Thiazolidine derivatives and production thereof

A new thiazolidine derivative of the formula: ##STR1## wherein n stands for an integer of 3 to 6 and salts thereof show strong aldose reductase inhibition and are useful for prophylaxis or therapy of diabetic cataracts and diabetic neuropathy in mammals.

This invention relates to novel thiazolidine derivatives useful as 
prophylactic and therapeutic agents against diabetic complications such as 
diabetic cataracts or diabetic neuropathy, and the production thereof. 
More specifically, this invention relates to thiazolidine derivatives of 
the formula: 
##STR2## 
wherein n denotes an integer of 3 to 6, preferably 3,4 or 5, and a method 
for production of the compound (I) which comprises hydrolyzing a compound 
of the formula: 
##STR3## 
wherein n has the same meaning as above. 
The compounds (I) are acid substances and are capable of forming basic 
salts, e.g. sodium salts, potassium salts, calcium salts or ammonium 
salts. 
Thiazolidine derivatives (I) or salts thereof of this invention are strong 
aldose reductase inhibitors and remarkably inhibit the accumulation of 
sorbitol in the lens or nerve fiber in diabetic rats induced by 
streptozotosin, and they are used for prophylaxis or therapy of diabetic 
cataracts, diabetic neuropathy, etc. in mammals, for instance, mouse, rat, 
dog and human being. 
Further, the compounds (I) or their salts are less toxic, the oral 
LD.sub.50 for, for example, 
5-(5,6,7,8-tetrahydro-2-naphthyl)thiazolidine-2,4-dione in mice being no 
less than 100 mg., and they can be safely administered for a long period 
of time. When the compounds (I) or their salts are administered for 
ophthalmic use, they do not cause irritation and can inhibit accumulation 
of sorbitol in the lens and thus can serve in ophthalmic use in treating 
cataracts. The compounds (I) or their salts may for example be 
administered orally in such dosage forms as tablets, capsules, powders and 
granules, parenterally in the form of injections and pellets, or locally 
as ophthalmic solutions. The dosage is usually 50 mg to 1000 mg daily per 
adult human, when given orally, in 1 to 4 divided doses a day. For 
ophthalmic use, 0.001 to 1% ophthalmic solution is desirably administered 
to the eye at the frequency of 3 to 5 times daily, one to a few drops a 
time. 
The thiazolidine derivatives (I) of this invention can be produced by the 
following manner: 
##STR4## 
In the formulae, n has the same meaning as above. 
The hydrolysis is conducted preferably in the presence of an acid in a 
suitable solvent. 
As the suitable solvents, there may for example be mentioned alkanols, e.g. 
methanol, ethanol, propanol or methoxyethanol, ethers, e.g. 
tetrahydrofuran or dioxane, acetone, dimethylformamide, dimethyl sulfoxide 
or sulfolane. As the acid, there may preferably be mentioned mineral 
acids, e.g. sulfuric acid or hydrochloric acid. The amount of the acid to 
be added is usually within the range of from 1 mole to 50 moles, 
preferably from 2 to 30 moles relative to the compound (II) employed. The 
amount of water to be added is usually in large excess. The hydrolysis 
reaction is preferably conducted at an elevated temperature, e.g. 
30.degree. to 150.degree. C. 
The thus-obtained object compound (I) can be isolated and purified by a 
conventional means such as concentration, solvent-extraction, 
recrystallization, chromatography, or the like. The compound (I) which is 
an acid compound can be converted to a salt with, for example, alkali 
metal, alkaline earth metals or organic bases such as sodium, potassium, 
calcium, amines, and the like. 
The compound (II) can be synthesized, for example, by the following manner. 
##STR5## 
In the formulae, R stands for hydrogen, alkyl or aralkyl, X stands for a 
group to be eliminated, and n has the same meaning as above. 
As the alkyl group represented by R, preferable are those having 1-4 carbon 
atoms, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 
sec.-butyl or t-butyl. As the aralkyl group represented by R, there may 
preferably be mentioned a phenyl lower alkyl, e.g. benzyl or phenylethyl. 
The group to be eliminated, represented by X, is exemplified by halogen, 
e.g. chlorine or bromine, or a sulfonyloxy group, e.g. mesyloxy, tosyloxy 
or benzenesulfonyloxy. n denotes an integer of 3-6, and especially 
preferable are 3, 4 and 5. 
Glyoxylic acid derivatives of the formula (IV) and their reduction products 
(V) can be synthesized by the method described in Austrian Patent No. 
344153 (1978) (C.A. 89, P179741e (1978)) or a method analogous thereto. 
The compound (III) can be obtained by halogenation or sulfonylation of the 
compound (V). 
The halogenation is carried out by reacting a halogenating agent such as 
phosphorus tribromide, thionyl chloride and phosphorus oxychloride with 
the compound (V) in the absence or presence of a suitable solvent such as 
dichloromethane and chloroform. The reaction is preferably conducted at an 
elevated temperature, for example, 20.degree. to 100.degree. C. 
Sulfonylation of a compound (V) can be conducted by reacting the compound 
(V) with sulfonylating agent, e.g. mesyl chloride, tosyl chloride or 
benzenesulfonyl chloride at 0.degree.-60.degree. C. in a suitable solvent, 
e.g. benzene, ethyl acetate, dichloromethane or chloroform in the presence 
of a base, e.g. pyridine or triethylamine. 
The compound (III) thus produced is allowed to react with thiourea to 
synthesize a compound (II), which is then subjected to hydrolysis to 
obtain the object compound (I). The reaction between a compound (III) and 
thiourea is usually conducted in a solvent. 
The solvents are exemplified by alkanols, e.g. methanol, ethanol, propanol 
or methoxyethanol, ethers, e.g. tetrahydrofuran or dioxane, acetone, 
dimethylformamide, dimethylsulfoxide or sulfolane. The amount of thiourea 
to be used is preferably 1-2 moles, relative to 1 mole of the compound 
(III) employed. The reaction temperature usually ranges from 50.degree. C. 
to 150.degree. C., preferably 60.degree. to 130.degree. C. 
The thus-produced compound (II) can be isolated in an optional purity by 
means of a conventional separation and purification method, for example, 
concentration, solvent-extraction, recrystallization or chromatography, or 
can be coverted to the compound (I) by subjecting the reaction mixture to 
the subsequent hydrolysis directly without isolating the compound (II).

The following reference examples, working examples and experimental data 
are given to further illustrate this invention. 
REFERENCE EXAMPLE 1 
Anhydrous aluminum chloride (9.1 g) was suspended in dichloromethane (80 
ml). To the suspension was added dropwise, while stirring under cooling, 
ethoxalyl chloride (9.2 g), followed by addition thereof of 
6,7,8,9-tetrahydro-5H-benzocycloheptadiene (9.0 g) dissolved in 
dichloromethane (10 ml). The mixture was stirred for 30 minutes under 
ice-cooling, and poured into ice-water. Then the resulting organic layer 
was separated, washed with water and dried over anhydrous magnesium 
sulfate, then the solvent was evaporated off. The residue was subjected to 
distillation under reduced pressure to leave 10.7 g(70.4%) of ethyl 
6,7,8,9-tetrahydro-5H-benzocycloheptadien-2-yl-glyoxylate as an oily 
substance, b.p. 153.degree.-155.degree. C./0.2 mmHg. 
IR (Neat); 1735, 1685 cm.sup.-1. 
NMR (CDCl.sub.3).delta.: 1.39(3H,t,J=7), 1.75(6H,broad s), 2.65-2.95(4H,m), 
4.40(2H,q,J=7), 7.10(1H,d,J=9), 7.6(2H,m). 
REFERENCE EXAMPLE 2 
By the same procedure as that in Reference Example 1, except for employing 
tetralin as the starting material, ethyl 
5,6,7,8-tetrahydro-2-naphthylglyoxylate, b.p. 148.degree.-153.degree. 
C./0.3 mmHg. was prepared. The yield was 70.5%. 
IR (Neat): 1735, 1680 cm.sup.-1. 
NMR(CDCl.sub.3).delta.: 1.38(2H,t,J=7), 1.6-2.0(4H,m), 2.75(4H,broad s), 
4.40(2H,q,J=7), 7.10(1H,d,J=9), 7.6(2H,m). 
REFERENCE EXAMPLE 3 
By the same procedure as that in Reference Example 1, except for employing 
indane as the starting material, ethyl 5-indanylglyoxylate was prepared. 
The yield was 74.8%. 
IR (Neat): 1735, 1680 cm.sup.-1. 
NMR (CDCl.sub.3).delta.: 1.40(3H,t,J=7), 1.8-2.4(2H,m), 2.93(4H,t,J=7), 
4.40(2H,q,J=7), 7.18(1H,d,J=9), 7.5-7.7(2H,m). 
REFERENCE EXAMPLE 4 
To ethyl 6,7,8,9-tetrahydro-5H-cycloheptadien-2-yl glyoxylate (10.3 g) 
dissolved in ethanol (50 ml) was added sodium borohydride (0.95 g) under 
ice-cooling, and the mixture was then stirred for 30 minutes. To the 
mixture was added dropwise acetic acid (4 ml), and the whole mixture was 
poured into water, followed by extraction with ethyl ether. The ether 
layer was washed with water, saturated aqueous solution of sodium 
bicarbonate and water, in that order, then dried over anhydrous magnesium 
sulfate. Removal of ethylether by evaporation left ethyl 
2-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocycloheptadien-2-yl)acetate as an 
oily product. The yield was 10.48 (100%). 
IR (Neat): 3470, 1730 cm.sup.-1. 
NMR (CDCl.sub.3):.delta. 1.20(3H,t,J=7), 1.7(6H,broad s), 2.6-2.9(4H,m), 
3.57(1H,d,J=6, D.sub.2 O disappear), 4.18(2H,q,J=7), 5.00(1H,d,J=6, 
D.sub.2 O changed to s), 7.00(3H, broad s). 
REFERENCE EXAMPLE 5 
Ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate was subjected to reduction in 
the same manner as in Reference Example 4 to prepare ethyl 
2-hydroxy-2-(5,6,7,8-tetrahydro-2-naphthyl)acetate as an oily product. The 
yield was 92.8%. 
IR (Neat): 3480, 1735 cm.sup.-1. 
NMR (CDCl.sub.3).delta.: 1.18(3H,t,J=7), 1.6-2.0(4H,m), 2.75(4H,broad s), 
3.60(1H,broad s, D.sub.2 O disappear), 4.18(2H,q,J=7), 5.03(1H,s), 
6.8-7.2(3H,m). 
REFERENCE EXAMPLE 6 
Ethyl 5-indanylglyoxylate was subjected to reduction in the same manner as 
in Reference Example 4 to prepare ethyl 2-hydroxy-2-(5-indanyl)acetate as 
an oily product. The yield was 92.9%. 
IR (Neat): 3480, 1735 cm.sup.-1. 
NMR(CDCl.sub.3).delta.: 1.17(3H,t,J=7), 1.8-2.4(2H,m), 2.83(4H,t,J=7), 
3.80(1H,d,J=6, D.sub.2 O disappear), 4.13(2H,q,J=7), 5.05(1H,d,J=6, 
D.sub.2 O change to s), 7.1-7.4(3H,m). 
REFERENCE EXAMPLE 7 
A mixture of ethyl 
2-hydroxy-2-(6,7,8,9-tetrahydro-(5H-benzocycloheptadien-2-yl)acetate (10.0 
g) and thionyl chloride (20 ml) was subjected to reflux for one hour. 
Excess thionyl chloride was evaporated off under reduced pressure. The 
remaining oily substance was further subjected to distillation under 
reduced pressure to leave ethyl 
2-chloro-2-(6,7,8,9-tetrahydro-5H-benzocycloheptadien-2-yl) acetate as an 
oily product, b.p. 145.degree.-148.degree. C./0.2 mmHg. The yield was 9.5 
g (88.8%). 
IR (Neat): 1750 cm.sup.-1. 
NMR(CDCl.sub.3).delta.: 1.23(3H,t,J=7), 1.7(6H,broad s), 2.65-2.95(4H,m), 
4.17(2H,q,J=7), 5.22(1H,s), 7.0-7.3(3H,m). 
REFERENCE EXAMPLE 8 
Ethyl 2-hydroxy-2-(5,6,7,8-tetrahydro-2-naphthyl)acetate was processed in 
the same manner as in Reference Example 7 to prepare ethyl 
2-chloro-2-(5,6,7,8-tetrahydro-2-naphthyl)acetate as an oily product, b.p. 
139.degree.-142.degree. C./0.3 mmHg. The yield was 94.5%. 
IR (Neat): 1750 cm.sup.-1. 
NMR(CDCl.sub.3).delta.: 1.23(3H,t,J=7), 1.6-2.0(4H,m), 2.75(4H,broad s), 
4.18(2H,q,J=7), 5.25(1H,s), 6.9-7.4(3H,m). 
REFERENCE EXAMPLE 9 
Ethyl 2-hydroxy-2-(5-indanyl)acetate was processed in a manner similar to 
that of Reference Example 7 to give ethyl 2-chloro-2-(5-indanyl)acetate as 
an oily substance, b.p. 128.degree.-132.degree. C./0.3 mmHg. The yield was 
92.1%. 
IR (Neat): 1750 cm.sup.-1. 
NMR(CDCl.sub.3).delta.: 1.20(3H,t,J=7), 1.8-2.2(2H,m), 2.83(4H,t,J=7), 
4.15(2H,q,J=7), 5.25(1H,s), 7.0-7.3(3H,m). 
EXAMPLE 1 
Thiourea (3.0 g) was added to ethyl 
2-chloro-2-(6,7,8,9-tetrahydro-5H-benzocycloheptadien-2-yl)acetate (9.0 g) 
dissolved in ethanol (100 ml). The mixture was stirred for two hours under 
reflux, and 2N-HCl (50 ml) was added thereto. The mixture was refluxed for 
a further 12 hours, cooled and poured into water. The resulting crystals 
were collected by filtration to yield 8.0 g (90.9%) of 
5-(6,7,8,9-tetrahydro-5H-benzocycloheptadien-2-yl)thiazolidine-2,4-dione. 
Recrystallization from 80% aqueous ethanol yielded colorless prisms, m.p. 
137.degree.-138.degree. C. 
Elemental Analysis for C.sub.14 H.sub.15 NO.sub.2 S: Calcd.: C 64.59; H 
5.42; N 5.38. Found: C 64.33; H 5.72; N 5.15. 
EXAMPLE 2 
Ethyl 2-chloro-2-(5,6,7,8-tetrahydro-2-naphthyl)acetate was allowed to 
react with thiourea in a manner similar to that in Example 1, then the 
reaction mixture was subjected to hydrolysis to yield crystals of 
5-(5,6,7,8-tetrahydro-2-naphthyl)thiazolidine-2,4-dione. The yield was 
92.3%. Recrystallization from 75% aqueous ethanol gave colorless plates, 
m.p. 157.degree.-158.degree. C. 
Elemental Analysis for C.sub.13 H.sub.13 NO.sub.2 S: Calcd.: C 63.14; H 
5.30; N 5.66. Found: C 63.35; H 5.15; N 5.66. 
EXAMPLE 3 
2.47 g of 5-(5,6,7,8-tetrahydro-2-naphthyl)thiazolidine-2,4-dione was 
dissolved in 100 ml of ethyl acetate. To the solution was added 2 ml of 
28% methanol solution of sodium methylate, whereupon fine crystals 
precipitated. Ethyl acetate was evaporated off. To the residue was added 
ethyl ether, and then the resulting fine crystals were collected by 
filtration. Recrystallization from methanol yielded 2.01 g (74.7%) of 
5-(5,6,7,8-tetrahydro-2-naphthyl)thiazolidine-2,4-dione as prisms. The 
melting point was higher than 300.degree. C. 
IR (Nujol)cm.sup.-1 : 1670, 1565, 1320, 1250. 
NMR (d.sub.6 -DMSO).delta.: 1.70(4H,bs), 2.32(4H,bs), 4.97(1H,s), 
6.93(3H,s). 
Elemental Analysis for C.sub.13 H.sub.12 NO.sub.2 S.Na: Calcd.: C 57.98; H 
4.49; N 5.20. Found: C 57.91; H 4.28; N 5.49. 
EXAMPLE 4 
Ethyl 2-chloro-2-(5-indanyl)acetate was allowed to react with thiourea in a 
manner similar to Example 1. The reaction mixture was then subjected to 
hydrolysis to yield crystals of 5-(5-indanyl)thiazolidine-2,4-dione. The 
yield was 83.3%. Recrystallization from ethanol afforded colorless plates, 
m.p. 124.degree.-125.degree. C. 
Elemental Analysis for C.sub.12 H.sub.11 NO.sub.2 S: Calcd.: C 61.78; H 
4.75; N 6.00. Found: C 61.67; H 4.67; N 5.89. 
EXPERIMENT 
(1) Test compounds 
The following Experiments were carried out on the compounds of the two 
groups, one group consisting of the present compounds and the other group 
consisting of the known compounds which are thought to be the closest in 
chemical structure to the present compounds and are disclosed in European 
Patent Publication No. 33617. 
(2) Aldose Reductase Inhibitory Action: 
Aldose reductase inhibitory action was assayed in accordance with the 
method disclosed by S. Haymen et al. in Journal of Biological Chemistry, 
Vol. 240, p. 877 (1965) and that disclosed by Jin H. Kinoshita et al. in 
Metabolism, Vol. 28, Nr. 4, Suppl. 1, 462 (1979). The enzyme used in the 
assay was a partially purified aldose reductase preparation from human 
placenta. The results for the respective compounds were expressed as % 
inhibition at the concentration of 10.sup.-6 mole and are shown in Table 
1. 
(3) Inhibition of Sorbitol Accumulation in the tissue of rats 
Sprague-Dawley rats (male, 5-7 week old, five rats/group) were fasted for 
18 hours. The rats were made diabetic by an intravenous injection of 70 
mg/kg of streptozotocin (Produced by Cal Biochem) at the site of the tail 
under ether anesthesia. After the administration of streptozotocin, these 
rats were administered orally with 25 mg/kg of the test compounds (5% 
suspension of gum-arabica) for two days twice a day (at 9.00 a.m. and at 
4.00 p.m.). During this period, these rats were allowed free access to 
CE-2 feedstuff (Produced by Clea Japan) and water while determining 
blood-sugar level of each animal. On the morning of the third day, these 
rats were decapitated and bled, then the lens and sciatic nerve were 
quickly excised. The respective contents of sorbitol in the lens and 
sciatic nerve were determined by the enzymatic assay method described by 
R. S. Clements et al., in Science, 166, p. 1007 (1969) applied to the 
extracts of these organs obtained by the method described by M. J. 
Peterson et al., in Metabolism, 28, 456 (1979). 
The results are shown in the Table below as % inhibition relative to the 
control. Incidentally, no significant difference in blood-sugar level was 
observed between the group of test animals to which the test compounds 
were administered and the control group of the test animals to which no 
test compounds were administered. 
TABLE 
______________________________________ 
Inhibition of 
Sorbitol 
Aldose Accumu- 
Reductase lation (%) 
Inhibition % Sciatic 
Test Compounds 10.sup.-6 M Lens Nerve 
______________________________________ 
Present 
Compounds 
Compound (I) 
n 3 30.0 62 66 
4 36.0 73 79 
5 34.0 65 83 
Comparative 
Compounds 
##STR6## 35.8 18 5 
##STR7## 57.1 62 -2 
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