesized in the same manner as in Reference Example 5.

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

[Table] Experimental Example 2 H. Obazawa et al. Invest. 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 5 as the inhibition rate (%) of water inflow into the lens at a concentration of 10 ^-6 molar.

【table】

Claims (1)

[Claims] 1. General 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) Iminothiazolidin-4-one derivatives. 2 Under acidic conditions, general formula (In the formula, R is 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, and R ¹ is hydrogen or General formula characterized by reacting a compound represented by (representing a lower alkyl group) with thiourea A method for producing a 2-iminothiazolidin-4-one derivative represented by the formula (wherein R has the same meaning as above).