THIAZOLIDINE-2,4-DIONE DERIVATIVE, SALT THEREOF, AND PRODUCTION OF THE SAME

Abstract: A novel thiazolidine-2,4-dione derivative with hypoglycemic and aldose reductase inhibitory activities, represented by the general formula (1) or (2), a salt thereof, a process for producing the same, and a medicine containing the same, wherein R¹ and R² may be the same or different from each other and each represents hydrogen or lower alkyl; R³ represents phenyl naphthyl, benzoyl, 5- or 6- membered heterocycle or a benzene-containing condensed ring thereof, all of which may have at least one substituent; A represents carbonyl, sulfonyl or a free bond; and B represents lower alkylene, lower alkenylene or a free bond, in formula (2) R⁴ represents hydrogen or lower alkyl, and R¹ and R³ are as defined above.

Description: 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. 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. JP-A-59-137 472 discloses 5-phenylthiazolidine-2,4-dione derivatives for use in therapy of chronic diabetic complication. 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 independently represent hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, R 3 denotes a phenyl group, naphthyl group, benzoyl group or 5-membered or 6-membered heteroring containing one or more nitrogen, oxygen and sulfur atoms and its benzene-condensed ring, which may have one or more substituents selected from the group consisting of halogen, lower alkyl group having 1 to 6 carbon atoms, hydroxyl group, lower alkoxy group having 1 to 6 carbon atoms, nitro group, amino group, phenyl group, lower alkanoyloxy group having 1 to 4 carbon atoms, carboxyl group, methylenedioxy group, sulfamoyl group and trifluoromethyl group, A denotes a carbonyl group, sulfonyl group or bonding hand, and B denotes a lower alkylene group having 1 to 6 carbon atoms, lower alkenylene group having 2 to 6 carbon atoms or bonding hand], or their salts and thiazolidine-2,4-dione derivatives represented by the general formula (2) [wherein R 4 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, and R 1 and R 3 are the same as above], or their salts have superior blood sugar-lowering action together with aldose reductase-inhibitory action, leading to the completion of the present 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. The "substituent" in "phenyl group, naphthyl group, benzoyl group or 5-membered or 6-membered heteroring and its benzene-condensed ring means halogen, lower alkyl group, hydroxyl group, lower alkoxy group, nitro group, amino group (said amino group may be substituted with lower alkyl group, lower alkanoyl group or benzoyl group), phenyl group( this phenyl group may be substituted with halogen, lower alkyl group or lower alkoxy group), lower alkanoyloxy group, carboxyl group, methylenedioxy group, sulfamoyl group (this sulfamoyl group may be substituted with lower alkyl group), trifluoromethyl group. 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. The "lower alkanoyloxy" means ones with carbon atoms of 1 to 4 such as acetyloxy and propionyloxy. The "5-membered or 6-membered heteroring and its benzene-condensed ring" mean saturated or unsaturated monocyclic or polycyclic heterocyclic groups capable of containing one or more nitrogen, oxygen and sulfur atoms and, piperidyl, piperazinyl, furyl, thienyl, imidazolyl, thiazolyl, pyridyl, benzofuryl, benzothienyl, indolyl, quinazolyl can be exemplified. "Lower alkylene" means ones with carbon atoms of 1 to 6 and methylene, ethylene, trimethylene are exemplified. "Lower alkenylene" applied similarly to "lower alkylene" but has carbon atoms of 2 to 6 and unsaturated bond(s). 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. The compounds of the present invention can be prepared through processes shown below. (A) Compounds represented by the general formula (1) can be obtained by reacting compounds represented by the general formula (3) [wherein R 1 and R 2 are same as above], with compounds represented by the general formula (4) R 3 - B - A - Z [wherein R 3 , A, Z and B are same as above], in the presence of a suitable base or condensing agent. 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. For the condensing agents, for example, dicyclohexylcarbodiimide and diethylphosphoryl cyanide are exemplified. The reaction temperature is within a range from 0 to 120 °C and the reaction completes for 1 to 5 hours. (B) Compounds represented by the general formula (2) can be obtained by condensing compounds represented by the general formula (3a) [wherein R 1 is same as above], or their salts with compounds represented by the general formula (5) [wherein R 3 and R 4 are same as above]. This reaction can be conducted in a solvent inert to reaction such as ethanol, toluene or xylene, for example, in the presence of, for example, p-toluenesulfonic acid as a catalyst or in the absence of catalyst. The reaction is conducted within a range from room temperature to the boiling point of solvent and the reaction completes for 1 to 5 hours. (C) Among compounds represented by the general formula (1), such compounds wherein R 2 is hydrogen atom, A is bonding hand and B is lower alkylene can also be obtained by reducing compounds represented by the general formula (2). This reaction can be conducted in a solvent inert to reaction such as methanol, ethanol, ether or tetrahydrofuran, for example in the presence of, for example, sodium borohydride or lithium aluminum hydride as a reducing agent. The reaction is conducted within a range from 0 °C to the boiling point of the solvent and the reaction completes for 1 to 5 hours. 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) or general formula (2) 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. Moreover, because the inventive compounds represented by the general formula (1) and general formula (2) have one or more asymmetric carbon atoms, there exist optical isomers, but the invention also includes those optical isomers and racemic modifications. 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-Benzoylaminophenyl)thiazolidine-2,4-dione Into 20 ml of dioxane were dissolved 0.5 g of 5-(4-aminophenyl)thiazolidine-2,4-dione, and, after added 0.34 g of benzoyl chloride and further added dropwise 0.24 g of triethylamine, the mixture was refluxed for 1 hour. After cooling by standing, the reaction mixture was poured into 150 ml of ice water and the crystals deposited were collected by filtration, washed with water and dried. These were recrystallized from chloroform to obtain 0.70 g of title compound. m.p. 240.0 - 245.0 °C Element alanalysis (%) As C 16 H 12 N 2 O 3 S Calculated C 61.53 H 3.87 N 8.97 Observed C 61.65 H 3.88 N 8.75 Example 2 5-(4-Piperonyloylaminophenyl)thiazolidine-2,4-dione Into 20 ml of dimethylformamide were dissolved 1.00 g of 5-(4-aminophenyl)thiazolidine-2,4-dione and 0.80 g of piperonylic acid, and, after added 1.12 g of diethylphosphoryl cyanide and then 0.50 g of triethylamine at 0 °C, the mixture was stirred for 1 hour as it was. Thereafter, the reaction mixture was brought to room temperature and stirred for 2 hours. Then, it was poured into 200 ml of water and, after made acidic with hydrochloric acid, the crystals deposited were collected by filtration. These were recrystallized from ethanol to obtain 1.05 g of title compound. m.p. 275.0 - 277.0 °C Element alanalysis (%) As C 17 H 12 N 2 O 5 S Calculated C 57.30 H 3.39 N 7.86 Observed C 57.39 H 3.28 N 7.81 Example 3 5-(4-(p-Toluenesulfonylamino)phenyl)thiazolidine-2,4-dione Into 10 ml of pyridine were dissolved 0.50 g of 5-(4-amino-phenyl)thiazolidine-2,4-drone, and after added 0.46 g of p-toluenesulfonyl chloride, the mixture was stirred for 1 hour at room temperature. After the completion of reaciton, the reaction mixture was poured into ice water, which was extracted with ethyl acetate. The organic layer was washed with 10 % hydrochloric acid, washed with water and dried. Then, solvent was distilled off. The residue was recrystallized from benzene to obtain 0.65 g of title compound. m.p. 215.0 - 218.0 °C Element alanalysis (%) As C 16 H 14 N 2 O 4 S 2 Calculated C 53.02 H 3.89 N 7.73 Observed C 53.29 H 3.86 N 7.75 Example 4 through 51 By the similar methods to Example 1 through 3, following compounds were obtained. Example 52 5-(4-(3,4-Dichlorobenzylideneamino)phenyl)thiazolidine-2,4-dione Into 20 ml of ethanol were suspended 0.50 g of 5-(4-aminophenyl)-thiazolidine-2,4-dione, and, after added 0.42 g of 3,4-dichlorobenzaldehyde thereto, the suspension was refluxed for 3 hours. After cooling by standing, the crystals deposited were collected by filtration. The crude crystals were recrystallized from ethanol to obtain 0.79 g of title compound. m.p. 216.5 - 218.0 °C Element alanalysis (%) As C 16 H 10 Cl 2 N 2 O 2 S Calculated C 52.62 H 2.76 N 7.67 Observed C 52.58 H 2.74 N 7.68 Example 53 5-(4-(3,4-Dichlorobenzylamino)phenyl)thiazolidine-2,4-dione Into 40 ml of ethanol were suspended 0.40 g of 5-(4-(3,4-dichlorobenzylideneamino)phenyl)thiazolidine-2,4-dione, and, after added 0.24 g of sodium borohydride, the suspension was stirred for 2 hours at 50 °C. The reaction mixture was poured into 200 ml of water, which was extracted with ethyl acetate. The organic layer was washed with water and dried. Then, solvent was distilled off. The residue was recrystallized from iso-propanol to obtain 0.20 g of title compound. m.p. 132.0 - 133.0 °C Element alanalysis (%) As C 16 H 12 Cl 2 N 2 O 2 S Calculated C 52.32 H 3.29 N 7.63 Observed C 52.26 H 3.28 N 7.64 Example 54 through 62 By the similar methods to Example 52 and 53, following compounds were obtained. Experiment 1 Enhancement of insulin sensitivity in rats After rats were orally administered with the compound of Example 23 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 23 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 50 value was obtained (Table 3). Experiment 4 Inhibition on sorbitol accumulation in tissues of diabetic rats After diabetic rats were prepared by injecting streptozotocin, they were orally administered with the compound of Example 23 once daily 2 weeks at 4, 16 or 64 mg/kg/day, respectively. The sorbitol content in nerve and retina was determined to calculate ED 50 value (Table 4). From these results in Table 3 and 4, 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 23 10mg/kg 5 19. 4 ± 1. 5 Compound OGTT (% of control) 10mg/kg 30mg/kg 100mg/kg Example 23 93. 5 89. 2 74. 1 Compound IC 50 value Example 23 9 × 10 -8 M Compound ED 50 value (mg/kg/day) Nerve Retina Example 23 14. 5 26. 5 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 independently represent hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, R 3 denotes a phenyl group, naphthyl group, benzoyl group or 5-membered or 6-membered heteroring containing one or more nitrogen, oxygen and sulfur atoms and its benzene-condensed ring, which may have one or more substituents selected from the group consisting of halogen, lower alkyl group having 1 to 6 carbon atoms, hydroxyl group, lower alkoxy group having 1 to 6 carbon atoms. nitro group, amino group, phenyl group, lower alkanoyloxy group having 1 to 4 carbon atoms, carboxyl group, methylenedioxy group, sulfamoyl group and trifluoromethyl group, A denotes a carbonyl group, sulfonyl group or bonding hand, and B denotes a lower alkylene group having 1 to 6 carbon atoms, lower alkenylene group having 2 to 6 carbon atoms or bonding hand], or their salts. Thiazolidine-2,4-dione derivatives represented by the general formula (2) [wherein R 4 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, and R 1 and R 3 are 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 (3) [wherein R 1 and R 2 are the same as defined in claim 1], or their salts with compounds represented by the general formula (4) R 3 - B - A - Z [wherein Z is an eliminating group, and R 3 , A and B are the same as defined in claim 1]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 2, characterized by reacting compounds represented by the general formula (3a) [wherein R 1 is the same as defined in claim 1], or their salts with compounds represented by the general formula (5) [wherein R 3 and R 4 are the same as defined in claim 2]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, wherein R 2 is a hydrogen atom, A is a bonding hand and B is a lower alkylene group having 1 to 6 carbon atoms, characterized by reducing compounds represented by the general formula (2) [wherein R 1 , R 3 and R 4 are the same as defined in claim 2]. 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, or thiazolidine-2,4-dione derivatives represented by the general formula (2) as defined in claim 2 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, or thiazolidine-2,4-dione derivatives represented by the general formula (2) as defined in claim 2 or their salts as effective ingredient(s). Claims for the following Contracting States : GR Thiazolidine-2.4-dione derivatives represented by the general formula (1) [wherein R 1 and R 2 each independently represent hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, R 3 denotes a phenyl group, naphthyl group, benzoyl group or 5-membered or 6-membered heteroring containing one or more nitrogen, oxygen and sulfur atoms and its benzene-condensed ring, which may have one or more substituents selected from the group consisting of halogen, lower alkyl group having 1 to 6 carbon atoms, hydroxyl group, lower alkoxy group having 1 to 6 carbon atoms, nitro group, amino group, phenyl group, lower alkanoyloxy group having 1 to 4 carbon atoms, carboxyl group, methylenedioxy group, sulfamoyl group and trifluoromethyl group, A denotes a carbonyl group, sulfonyl group or bonding hand, and B denotes a lower alkylene group having 1 to 6 carbon atoms, lower alkenylene group having 2 to 6 carbon atoms or bonding hand], or their salts. Thiazolidine-2,4-dione derivatives represented by the general formula (2) [wherein R 4 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, and R 1 and R 3 are 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 (3) [wherein R 1 and R 2 are the same as defined in claim 1], or their salts with compounds represented by the general formula (4) R 3 - B - A - Z [wherein Z is an eliminating group, and R 3 , A and B are the same as defined in claim 1]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 2, characterized by reacting compounds represented by the general formula (3a) [wherein R 1 is the same as defined in claim 1], or their salts with compounds represented by the general formula (5) [wherein R 3 and R 4 are the same as defined in claim 2]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, wherein R 2 is a hydrogen atom, A is a bonding hand and B is a lower alkylene group having 1 to 6 carbon atoms, characterized by reducing compounds represented by the general formula (2) [wherein R 1 , R 3 and R 4 are the same as defined in claim 2]. 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 independently represent hydrogen atoms or lower alkyl groups having 1 to 6 carbon atoms, R 3 denotes a phenyl group, naphthyl group, benzoyl group or 5-membered or 6-membered heteroring containing one or more nitrogen, oxygen and sulfur atoms and its benzene-condensed ring, which may have one or more substituents selected from the group consisting of halogen, lower alkyl group having 1 to 6 carbon atoms, hydroxyl group, lower alkoxy group having 1 to 6 carbon atoms, nitro group, amino group, phenyl group, lower alkanoyloxy group having 1 to 4 carbon atoms, carboxyl group, methylenedioxy group, sulfamoyl group and trifluoromethyl group, A denotes a carbonyl group, sulfonyl group or bonding hand, and B denotes a lower alkylene group having 1 to 6 carbon atoms, lower alkenylene group having 2 to 6 carbon atoms or bonding hand], or their salts, characterized by reacting compounds represented by the general formula (3) [wherein R 1 and R 2 are the same as defined above], or their salts with compounds represented by the general formula (4) R 3 - B - A - Z [wherein Z is an eliminating group, and R 3 , A and B are the same as defined above]. A process for preparing thiazolidine-2,4-dione derivatives represented by the general formula (2) [wherein R 4 denotes a hydrogen atom or lower alkyl group having 1 to 6 carbon atoms, and R 1 and R 3 are the same as defined in claim 1] or their salts, characterized by reacting compounds represented by the general formula (3a) [wherein R 1 is the same as defined in claim 1], or their salts with compounds represented by the general formula (5) [wherein R 3 and R 4 are the same as defined above]. A process for preparing the thiazolidine-2,4-dione derivatives or their salts of claim 1, wherein R 2 is a hydrogen atom, A is a bonding hand and B is a lower alkylene group having 1 to 6 carbon atoms, characterized by reducing compounds represented by the general formula (2) [wherein R 1 , R 3 and R 4 are the same as defined in claim 2].

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, MURAKAMI, KOJI 6095, TOMONUMA, OHASHI, MITSUO 1674-2, SUNA, OHNOTA, MICHIRO 6095, TOMONUMA NOGI-MACHI, OKAMURA, KYUYA 651-10, NISSHINCHO 3-CHOME
Applicants: KYORIN SEIYAKU KK, KYORIN PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: C07D277
IPC codes: C07D277, A61K31, A61P3, C07D417, A61P5