Thiazolidine-2,4-dione derivatives, salts and preparation processes thereof

The present invention provides novel thiazolidine-2,4-dione derivatives possessing blood sugar-lowering action and aldose reductase-inhibitory action, their salts, their preparation processes and drugs containing them, and relates to thiazolidine-2,4-dione derivatives represented by a general formula (1) ##STR1## [wherein R.sup.1 and R.sup.2 denote identically or differently hydrogen atoms, halogens, lower alkyl groups, hydroxyl groups, lower alkoxy groups, nitro groups or amino groups (said amino group may be substituted with lower alkyl group or lower alkanoyl group, R.sup.3 denotes a hydrogen atom or lower alkyl group, A denotes a lower alkylene or carbonyl group, and B and W denote differently lower alkylenes, carbonyl groups or bonding hands], or their salts.

TECHNICAL FIELD 
The present invention relates to novel thiazolidine-2,4-dione derivatives 
possessing blood sugar-lowering action and aldose reductase-inhibitory 
action, their salts, their preparation processes and a drug containing 
them. 
BACKGROUND TECHNIQUES 
As therapeutic agents for diabetes, various biguanide type and sulfonylurea 
type compounds have been used so far. However, the biguanide type 
compounds cause the lactic acid acidosis and the sulfonylurea type 
compounds cause serious hypoglycemia posing a problem on their adverse 
effect, thus the advent of therapeutic agent for diabetes without such 
defect is desired. 
On the other hand, it has been made clear that the aldose reductase takes 
part in the crisis of diabetic complication (J. H. Kinoshita et al, J. Am. 
Med. Assoc. 246, 257 (1981)). Thus inhibition of the aldose reductase may 
bring prevention and therapy of diseases occurring as diabetic 
complications. 
Compounds possessing blood sugar-lowering action and compounds possessing 
inhibitory action of aldose reductase have been extensively searched each 
separately, and, with regard to particular thiazolidine-2,4-dione 
derivatives, compounds having aldose reductase-inhibitory action or blood 
sugar-lowering action are known. 
For example, as the aldose reductase-inhibitory agents, particular 
thiazolidine-2,4-dione derivatives are already publicly known (Japanese 
Unexamined Patent Publication No. Sho 57-28073, Chem. Pharm. Bull. 30(10), 
3601, (1982)). Namely, it is publicly known that 
5-phenylthiazolidine-2,4-dione derivatives represented by a general 
formula 
##STR2## 
[wherein R denotes a hydrogen atom, lower alkyl group, hydroxyl group, 
alkoxy group, nitro group, amino group, lower acylamino group, halogen or 
trifluoromethyl group], have aldose reductase-inhibitory action. 
However, thiazolidine-2,4-dione derivatives of the present invention 
represented by a general formula (1) 
##STR3## 
[wherein R.sup.1 and R.sup.2 each independently represent hydrogen atoms, 
halogens, lower alkyl groups, hydroxyl groups, lower alkoxy groups, nitro 
groups or amino groups (said amino group may be substituted with lower 
alkyl group or lower alkanoyl group), R.sup.3 denotes a hydrogen atom or 
lower alkyl group, A denotes a lower alkylene or carbonyl group, and B and 
W denote differently lower alkylenes, carbonyl groups or bonding hands], 
were not known at all, and also it could not be anticipated that 
thiazolidine-2,4-dione derivatives of the present invention had superior 
blood sugar-lowering action together with strong aldose 
reductase-inhibitory action. 
The purpose of the present invention is to provide compounds having 
superior blood sugar-lowering action and simultaneously strong aldose 
reductase-inhibitory action and being useful as effective and highly-safe 
drugs capable of preventing and treating diabetes and complication 
thereof. 
DISCLOSURE OF THE INVENTION 
As a result of diligent studies for solving such problems, the inventors 
have found that thiazolidine-2,4-dione derivatives represented by the 
general formula (1) 
##STR4## 
[wherein R.sup.1 and R.sup.2 each identically represent hydrogen atoms, 
halogens, lower alkyl groups, hydroxyl groups, lower alkoxy groups, nitro 
groups or amino groups (said amino group may be substituted with lower 
alkyl group or lower alkanoyl group), R.sup.3 denotes a hydrogen atom or 
lower alkyl group, A denotes a lower alkylene or carbonyl group, and B and 
W denote differently lower alkylenes, carbonyl groups or bonding hands], 
or their salts have superior blood sugar-lowering action and aldose 
reductase-inhibitory action in combination, leading to the completion of 
the invention. 
For the "lower alkyl" shown in the present invention, straight chain or 
branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, n-propyl 
and i-propyl are exemplified. For "halogen", fluorine, chlorine, bromine 
and iodine are exemplified. For "lower alkoxy", straight chain or branched 
ones with carbon atoms of 1 to 6 such as methoxy, ethoxy, n-propoxy and 
i-propoxy are exemplified. For "lower alkanoyl", ones with carbon atoms of 
1 to 4 such as acetyl and propionyl are exemplified. "Lower alkylene" 
means ones with carbon atoms of 1 to 3 and methylene, ethylene, 
trimethylene, etc. are exemplified. The "eliminating group" is halogen, 
lower alkoxy or hydroxy and preferable one is halogen. "Their salts" mean 
salts admissible as drugs and, for example, salts with cations such as 
sodium and potassium or with inorganic acids (hydrochloric acid, sulfuric 
acid, etc.) or organic acids (p-toluenesulfonic acid etc.) can be 
included. (1) Compounds represented by the general formula (1) can be 
obtained by reacting compounds represented by a general formula (2) 
##STR5## 
[wherein R.sup.3 is same as above], with compounds represented by a 
general formula (3) 
##STR6## 
[wherein m and n indicate integers of 0 to 2, M denotes carboxyl group or 
its reactive derivative, and R.sup.1 and R.sup.2 are same as above], in a 
solvent inert to reaction such as ethanol in the presence of reducing 
agent such as sodium borohydride, for example, to obtain compounds 
represented by a general formula (4) 
##STR7## 
[wherein R.sup.1, R.sup.2, R.sup.3, m, n and M are same as above], and 
then by cyclizing. The cyclization can be conducted in the presence of 
base or acid. As the bases, alkali metal alkoxide such as sodium 
methoxide, for example, and alkali metal hydride such as sodium hydride, 
for example, are exemplified, and the reaction is carried out within a 
temperature range from room temperature to boiling point of solvent. The 
acids are organic acids such as acetic acid and p-toluenesulfonic acid, 
for example, and inorganic acids such as hydrochloric acid and hydrobromic 
acid, for example, and the reaction is conducted usually under heat using 
excess quantity of acid. In both cases, reaction is conducted in a solvent 
inert to reaction such as methanol, ethanol or dimethylformamide. 
(2) Compounds of the general formula (1) can be obtained by reacting 
compounds represented by the general formula (2) with compounds 
represented by a general formula (5) 
##STR8## 
[wherein Z denotes an eliminating group, and R.sup.1, R.sup.2, A, B and W 
are same as above], in the presence of suitable base. This reaction can be 
conducted beneficially in a solvent such as dioxane, dimethylformamide or 
ethyl acetate in the presence of alkali metal hydride such as sodium 
hydride, for example, alkali metal hydroxide such as sodium hydroxide, for 
example, alkali metal carbonate such as potassium carbonate, for example, 
or organic base such as pyridine or triethylamine, for example, as a base. 
The reaction temperature is within a range of 40.degree.to 120.degree. C. 
and the reaction completes for 1 to 5 hours. 
(3) Moreover, compounds of the general formula (1) are obtained by reacting 
compounds represented by the general formula (2) with compounds 
represented by a general formula (6) 
##STR9## 
[wherein R.sup.1, R.sup.2 and W are the same as above]. in a solvent inert 
to reaction such as dioxane to obtain compounds represented by a general 
formula (7) 
##STR10## 
[wherein R.sup.1, R.sup.2 and W are same as above], or compounds 
represented by a general formula (8) 
##STR11## 
[wherein R.sup.1, R.sup.2, R.sup.3 and W are same as above], and then by 
cyclizing. The cyclization is conducted usually under heat using excess 
quantity of acetic acid. Also, the addition of base such as doium acetate 
is beneficial. The compounds obtainable through said processes can be 
isolated. and purified by publicly known separation and purification 
means, for example, solvent extraction, recrystallization, chromatography, 
etc. If pharmaceutically admissible salts of compounds represented by the 
general formula (1) are further needed, they can be obtained by reacting 
with cation-copossessing bases such as sodium hydroxide and potassium 
hydroxide, for example, inorganic acids such as hydrochloric acid and 
sulfuric acid, for example, and organic acids such as fumaric acid and 
oxalic acid, for example. 
BEST EMBODIMENT TO PUT THE INVENTION INTO PRACTICE 
The preparative examples and examples of the inventive compounds will be 
described to illustrate the invention in more detail.

EXAMPLE 1 
5-(4-(1-Oxoisoindoline-2-yl)Phenyl)Thiazolidine-2,4-Dione 
Into 50 ml of ethanol were dissolved 4.90 g of 
5-(4-aminophenyl)-thiazolidine-2,4-dione and 3.54 g of phthalaldehydic 
acid, and the solution was refluxed for 2 hours. After cooling by 
standing, 1.78 g of sodium borohydride were added and the mixture was 
stirred for 20 minutes at room temperature. Thereafter, solvent was 
distilled off under reduced pressure and 10 ml of glacial acetic acid were 
added to the residue, which was stirred for 10 minutes at 100 .degree. C. 
After cooling by standing, 100 ml of water were added and the crystals 
deposited were collected by filtration, washed with water and dried. These 
were recrystallized from ethanol to obtain 6.90 g of title compound. 
m p 257.0.degree.-259.0.degree. C. 
Elemental analysis (%) As C.sub.17 H.sub.12 N.sub.2 O.sub.3 S 
Calculated: C; 62.95; H; 3.73; N; 8.64. 
Observed: C; 63.11; H; 3.72; N; 8.59. 
EXAMPLE 2 
By the similar method to Example 1, following compound was obtained. 
5-(4-(5-Chloro-1-Oxoisoindoline-2-yl)Phenyl)Thiazolidine-2,4-Dione 
m.p.&gt;300.degree. C. 
Elemental analysis (%) As C.sub.17 H.sub.11 Cln.sub.2 O.sub.3 S 
Calculated: C;56.91; H;3.09 N; 7.81. 
Observed: C; 57.21; H; 2.99; N; 7.75. 
EXAMPLE 3 
5-(4-(1,3-Dioxoisoindoline-2-yl)Phenyl)Thiazolidine-2,4-Dione 
Into 30 ml of dioxane were dissolved 1,00 g of 
5-(4-amino-phenyl)thiazolidine-2,4-dione and 0.74 g of phthalic anhydride, 
and the solution was refluxed for 2 hours. Thereafter, 30 ml of acetic 
acid and 0.5 g of sodium acetate were added and the mixture was refluxed 
for 2 hours. The reaction liquor was poured into 400 ml of water, and the 
crystals deposited were collected by filtration. These were recrystalized 
from ethanol to obtain 1.50 g of title compound. 
m.p. 243.0.degree.-245.0.degree. C. 
Elemental analysis (%) As C.sub.17 H.sub.10 N.sub.2 O.sub.4 S 
Calculated: C; 60.35; H; 2.98; N; 8.28. 
Observed: C; 60.44; H; 2.78; N; 8.21. 
EXPERIMENT 1 
Enhancement of Insulin Sensitivity in Rats 
After rats were orally administered with the compound of Example 1 once 
daily for 5 days at 10 mg/kg/day, they were fasted for 18 hours and then 
insulin was intraperitoneally injected at 0.1 unit/kg. Blood samples were 
collected from the tail vein 0 and 1 hour after the injection of insulin 
for the determination of blood glucose (Table 1). 
EXPERIMENT 2 
Improvement of Glucose Tolerance in Genetically Obese Mice 
Genetically obese mice (CS57BL ob/ob mice) were orally administered with 
the compound of Example 1 once daily for 5 days at 10, 30 or 100 
mg/kg/day, respectively. They were fasted for 18 hours and then 2 g/kg of 
glucose was orally administered. Blood samples were collected from the 
tail vein 0, 30, 60 and 120 minutes after the administration of glucose 
for the determination of blood glucose (Table 2). 
From these results in Tables 1 and 2, it was shown that the compound of the 
present invention possessed potent blood glucose lowering action. 
EXPERIMENT 3 
Inhibition of Aldose Reductase in Vitro 
According to the method of Hyman and Kinoshita (J. Biol. Chem., 240, 877, 
1965), inhibitory activity of the compound of Example 23 on aldose 
reductase extracted from rat lens was investigated. As a result, the 
following IC.sub.50 value was obtained (Table 3). 
From these result in Table 3, it was suggested that the compound of the 
present invention possessed potent inhibitory activity on aldose 
reductase. 
TABLE 1 
______________________________________ 
Group n 0 hour value-1 hour value (mg %) 
______________________________________ 
Reference (insulin only) 
5 11.0 .+-. 0.8 
Example 1 10 mg/kg 
5 23.0 .+-. 1.2* 
______________________________________ 
*P &lt; 0.01 
TABLE 2 
______________________________________ 
OGTT (% of control) 
Compound 10 mg/kg 30 mg/kg 100 mg/kg 
______________________________________ 
Example 1 98.2 84.1 81.1 
______________________________________ 
TABLE 3 
______________________________________ 
Compound IC.sub.50 value 
______________________________________ 
Example 1 9 .times. 10.sup.-8 M 
______________________________________ 
UTILIZABILITY IN THE INDUSTRY 
The novel thiazolidine-2,4-dione derivatives and their salts in accordance 
with the invention possess superior blood sugar-lowering action together 
with remarkable aldose reductase-inhibitory action, thus they are useful 
as the drugs for the therapy and prevention of diabetes and the 
complication thereof: