THIAZOLIDINE-2,4-DIONE DERIVATIVE, SALT THEREOF, AND PRODUCTION THEREOF

Abstract: A novel thiazolidine-2,4-dione derivative with hypoglycemic and aldose reductase inhibitory activities, represented by general formula (1), a salt thereof, a process for producing the same, and a pharmaceutical containing the same, wherein R¹ and R² may be the same or different from each other and each represents hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, nitro or amino which may be substituted by lower alkyl or lower alkanoyl; R³ represents hydrogen or lower alkyl; A represents lower alkylene or carbonyl; and B and W are different from each other and each represents lower alkylene, carbonyl or a free bond.

Description: SPECIFICATION Technical field The present invention relates to 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 (JP-A-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 [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. 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) [wherein R 1 and R 2 each identically represent hydrogen atoms, halogens, lower alkyl groups having 1 to 6 carbon atoms, hydroxyl groups, lower alkoxy groups having 1 to 6 carbon atoms, nitro groups or amino groups (said amino group may be substituted with lower alkyl group having 1 to 6 carbon atoms or lower alkanoyl group having 1 to 4 carbon atoms), R 3 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, A denotes a lower alkylene group having 1 to 3 carbon atoms or carbonyl group, and B and W denote differently lower alkylene groups having 1 to 3 carbon atoms, 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. The "lower alkyl" shown in the present invention means straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, n-propyl and i-propyl. For "halogen", fluorine, chlorine, bromine and iodine are exemplified. The "lower alkoxy" means straight chain or branched ones with carbon atoms of 1 to 6 such as methoxy, ethoxy, n-propoxy and i-propoxy. The "lower alkanoyl" means ones with carbon atoms of 1 to 4 such as acetyl and propionyl. "Lower alkylene" means ones with carbon atoms of 1 to 3 and methylene, ethylene and trimethylene 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 (e.g. hydrochloric acid and sulfuric acid) or organic acids (e.g. p-toluenesulfonic acid) can be included. (1) Compounds represented by the general formula (1) can be obtained by reacting compounds represented by the general formula (2) [wherein R 3 is same as above], with compounds represented by the general formula (3) [wherein m and n indicate integers of 0 to 2, M denotes carboxyl group or its reactive derivative, and R 1 and R 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 the general formula (4) [wherein R 1 , R 2 , R 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 the boiling point of the 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, the 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 the general formula (5) [wherein Z denotes an eliminating group, and R 1 , R 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 to 120 °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 the general formula (6) [wherein R 1 , R 2 and W are same as above], in a solvent inert to reaction such as dioxane to obtain compounds represented by the general formula (7) [wherein R 1 , R 2 and W are same as above], or compounds represented by the general formula (8) [wherein R 1 , R 2 , R 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 a base such as sodium 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, or chromatography. 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 °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 - 259.0 °C Elemental analysis (%) As C 17 H 12 N 2 O 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, the following compound was obtained. 5-(4-(5-Chloro-1-oxoisoindoline-2-yl)phenyl)thiazolidine-2,4-dione m.p. >300 °C Elemental analysis (%) As C 17 H 11 ClN 2 O 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 recrystallized from ethanol to obtain 1.50 g of title compound. m.p. 243.0 - 245.0 °C Elemental analysis (%) As C 17 H 10 N 2 O 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 1 on aldose reductase extracted from rat lens was investigated. As a result, the following IC 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. Group n 0 hour value - 1 hour value (mg %) Reference (insulin only) 5 11.0±0.8 Example 1 10mg/kg 5 23.0±1.2 Compound OGTT (% of control) 10mg/kg 30mg/kg 100mg/kg Example 1 98.2 84.1 81.1 Compound IC 50 value Example 1 9 × 10 -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.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE Thiazolidine-2,4-dione derivatives represented by the general formula (1) [wherein R 1 and R 2 each identically represent hydrogen atoms, halogens, lower alkyl groups having 1 to 6 carbon atoms, hydroxyl groups, lower alkoxy groups having 1 to 6 carbon atoms, nitro groups or amino groups (said amino group may be substituted with lower alkyl group having 1 to 6 carbon atoms or lower alkanoyl group having 1 to 4 carbon atoms), R 3 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, A denotes a lower alkylene group having 1 to 3 carbon atoms or a carbonyl group, and B and W denote differently lower alkylene groups having 1 to 3 carbon atoms, carbonyl groups or bonding hands], or their salts. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, characterized by reacting compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1], or their salts with compounds represented by the general formula (3) [wherein m and n indicate integers of 0 to 2, M denotes a carboxyl group or its reactive derivative, and R 1 and R 2 are the same as defined in claim 1], in the presence of a reducing agent to obtain compounds represented by the general formula (4) [wherein R 1 , R 2 , R 3 , m, n and M are the same as defined above], and then by cyclizing. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, characterized by reacting compounds represented by the general formula (5) [wherein Z denotes an eliminating group, and R 1 , R 2 , A, B and W are the same as defined in claim 1], with compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, characterized by reacting compounds represented by the general formula (6) [wherein R 1 , R 2 and W are the same as defined in claim 1], with compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1], to obtain compounds represented by the general formula (7) or the general formula (8) [wherein R 1 , R 2 , R 3 and W are the same as defined in claim 1], and then by cyclizing. A blood sugar-lowering agent having at least one kind of thiazolidine-2,4-dione derivatives represented by the general formula (1) as defined in claim 1 or their salts as effective ingredient(s). An aldose reductase-inhibitory agent having at least one kind of thiazolidine-2,4-dione derivatives represented by the general formula (1) as defined in claim 1 or their salts as effective ingredient(s). Claims for the following Contracting State : ES A process for preparing thiazolidine-2,4-dione derivatives represented by the general formula (1) [wherein R 1 and R 2 each identically represent hydrogen atoms, halogens, lower alkyl groups having 1 to 6 carbon atoms, hydroxyl groups, lower alkoxy groups having 1 to 6 carbon atoms, nitro groups or amino groups (said amino group may be substituted with lower alkyl group having 1 to 6 carbon atoms or lower alkanoyl group having 1 to 4 carbon atoms), R 3 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, A denotes a lower alkylene group having 1 to 3 carbon atoms or a carbonyl group, and B and W denote differently lower alkylene groups having 1 to 3 carbon atoms, carbonyl groups or bonding hands], or their salts, characterized by reacting compounds represented by the general formula (2) [wherein R 3 is the same as defined above], or their salts with compounds represented by the general formula (3) [wherein m and n indicate integers of 0 to 2, M denotes a carboxyl group or its reactive derivative, and R 1 and R 2 are the same as defined above], in the presence of a reducing agent to obtain compounds represented by the general formula (4) [wherein R 1 , R 2 , R 3 , m, n and M are the same as defined above], and then by cyclizing. A process for preparing thiazolidine-2,4-dione derivatives represented by the formula (1) or their salts as defined in claim 1, characterized by reacting compounds represented by the general formula (5) [wherein Z denotes an eliminating group, and R 1 , R 2 , A, B and W are the same as defined in claim 1], with compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1]. A process for preparing thiazolidine-2,4-dione derivatives represented by the formula (1) or their salts as defined in claim 1, characterized by reacting compounds represented by the general formula (6) [wherein R 1 , R 2 and W are the same as defined in claim 1], with compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1], to obtain compounds represented by the general formula (7) or the general formula (8) [wherein R 1 , R 2 , R 3 and W are the same as defined in claim 1], and then by cyclizing. Claims for the following Contracting State : GR Thiazolidine-2,4-dione derivatives represented by the general formula (1) [wherein R 1 and R 2 each identically represent hydrogen atoms, halogens, lower alkyl groups having 1 to 6 carbon atoms, hydroxyl groups, lower alkoxy groups having 1 to 6 carbon atoms, nitro groups or amino groups (said amino group may be substituted with lower alkyl group having 1 to 6 carbon atoms or lower alkanoyl group having 1 to 4 carbon atoms), R 3 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, A denotes a lower alkylene group having 1 to 3 carbon atoms or a carbonyl group, and B and W denote differently lower alkylene groups having 1 to 3 carbon atoms, carbonyl groups or bonding hands], or their salts. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, characterized by reacting compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1], or their salts with compounds represented by the general formula (3) [wherein m and n indicate integers of 0 to 2, M denotes a carboxyl group or its reactive derivative, and R 1 and R 2 are the same as defined in claim 1], in the presence of a reducing agent to obtain compounds represented by the general formula (4) [wherein R 1 , R 2 , R 3 , m, n and M are the same as defined above], and then by cyclizing. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, characterized by reacting compounds represented by the general formula (5) [wherein Z denotes an eliminating group, and R 1 , R 2 , A, B and W are the same as defined in claim 1], with compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, characterized by reacting compounds represented by the general formula (6) [wherein R 1 , R 2 and W are the same as defined in claim 1], with compounds represented by the general formula (2) [wherein R 3 is the same as defined in claim 1], to obtain compounds represented by the general formula (7) or the general formula (8) [wherein R 1 , R 2 , R 3 and W are the same as defined in claim 1], and then by cyclizing.

Inventors: HIRATA YOSHIHIRO, MURAKAMI KOJI, OHASHI MITSUO, OHNOTA MICHIRO, OKAMURA KYUYA, HIRATA, YOSHIHIRO, MURAKAMI, KOJI, OHASHI, MITSUO, OHNOTA, MICHIRO, OKAMURA, KYUYA, HIRATA, YOSHIHIRO 29-24, BESSHO-MACHI, OHASHI, MITSUO 1674-2, SUNA, OHNOTA, MICHIRO 6095, TOMONUMA, OKAMURA, KYUYA 651-10, NISSHINCHO 3-CHOME
Applicants: KYORIN SEIYAKU KK, KYORIN PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: C07D417
IPC codes: A61K31, C07D417, C07D277, A61P3