JPH0377875A - Thiazolidine-2,4-dione derivative and its production - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is 1-8C alkyl or 3-6C cycloalkyl; R<2> is H or 1-4C alkyl; R<3> is H or 1-2C alkyl; (n) is integer of 0-3) and non-toxic salt thereof. EXAMPLE:3-Carboxymethyl-5-(2,2-dimethylpropyl)thiazolidine-2,4-dione. USE:A therafeutic agent for complication of diabetes mellitus. PREPARATION:A compound expressed by formula II is dissolved in methanol, DMF, etc., and a metallic reducing agent such as sodium borohydride 1-10 times by equivalent based on the said compound is added thereto at -10 to 10 deg.C and the reaction mixture is further stirred at -10 to 10 deg.C for 0.5-1hr. Then an aqueous solution of hydrochloric acid is added thereto and the reaction product is extracted with ether, etc., to provide the compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to general formula (I): 1 (wherein R1 is an alkyl group having 1 to B carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms M% R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms JL, R3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer of θ to 3), or a thiazolidine-2,4-dione derivative represented by This invention relates to a method for producing the non-toxic salt.

[Prior Art] Conventionally, insulin and hypoglycemic agents have been widely used as antidiabetic agents, but since diabetes is a disease accompanied by not only abnormal glucose metabolism but also various complications, the above-mentioned drugs have not been used. alone is insufficient. For the purpose of treating diabetic complications, for example, JP-A-57-28073, JP-A-5γ-28O74, JP-A-57-28075, and JP-A-57-404H;
0=LH575, B1-53271, LH64-5
276 [1] and the specifications of Japanese Patent Application No. 883-27H1.

[Problem to be solved by the invention] Complications include neurological disorders, kidney disorders, and vascular complications, and eye diseases such as retinopathy and leukosarcosis are also serious diabetic complications and are the most common cause of blindness in the elderly. It is the cause. Microangiopathies are important for the onset of these diseases, and a certain type of sugar rate W abnormality is also associated with them (K, H.

Gabbay) %Advance in Metabolism
Disorders (Adv, Metah, Dlsord
, ) s 2 @ (2), p. 424 (1973)) , TS * Q sugar g disease state [te is abnormal accumulation of polyols such as sorbitol, which causes water retention due to increased osmotic pressure, causing am disorder. It becomes. Therefore, it is possible to prevent and treat the above diseases by inhibiting aldose reductase, which synthesizes polyols (
RφG Jujiru Mitsushi x (R,G.

Judzemitseh) et al., Niney and England φ
Journal of φ Medicine (New Hng, j,
Med, ), vol. 308, pp. 119-125 (1983
) and J.H.Kino
slta) et al., Metabolism (Metabollsv)
, u@(1), 4B2 = page 469 (1979))
.

In view of this situation, the present inventors have conducted intensive research and have discovered a thiazolidine-2,4-dione derivative that strongly inhibits aldose reductase and has low toxicity.

[Means for Solving the Problems] The present invention is based on the general formula (■): 1 (wherein, R1 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to G carbon atoms, and R2 is a hydrogen atom or C1-4 alkyl group, R3 is a hydrogen atom or C1
~2 argyl groups, and n represents an integer of 0 = 3)
A thiazolidine-2,4-dione derivative or a non-toxic salt thereof, represented by the general formula (I): (wherein, R' is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R'' is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
~2 alkyl groups, and n represents an integer of 0 to 3)
The general formula (
I): 1 elementary atom or alkyl group having 1 to 4 carbon atoms, R3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is 0 to 3
thiazolidine-2,4-dione derivative (representing an integer of ) or a non-toxic salt thereof.

[Example] The compound represented by the general formula (1) of the present invention can be synthesized as follows.

General formula (■): 1 (wherein R1 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, R2 is water (in the formula, R1 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer of 0 to 3); The indicated compound is dissolved in a polar protic solvent such as a lower alcohol such as methanol, ethanol, propatool, etc. or a polar aprotic solvent such as N,N-dimethylformamide or dimethyl sulfoxide, and heated at -20 to 30°C, preferably at -11°C.
1 to 20 times equivalent, preferably 1 to 10 times equivalent, of a metallic reducing agent such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride is added at 0 to 10°C, and the mixture is further heated for 0.5 to 5 hours. , preferably 0.5
-20 to 30°C, preferably -10 to 10°C for ~2 hours
After stirring with aqueous hydrochloric acid solution, extraction is performed with a solvent such as ether or ethyl acetate. After distilling off the solvent, the residue is mixed with ethanol, methanol, dichloromethane, dichloroethane, ethyl acetate, ethanol-water, methanol-water, dichloromethane-cyclohexane, The compound of general formula (1) is obtained by recrystallization from a polar or non-polar solvent such as a dichloroethane-cyclohexane mixture, or a mixed solvent thereof.

Alternatively, the compound of the general formula (1) is dissolved in a polar solvent such as methanol, ethanol, acetic anhydride, acetic acid, or a mixed solvent thereof, and preferably 1 to 10% by weight of palladium is added to the amount of the compound of the general formula (1). Add carbon 20-10
Palladium on carbon is removed from the reaction product obtained by applying hydrogen gas at 0°C, preferably 25 to 70°C, for 0.5 to 10 hours at normal pressure to 150 atm, and the solvent is distilled off to obtain a crude product. The product is recrystallized from polar or non-polar solvents such as ethanol, methanol, dichloromethane, dichloroethane, ethyl acetate, ethanol-water, methanol-water, dichloromethane-cyclohexane, dichloroethane-cyclohexane mixture, or a mixture thereof to obtain the general formula ( Obtain the compound of 1).

The compound represented by the general formula (1) used in the present invention can be synthesized as follows.

General formula 01゜[blank below] (In the formula, R' is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, 2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R3 is a hydrogen atom or carbon number 1
~2 alkyl group, and n represents an integer of θ~3)
Benzene, toluene, carbon tetrachloride,
Chloroform, N,N-dimethylformamide (hereinafter referred to as
(referred to as DMF), dioxane, a dioxane-water mixture, or a mixed solvent thereof, and the solution is dissolved in a polar or non-polar solvent such as DMF, dioxane, a dioxane-water mixture, or a mixed solvent thereof, and heated at -20 to 80°C, preferably from 1 to 10°C to 30°C.
5 times the molar amount, preferably 3 to 5 times the molar amount of N-bromosuccinimide is added several times, preferably 2 to 5 times, over a period of 0.5 to 5 hours, and the mixture is further added for 0.5 to 5 hours. , -20
After stirring at ~Bo°C, preferably -10~30°C,
Add to ice water and extract with a solvent such as ether or ethyl acetate. After distilling off the solvent, the residue can be extracted with ethanol, methanol, dichloromethane, dichloroethane, ethyl acetate, or ethanol.
polar, such as water, methanol-water, dichloromethane-cyclohexane, dichloroethane-cyclohexane mixture;
The compound represented by the general formula (1) can be obtained by recrystallizing from a nonpolar solvent or a mixed solvent thereof.

Furthermore, the compound represented by the soft formula (1) can also be synthesized as follows.

- Soft type (goods);

is an alkyl group having 1 to 4 carbon atoms, R3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, R4 is an alkyl group having 1 to 2 carbon atoms, and n is an integer of 0 to 3). is dissolved in a polar solvent such as ethanol, methanol, tetrahydrofuran, water, or a mixed solvent thereof, and an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, etc. in an equimolar amount to 5 times the molar amount, preferably an equimolar amount. Alternatively, add the aqueous solution for 0.5 to 24 hours, -
After stirring at 20 to 60°C, preferably -10 to 10°C, while cooling, add an aqueous solution of hydrochloric acid and extract with an inert organic solvent such as ether or ethyl acetate. After distilling off the solvent, the residue is diluted with ethanoyl, methanol, or dichloromethane. , dichloroethane, ethyl acetate, ethanol-water, methanol-water,
The compound represented by formula (1) can be obtained by recrystallization from a polar or non-polar solvent such as dichloromethane-cyclohexane, dichloroethane-cyclohexane mixture, or a mixed solvent thereof.

In addition, the compound represented by -Soft Formula is dissolved in a polar proton solvent such as ethanol, methanol, or acetic acid, and hydrochloric acid is added thereto for 0.5 to 24 hours at 5O-150°C, preferably g
After heating at O=100°C, the solvent is distilled off, and the residue is extracted with a solvent such as ether or ethyl acetate. After the solvent is distilled off, the residue is mixed with ethanol, methanol, dichloromethane, dichloroethane, ethyl acetate, ethanol-water, or The compound represented by the general formula (1) can be obtained by recrystallizing from a polar or non-polar solvent such as methanol-water, dichloromethane-cyclohexane, dichloroethane-cyclohexane mixture, or a mixed solvent thereof.

The compound represented by one soft formula used in the present invention can be synthesized, for example, as follows.

-Aya formula M: (wherein, R3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, R4 is an alkyl group having 1 to 2 carbon atoms, and n is 0 to
represents an integer of 3) and the general formula (material): (wherein, R' is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and R2 is a hydrogen atom or a carbon It can be obtained by reacting a carbonyl compound (representing an alkyl group of numbers 1 to 4) in a solvent in the presence of a basic catalyst.

The compound of general formula M was obtained by the method described in Japanese Patent Publication No. 47-44621.

To explain in more detail, the compound represented by ``--'' refers to the compound represented by ``-M'' or its salt.
, dissolved in a polar solvent such as acetic acid, ethanol, dimethyl sulfoxide, ethyl acetate, or a mixed solvent thereof, and added a basic catalyst such as sodium acetate or potassium carbonate to the compound represented by general formula M or a salt thereof at a concentration of 0.5%. Add ~8 times the molar amount, preferably 1 to 4 times the molar amount, and add 20 to 10 times the molar amount.
At 0°C, preferably from 20 to 70°C, equimole-10 times the molar amount represented by the general formula (capital), preferably equimolar-6
Double molar amount of carbonyl compound such as aldehyde or ketone is added dropwise to 20-150°C, preferably 80-110°C.
It is obtained by a method such as recrystallization after reacting at a temperature of 0.5 to 20 hours and removing the catalyst and solvent from the obtained reaction product.

The compound represented by the general formula (2) used in the present invention can be synthesized, for example, as follows.

A rhodanine derivative or a salt thereof represented by the soft formula @: (wherein R3 represents a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n represents an integer of 0 to 3) and the general formula (I): 1 ( In the formula, R' represents an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and R2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. It can be obtained by reacting in a solvent in the presence of a catalyst.

To explain in more detail, the compound represented by the soft formula 1 is a rhodanine derivative represented by the soft formula 1 or its salt D) 4F, a polar solvent such as acetic acid, ethanol, dimethyl sulfoxide, ethyl acetate, or a mixed solvent thereof. Dissolve, add a basic catalyst such as sodium acetate or potassium carbonate in a molar amount of 0.5 to 8 times, preferably 1 to 4 times the amount of the rhodanine derivative or its salt represented by formula (1), and then add 20 ~100°C, preferably 25-7
At 0°C, a carbonyl compound such as an aldehyde or ketone represented by the general formula is used in an amount equivalent to 10 times the molar amount of the rhodanine derivative or its salt represented by the general formula, preferably in an amount equivalent to 6 times the molar amount. Drop 20 to 150
C., preferably 40 to 100.degree. C. for 0.5 to 10 hours, and after the reaction is completed, the catalyst and solvent are removed from the reaction product, followed by recrystallization, column chromatography, or other methods.

The compound of general formula (1) thus obtained in the present invention is the following general formula (I): 1 (wherein R1 is an alkyl group having 1 to 8 carbon atoms or a cyclo thiazolidine-2, represented by an alkyl group, R'' is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer of 0 to 3; It is a 4-dione derivative or a non-toxic salt thereof.The thiazolidine-2,
Non-toxic salts of 4-dione derivatives include sodium salts,
Salts such as potassium salts, magnesium salts, calcium salts,
and salts of methylamine, morpholine, etc., which are pharmaceutically acceptable.

Note that the thiazolidine-2,4-dione derivative of the present invention includes optical isomers or mixtures thereof.

The compound represented by the general formula (I) of the present invention has a strong aldose reductase inhibitory activity and is an excellent drug for treating diabetic complications with extremely low toxicity.

Specific examples of the compounds represented by the general formula (1) of the present invention are shown in Table 1 along with their structures.

In the following explanation, when compounds in Table 1 are indicated, they are indicated by compound number. The present invention will be described in more detail below, but the present invention is not limited to such embodiments.

Production Example 1 Production of 3-carboxymethyl-5-(2,2-dimethylpropylidene)thiazolidine-2,4-dione 10 g (0,0524 mol) of rhodanine-3-acetic acid was added to DMFlo.
865 ml of acetic acid and sodium acetate (
(hereinafter referred to as AcONm) 11.6g (0,0524
Then, at 25° C., 6.8 g (0,0524 X L, S mol) of bivalaldehyde were added. This mixture was stirred at 80 to 115° C. for 5 hours and filtered, and then the solvent was distilled off from the filtrate, and dilute hydrochloric acid was added to the residue to obtain a precipitate. This was recrystallized from an ethanol-water mixture or dichloroethane and 3-carboxymethyl-5-(
2,2-dimethylpropylidene)rhodanine 11.3g
(Yield B3%) was obtained. Obtained 3-carboxymethyl-5-(2,2-dimethylpropylidene)rhodanine 3
g (0,011 (1 mol)) was dissolved in a mixed solvent of 21 ml of dioxane and 9 ml of water, and 27 g (0,0521 mol) of N-bromosuccinimide s was added in three portions every 30 minutes under water cooling. After stirring at room temperature for 30 minutes, it was added to ice water and extracted with ethyl acetate, and the crude product obtained from the ethyl acetate layer was recrystallized from a mixed solvent of dichloroethane-cyclohexane (1:3 (volume ratio, same hereinafter)). .05g
(yield 72.7%) of 3-carboxymethyl-5-(
2,2-dimethylpropylidene)thiazolidine-2,4
-I got Zeon.

Example 1 Production of 3-carboxymethyl-5-(2,2-dimethylpropyl)thiazolidine-2,4-dione (compound number 1) 3-carboxymethyl-5-(2,
2-dimethylpropylidene) thiazolidine-2,4-dione log (0,0411 mol) was dissolved in 50 ml of N,N-dimethylformamide, and under water cooling, 1.2 g (0,0329 mol) of sodium borohydride was dissolved in N, A solution of N-dimethylformamide (50 ml) was added, and the mixture was stirred for 1 hour under water cooling. It was then added to an aqueous hydrochloric acid solution and extracted with 21 chloride. The crude product obtained from the ether layer was dichloroethane-cyclohexane (i:3 (volume 7.27 g (yield 71.8%) of 3-carboxymethyl-5-(2,2-dimethylpropyl)thiazolidine-2#4-dione was obtained by recrystallization from a mixed solvent.

Next, the properties of the obtained compound are shown.

sp: 112-115°C IH-NMR (80MHz, CDC#3) δ: 0
．． 9B (9H, s, -OH5), 1.74 (IH, dd
, -C1i2C(CH3) 3), 2.43 (IH.

dd, -CoutC(CHs) 3), 4.19 (IH,
dd.

Engineering IC) b C (CHj) s>, 4.37 (2H, s
, NC12-), 9.78 (LH, s, -0H) IR (KBr) ν(as-”): 277G(
OR), 1757aX (C-0), 1724(C-0), 1697(C-
0) MS vthlz: 245(M), 18
9 (Standard) Example 2 Production of 3-carboxymethyl-5-(2-methylpropyl)thiazolidine-2,4-dione (Compound No. 2) 3-carboxymethyl-5-(2°) used in Example 1 2
-3-carboxymethyl-5-(2-methylpropylidene)thiazolidine-2 obtained in the same manner as in Production Example 1 from -dimethylpropylidene)thiazolidine-2,4-dione
, 4-dione was used in the same manner as in Example 1, except that 3-dione was used.
Carboxymethyl-5-(2-methylpropyl)thiazolidine-2,4-dione was obtained (yield 35.1%).

Next, the properties of the obtained compound are shown.

ap: 92-94°C “H-NMR (80MHz, CDC#3) δ: 0
．． 95(,3H,d,-CPIs>,1.03((11
, d, -OH5), 1.50-2.42 (3H.

ton CHCToCH (Ch) 2), 4.42 (lH,
dd.

C3iC)b C11(CHs)2)
, 4.39 (211,S, NCH2-)
, 9.98 (lH, s, -0H) IR (KBy) ν (Ql-1):
27 a 0 (OR), 1750 Kasumi ax (C-0), 1712 (C-0), 1697 (C
-0) MS mlz: 231 (M), 174 (
Standard) Example 3 Production of 3-carboxymethyl-5-(3-methylbutyl)thiazolidine-2,4-dione (compound number 3) 3-carboxymethyl-5-(2゜2-dimethyl used in Example 1) 3-carboxymethyl-5 obtained from Propylidene) thiazolidine-2,4-dione in the same manner as in Production Example 1
-(3-Methylbutylidene)thiazolidine-2, 3-carboxymethyl-5-(3-methylbutyl)thiazolidine-2
,4-dione was obtained (yield 37.1%).

Next, the properties of the obtained compound are shown.

mp: 82-69°C ”H-NNR (80MHz, CDC#s) δ: 0
．． 92 (6H, d.

-OH5), 1.11-2.47 (5H, Sono.

CHC)iz C1jzCll(CH3) 2), 4
．． 30 (1■, dd.

CICHz CH2CH(Ch) 2), 4.41(
2H,s.

NCHr), 11.5 (IH,s, -011)IR
(KBr) ν(cs-1): 2760(OH)
, 1753ax (C-0) , 1718 (C-O) , 189B (C-
0) MS mlz: 245 (M”),
227 (M''-18), 175 (standard) Implementation N4 3-carboxymethyl-5-(1-methylethyl)thiazolidine-2,4-dione (compound number 4) used in Example 1 Methyl-5-(2゜2
-dimethylpropylidene)thiazolidine-2,4-dione in the same manner as in Production Example 1, 3-carboxymethyl-5-(l-methylethylidene)thiazolidine-2,
3-carboxymethyl-5-(l-methylethyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 except that 4-dione was used (yield: 13.9%).

Next, the properties of the obtained compound are shown.

mp: 105-111°C lH-NNR (80MHz, CDC#5) 68 0.
99 (3H, d, -CILs), 1.08 (3u, d,
-OH5), 2.30-2.94 (IH.

m, -Cg (CHI)2), 4.32-4.
38 (311, m.

;NC)12-and>CICI(CHs)2),
7.93 (LH, s.

-OH) IR (KBr) p (cx-1): 2780
(OH), 17551a! (C-0), 1740(C-0), 167G(
C-0) MSmHz: 217 (M”), 12B
(Standard) Example 5 Production of 3-carboxymethyl-5-(1-methylpropyl)thiazolidine-2,todione (compound number 5) 3-carboxymethyl-5-(2゜2) used in Example 1
-dimethylpropylidene)thiazolidine-2, 3-carboxymethyl-5-(1-methylpropylidene)thiazolidine-2, obtained in the same manner as in Production Example 1,
3-carboxymethyl-5-(1-methylpropyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 except that the dione was used (yield: 6368%).

Next, the properties of the obtained compound are shown.

sp: H~83.5℃'H-NMR (60MIIz, CDCJ s) δ:
1.01 (3H, t.

-CII2CIs), 1.25 to 1.67
(211, m.

-CIi2CHs), 1.02(3H,d,nC
HCl1g), 2.02-2.55 (IH, m
,;CIIC)b), 4.29-4.45 (8H, m.

s, -0H) IR(KBr) ν (ell-'):
287G (011), 1742W+aX (C-0), 187g (C-0) MS l/Z:
231 (M), 128 (standard) Example δ Production of 3-carboxymethyl-5-(1-ethylbutyl)thiazolidine-284-dione (compound number δ) 3-carboxymethyl-5-( 2゜2
-dimethylpropylidene)thiazolidine-2,4-dione in the same manner as in Production Example 1, 3-carboxymethyl-5-(l-ethylbutylidene)thiazolidine-2,
3-carboxymethyl-5-(1-ethylbutyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 except that 4-dione was used (yield: 51.5%).

Next, the properties of the obtained compound are shown.

■p: 68-72℃ ”H-NMR (60MHz, CDCj s) δ:
0.97 (8H, m, -OH5), 4.28 (2H, s
, '/NCHz -), 4.42 (l11.m.

IR (KBr) v (cm-'): 2
77G(OH), 1145■ax (C-0), 1680(C-0)MS mlz
: 259 (M), 175 (standard) Production Example 2 3-(l-carboxyethyl)-5-(hebutylidene)
Production of thiazolidine-2,4-dione 3-(1-ethoxycarbonylethyl)thiazolidine-
5 g (0,023 mol) of 2,4-dione in DIP 5
Acetic acid 4.14g dissolved in 0ml, Ac0Na 5.6
7 g and n-heptylaldehyde 13.1 g (0,1
15 mol) was added and the mixture was stirred at 90°C for 3 hours. The reaction solution was added to ice water and extracted with ether, and the crude product obtained from the ether layer was applied to a silica gel column (Kleselgel 607734: trade name,
Merck & Co., 3.5 (inner diameter) x 19cst, solvent: hexane), hexane, hexane:toluene (3:1
) mixed solvent, hexane:toluene (1:1) mixed solvent was eluted in this order, and the hexane:toluene (1:1) eluted fraction was concentrated under reduced pressure to give 3-(l-ethoxycarbonylethyl)- as an oil. 5-(hebutylidene)thiazolidine-
5.18 g (yield 71.7%) of 2,4-dione was obtained. The obtained 3-(l-ethoxycarbonylethyl)-5
-(heptylidene)thiazolidine-2,4-sion4.
1 g (0,0131 mol) was dissolved in 40 ml of acetic acid, 20 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 90 to 100°C for 3 hours.

The reaction solution was concentrated under reduced pressure, extracted with ether, and the crude product obtained from the ether layer was recrystallized from a dichloroethane-cyclohexane (1:5) mixed solvent to give 2.69 g (
3-(1-carboxyethyl)-5 (yield 72.0%)
-(heptylidene)thiazolidine 2,4-dionedione was obtained.

Example 7 Production of 3-(1-carboxyethyl)-=5-(heptyl)thiazolidine-2,4-dione (Compound No. 7) 3-carboxymethyl-5-(2゜2) used in Example 1
-dimethylpropylidene)thiazolidine-2,4-dione obtained in Production Example 2 3-(1-carboxyethyl)-5
3-(1-carboxyethyl)-5-(heptyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 except that -(hebutylidene)thiazolidine-2,4-dione was used (yield: 98 .8%).

Next, the properties of the obtained compound are shown.

mp: 61-65°C 'H-NMR (BOMHz, CDCJl s') 68
0.89 (311,1:.

-CH2Cl), 1.32 (1011, bs, -CHr
), 1.58 (3Ld, '0:CHC Street), 2゜0
5 (21', m.

-CH2-), 4.22 (IH, dd,::CHCH
r), 4.95 (IH, q, N C7 (CHs), 8.9
4(11,hs,-0H)IR(KBF) ν(cs-
1): 2780 (Ou), 1750aX (eo), 171B (C-0), 1689 (C=
0) MSmlz: 287 (M”), 115 (standard) Example 8 Production implementation of 3-(1-carboxyethyl)-to(2,2-dimethylpropyl)thiazolidine-2,4-dione (compound number 8) 3-carboxymethyl-5-(2,2
-dimethylpropylidene)thiazolidine-2,4-dione was obtained similarly to Preparation Example 2: 1-(1-carboxyethyl)-5-(2,2-dimethylpropylidene)
Example 1 except that thiazolidine-2,4-dione was used
Similarly, 3-(l-carboxyethyl)=5-(2
, 2-dimethylpropyl)thiazolidine-2,4-dione was obtained (yield 75.6%).

Next, the properties of the obtained compound are shown.

198 140~142℃ 'H-NMI? (BOMHz, CD (J s”) δ:
1.01 (9H, s.

-C(CH3)s>,1.61(3H,d,';C
HCH3), 1.73 (111, dd, nCHCHHz
C(CHs) 3), 2.44(1!(, dd, :;
CIICjb C (CII3) 3), 4.15 (11
! ,dd,nC! 1CHZ C(CH3) 3), 5.
01 (IH, q, C3CHa), 10.52 (
IH, a, -011) IR(MBr) p (
cs-'): 2720 (OH), 1760ax (C-0), 17'17 (C-0), 168B (C
-0) MS */z: 259 (M ), 189 (
Standard) Production Example 3 3-(3-carboxypropyl)-5-(butylidene)
Thiazolidine-2,4-dione 9J 1FJ3-(3
-ethoxycarbonylprobyl) thiazo'J Syn-2
,4-dione 5 g (0,0215 mol) ODNF1
50 ml of acetic acid, 5.3 g of AeONa and 7.8 g of n-butyraldehyde (0,108 mol) dissolved in 5 ml of
was added, and the mixture was stirred at 80-90"C for 6 hours. The reaction solution was added to ice water, extracted with ether, and the crude product obtained from the ether layer was transferred to a silica gel column (Kiesell 60γ7348 trade name, Merck, 3.5 (inner diameter) x 19cs, solvent: hexane)
In addition, hexane, a hexane:toluene (3:1) mixed solvent, and a hexane:toluene (i:t) mixed solvent were eluted in this order, and the hexane:toluene (1:1) eluted fraction was concentrated under reduced pressure to form an oil. 3=(8-ethoxycarbonylprobyl)-5-(butylidene)thiazolidine-2,
4.5 g (yield: 3.5%) of 4-dione was obtained. The obtained 3-(3-ethyloxycarbonylpropyl l-5-(
Butylidene) Thi°γSylydine-2,4-dione 4°5g
(0,0158 mol) was dissolved in 45 ml of acetic acid,
22.5 ml was added and stirred at 90-100°C for 5 hours. The reaction solution was concentrated under reduced pressure and extracted with ether.
The crude product obtained from the ether layer was recrystallized from a dichloroequune-cyclohexane (1:5) mixed solvent to give 3゜j, 3.
g (yield 77.2%) of 3-(3-carboxypropyl)-5-(butylidene)thiazolidine-2,4-dione was obtained.

Example 9 Production of 3-(3-carboxypropyl)=5-(butyl)thiazolidine-2,4-dione (Compound No. 9) 3-carboxymethyl-5-(2゜2) used in Example 1
-dimethylpropylidene)thiazolidine-2,4-dione obtained in Production Example 3 3-(3-carboxypropyl)-
3-(3-carboxypropyl)-5-(butyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 except that 5-(butylidene)thiazolidine-2,4-dione was used (yield 38.3%).

Next, the properties of the obtained compound are shown.

sp: 52~B2℃"H-NMR (60MHz, CDCf3) δ: 0
．． 93(lIH,t,-CD5), 1.18 to 1.6
1(4)1. m, -Cur), 1.78 ~ 2
．． 88 (8H2l, -Cal2-), a, 71 (21
1,t.

)NCH2−), 4.21<IH, dd, ′/cll
(CI2) sCHs ), 9.83 (LH,s, -0
R) IR(KBr) v (Cal-1): 28
60 (OH), 1742 Otori aX (C-0), 1893 (C-0) MS @/z: 259 (M), 175 (standard)
Example 10 Production of 3-(3-carboxypropyl)-5-(cyclohexylmethyl)thiazolidine-2,4-dione (Compound No. 10) 3-carboxymethyl-5-(2゜2) used in Example 1
-dimethylpropylidene)thiazolidine-2,4-dione was changed to 3-(8-carboxypropyl)-5-(cyclohexylmethylene)thiazolidine-2,4-dione obtained in the same manner as in Production Example 3. 3-(3-carboxypropyl)-5-(cyclohexylmethyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 (yield: 81.3%).

Next, the properties of the obtained compound are shown.

Table p: 96.5-105°C "H-NMR (80MHz, CDCf3) δ: 0.9
8-2.58 (17H, m.

': NCjjr), 4.25(11(, dd, nCHC
H2() ), 9.06 (IH, bs, -0H) IR(KBr) v (C1l-1):
8250 (OH), 1737■ax (C-0), 166G (C-0) MS s/z: 299 (M also, 2g1 (M -18)
, 1g11 (Standard) Example 11 3-(3-carboxypropyl)-5-(2-methylpropyl)thiazolidine-2,4-dione (Compound No. 1
1) 3-carboxymethylate (2゜2-
Dimethylpropylidene)thiazolidine-2,4-dione was replaced with a-(S-carboxypropyl)-5-(2-methylpropylidene)thiazolidine-2,4-dione obtained in the same manner as in Production Example 3. Otherwise, 3-(3-carboxypropyl)-5-(2-methylpropyl)thiazolidine-2°4-dione was obtained in the same manner as in Example 1 (yield: 72.0%).

Next, the properties of the obtained compound are shown.

mps88-94℃ IH-NMR (60MHz, CDCf 1) δ: 0
．． 92 (IH, d, -CD5), 1.01 (3H, d,
-CIls), 1.42 to 2.57 (7H, s+, -C
H2-and -C and (CHs) 2), 8.89(
2H,t,,NCIh-), 4.21(LH,dd.

>CdanCH2C1(CHI)2), 9.85
(IH, s+rOH>IR(KBr) ν(am-1)
: 3240(OH), 1738maroa! (C-0), 16l64-1-(C-0) m+/z
: 259 (M), 241 (N-III),
188 (Standard) Production Example 4 3-(1-carboxypropyl)-5-(butylidene)
Preparation of thiazolidine-2,4-dione $-(1-ethoxycarbonylprobyl)thiazolidine-2,4-dione (5 g < 0.0215 mol) by DM
Dissolved in P15ml, acetic acid 50ml, Ac0Na 5.3
g and n-butyraldehyde (7.8 g<0.108 mol) were added and the mixture was stirred at 80-90<0>C for 7 hours. The reaction solution was added to ice water and extracted with ether, and the crude product obtained from the ether layer was applied to a silica gel column (Kieselgel 807734: trade name, manufactured by Merck & Co., Ltd., 3.5 (inner diameter) x 19 as, solvent: hexane). In addition to hexane, hexane:toluene (3:l
) Mixed solvent, hexane: toluene (1: L) was eluted in the order of mixed solvent, and the hexane: toluene (1: L) eluted fraction was concentrated under reduced pressure to obtain 3-(1-ethoxycarbonylprobyl) as an oil. -5-(butylidene)thiazolidine-2
,4-dione 4.5g (yield 73.5%) was obtained. The obtained 3-(l-ethoxycarbonylprobyl)-5-(
butylidene) thiazolidine-2,4-dione 3.5 g (
0,0123 mol) Vinegar* 35ml Dissolved L, 1 Tbsp concentrated hydrochloric acid. 5 ml was added and stirred at go-so°C for 3 hours.

Reaction #1 solution was concentrated under reduced pressure and extracted with ether.
The crude product obtained from the ether layer was recrystallized from a dichloroethane-cyclohexane (1:5) mixed heating medium to obtain 2.9 g (yield 91.9%) of 3-(1-carboxypropyl)-to(butylidene)thiazolidine. 2°4-dione was obtained.

Example 12 Production of 3-(1-carboxypropyl)-5-(butyl)thiazolidine-2,4-dione (Compound No. 12) 3-carboxymethyl-5-(2,2
-Dimethylpropylidene)thiazolidine-2#Production of 4-dione 3-(1-carboxypropyl)- obtained with N4
3-(l-carboxypropyl)-5-(butyl)thiazolidine-2,4-dione was obtained in the same manner as in Example 1 except that 5-(butylidene)thiazolidine-2,4-dione was used (yield 66.1%).

Next, the properties of the obtained compound are shown.

sp Near 3~76℃'H-N)4R(60MHz, CD(Js)δ:
0.77'-1,00 (611, m, -CH3),
1.48 (41N, m, -CHr), 2.18 (
4H,m,-C)b-), 4.27(111,dd.

:>CJI(C114)sC)b), 4.75
(111, dd.

:>CuCl2CHs), 6.64(IH, bs,
=OB)IR(KBr) ν (esa-1)
: 2640 (OH), 1745 Otori aX (C-0), 1714 (C-0), 1B87 (
C-0)) Is go/z: 259 (N)
, 241 (14-18), 186 (standard) Example 13 Production example of 3-(1-carboxypropyl)-5-(2,2-dimethylpropyl)thiazolidine-2,4-dione (compound number 13) 3-carboxymethyl-5-(2゜2
a-(i-carboxypropyl)-5-(2,2-dimethylpropylidene) obtained from thiazolidine-2,4-dione in the same manner as in Production Example 4
Example 1 except that thiazolidine-2,4-dione was used
3-(1-carboxypropyl)-5-(
2,2-dimethylpropyl)thiazolidine-2,4-dione was obtained (yield: 3z, 9%). Next, the properties of the obtained compound are shown.

mp; 93-95.5°C 'H-NMR (60MHz, CDCl s) δ: 0
．． 93(811,1°-CHzCJis), 1.00(
9H,s, -C(C1ls)s), 1.50-2.5
8 (4B, m, -CH2-), 4゜15 (11, dd
, '>ClIC82C(CHs)s), 4.79
(ill, dd.

NCH::), 9.79 (ltl, s, -0 ■) IR
(KBr) v (agi-1) -: 2620
(OH), 17501x (C-0), 1710(C-0), 161B5(C
-0) MS @/Z H273(N”), 255(
M-tg), 18B (standard) Next, the pharmacological action of the compound represented by the general formula (I) of the present invention will be explained in detail.

(Aldose reductase inhibitory effect) The compound represented by the general formula (1) of the present invention or its non-toxic salt has an aldose reductase inhibitory activity, which can lead to neuropathy caused by abnormal accumulation of polyols and diabetic retinopathy. and useful in the prevention or treatment of cataracts. For example, when the inhibitory activity against aldose reductase obtained from rat lens was investigated in a laboratory-level demonstration, 50% inhibition was observed at 10-7 to 104 M as shown in Table 2.

Experimental method The method of Hyman et al.
Kinoshita, Journal φ of C Biological Chemistry (J, Blol, Chem,), vol. 240, 87T.
-882 pages (1965)).

Male Wistar rats (8 to 12 weeks old) were sacrificed by decapitation, and the lens was removed. IN phosphate buffer (pne,s
, IsM mercaptoethanol and 1 mM nicotinamide adenine dinucleotide phosphate (hereinafter referred to as NADP)). Then io, 0OO
The mixture was centrifuged at Xg for 15 minutes, and the supernatant was prepared into 3 ml of crude enzyme solution.

Separately, NADPII (reduced NADP) at 0°25s
) and 0 containing 1°5d DL-glyceraldehyde
．． Prepare IN phosphate buffer (p+[I6.2), add 15 gg of various concentration solutions of the compound represented by general formula (1) to this solution, and then add 25 μg of the crude enzyme solution prepared in advance. The reaction started. The decrease in absorbance at 340n was measured using a new model 150-20 double beam spectrophotometer manufactured by Hitachi. 50 of those results
It is expressed as % inhibition level (hereinafter referred to as IC5D (M)) and is shown in Table 2.

Table 2 shows that the thiazolidine-
2,4-dione derivatives have proven to be extremely low toxicity drugs.

Experimental method: 1 group of 4 male ddY mice (5 withdrawals): 10%
Test compound (0.75 g) suspended in gum arabic aqueous solution
%1.5g, 3g/kg body weight) was forcibly administered orally, and death was observed for 2 weeks.

【Effect of the invention〕

The thiazolidine-2,4-dione derivatives or non-toxic salts thereof according to the present invention strongly inhibit aldose reductase and have very low toxicity, making them useful as therapeutic agents for diabetic complications.

(acute toxicity)

Claims (1)

[Claims] 1 General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, R^2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, R^3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer of 0 to 3. Thiazolidine-2,4 - Dione derivatives or non-toxic salts thereof. 2 General formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and R^2 is a hydrogen atom. or an alkyl group having 1 to 4 carbon atoms, R^3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer of 0 to 3. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 is an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, and R^2 is a hydrogen atom or carbon A thiazolidine-2,4-dione derivative represented by an alkyl group of numbers 1 to 4, R^3 is a hydrogen atom or an alkyl group having 1 to 2 carbon atoms, and n is an integer of 0 to 3, or its non-toxic Salt manufacturing method.