長い直線的共役系構造部分を持つベンゼン誘導体、その製造方法及び液晶性材料

Japanese Patent JPWO2004085380

A1

液晶状態の分子配向を利用した電荷輸送方法において、光励起しないでも優れた電荷輸送性が期待できる新規な長い直線的共役系構造部分を持つベンゼン誘導体、その製造方法、該化合物を含有する液晶性材料を提供する。即ち、下記一般式（１）｛式中、Ｒ１は下記一般式（２）（式中、Ｒ５が水素原子又はメチル基、Ｂはアルキレン基等を示す。）で表される不飽和結合を有する基等を示し、Ｒ２、Ｒ３及びＲ４はアルキル基、Ａはアルキレン基、Ｘはハロゲン原子を示す。｝で表されることを特徴とする長い直線的共役系構造部分を持つベンゼン誘導体である。

JP2991985

INDUSTRIAL APPLICABILITY [Title of Invention] 3-Triphenylmethylthiazolidine-2,4-dione derivative 1. 5- (4-Hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione. 2. 5- (4-Acetoxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione. The present invention provides an intermediate useful for the production of an aminoalcohol derivative having an aldose reductase inhibitory action or a salt thereof, which improves hyperlipidemia, hyperglycemia, obesity and impaired glucose tolerance. 1) General formula [0003] [Chemical 1] In, compounds in which Q is an i-propyl group or a t-butyl group are known to have β-adrenoceptor agonist activity (eg, DT Collin, Journal of Medicinal Chemistry (J.Med.Chem.), Vol. 13, pp. 674-680, 1970). It is known that a compound in which Q is a phenylaminoethyl group has a similar activity (UK Patent No. 1551260 [= JP-A-52-97926]). It is known that a compound in which Q is a hydroxybenzyl group or an alkoxybenzyl group has β-adrenagic stimulant property and blocking property (UK Patent No. 1200886 [= Special Publication No. 46-2653]). Based on Q [0007] [Chemical 2] (In the formula, R Is a carboxyl group or a salt thereof, an alkyloxycarbonyl group having 2 to 5 carbon atoms or an alkylcarbamoyl group having 2 to 5 carbon atoms; R Is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, a methoxy group, a hydroxy group, a carboxy group or a salt thereof, an alkyloxycarbonyl group having 2 to 5 carbon atoms or an alkylcarbamoyl group having 2 to 5 carbon atoms; R Is a hydrogen atom, methyl group, ethyl group or propyl group; R Is a hydrogen atom, methyl group, ethyl group or propyl group; X Is an oxygen atom or a single bond; Y Indicates an alkylene group or a single bond with up to 6 carbon atoms. ) Is known to have anti-mucopolysaccharidosis activity and anti-obesity activity (European Patent Publication No. 000 6735A [= Japanese Patent Application Laid-Open No. 55-9085 (= Special Fair 1-30820)]) .. 2) General formula [0008] [Chemical 3] (In the formula, R And R Are independently hydrogen, halogen, hydroxy, hydroxymethyl or trifluoromethyl groups; R Is a hydrogen atom; R Is a lower alkyl group substituted with hydroxy, lower alkoxy or lower acyloxy; R Is a hydrogen atom; R And R Are independent hydrogen atoms or methyl groups; X Is an oxygen atom or a single bond; Y Indicates a methylene group or an ethylene group; ) Is known to have antihyperglycemic and antiobesity (European Patent Publication No. 0021636A [= Japanese Patent Application Laid-Open No. 56-5445 (= Japanese Patent Application Laid-Open No. 63-26741)]). However, X However, the compound showing an oxygen atom is not specifically described (European Patent No. 0021636B). 3) General formula [0010] [Chemical 4] (In the formula, R , R And R Are the same or different hydrogen atom, fluorine atom, chlorine atom, bromine atom or trifluoromethyl group; R Is a hydrogen atom or a lower alkyl group; R Is a hydrogen atom or a lower alkyl group; R Is a hydrogen atom or a lower alkyl group; R Is a hydrogen atom or a lower alkyl group; R Is a carboxy group, its lower alkyl ester or group-CONHR (R Is a hydrogen atom or lower alkyl group); Y Indicates an alkylene group having 2 or less carbon atoms; ) Is known to have antihyperglycemic activity and antiobesity activity (European Patent Publication No. 0025331A [= Japanese Patent Application Laid-Open No. 56-59739 (= Japanese Patent Application Laid-Open No. 63-40420)]). 4) General formula [0011] [Chemical 5] (In the formula, R Is a hydrogen atom, halogen atom, hydroxy group, hydroxymethyl group or trifluoromethyl group; R And R Are the same or different hydrogen atom, or a halogen atom hydroxy groups were; R Is a hydrogen atom or a methyl group; R Is a hydrogen atom or a methyl group; R Is a hydrogen atom; X Is an oxygen atom or a single bond; Y Is a methylene group or an ethylene group; Z Indicates an alkylene group having 3 or less carbon atoms or an alkenylene group having 3 or less carbon atoms; ) Compounds and their salts, esters, and amides are known to have antihyperglycemic and antiobesity effects (US Pat. Nos. 4, 338, 333 [= JP-A 56-5444 (= Special)). Kosho 63-26744)]). Furthermore, among the compounds contained in the above formula, N- [2- (4-carboxymethoxyphenyl) -1- (S) -1-methylethyl] -2- (S) -2-hydroxy-2- ( 3-chlorophenyl) ethaneamine, a methyl ester thereof or a pharmaceutically acceptable salt thereof (SS-isomer) may be optionally mixed with N- [2- (4-carboxymethoxyphenyl) -1- ( R) -1-Methylethyl] -2- (R) -2-Hydroxy-2- (3-chlorophenyl) ethaneamine, its methyl ester or a pharmaceutically acceptable salt thereof (RR-isomer) (provided that SS-isomers form less than 50% by weight of the mixture of RR- and SS-isomers) are known to be particularly effective as antihyperglycemic and / or anti-obesity agents (European patent publication). No. 0262785A [= Japanese Patent Application Laid-Open No. 63-79857]). The present inventors have conducted intensive studies on aminoalcohol derivatives for the purpose of developing highly safe antihyperlipidemic agents, antidiabetic agents, antiobesity agents, glucose intolerant improving agents and therapeutic agents for diabetic complications. The present invention has been completed by finding a compound useful as an intermediate. [Means for solving problems] The present invention relates to 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione and 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione. The compound of the present invention has the general formula (I). [0016] [Chemical 6] It is useful as an intermediate for producing a novel aminoalcohol derivative having or a salt thereof. In the above formula, R Indicates a hydrogen atom, a methyl group or a hydroxymethyl group. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is the basis (II) [0022] [Chemical 7] (In the formula, R Is a hydrogen atom, a halogen atom, a hydroxy group, a hydroxymethyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, or a linear or branched alkoxy group having 1 to 5 carbon atoms. Alkyl group, linear or branched acyloxy group having 1 to 6 carbon atoms, nitro group, cyano group, linear or branched alkyl moiety having 1 to 3 carbon atoms However, the alkyl moiety may have a substituent, an aralkyloxy group having 1 or 2 aryls, an aryloxy group having 6 to 10 carbon atoms, which may have a substituent, and a substituent. Indicates an aryl group having 6 to 10 carbon atoms or a linear or branched haloalkyl group having 1 to 4 carbon atoms which may have. R Is a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched alkoxy group having 1 to 5 carbon atoms, a linear or branched alkyl group having 1 to 5 carbon atoms, or Shows a nitro group. R Is a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched alkoxy group having 1 to 5 carbon atoms, or a linear or branched alkyl group having 1 to 5 carbon atoms. Shown. ) Or group (III) [0025] [Chemical 8] (In the formula, R , R And R Shows the same meaning as described above. ) Is shown. Here, R , R , R , R in group (II) , R And R Can be in the ortho, meta, or para position with respect to the side chain. Also, R in group (III) , R And R Can be in any of the 2-, 3-, 4-, 5-, 6-, 7- and 8-positions when the side chain is in the α-position and 1-, when the side chain is in the β-position. It may be in any of the 3-, 4-, 5-, 6-, 7- and 8-positions. R When is a halogen atom, for example, it is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom, and optimally, a fluorine atom or a chlorine atom. R When is a linear or branched alkoxy group having 1 to 5 carbon atoms, it may include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and the like. A linear or branched alkoxy group having 1 to 3 carbon atoms is preferable. Optimal is a methoxy group or an ethoxy group. R If is a linear or branched alkyl group with 1 to 5 carbon atoms, it is, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, s-butyl, t-butyl, 2 -Pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, etc. can be mentioned. A linear or branched alkyl group having 1 to 4 carbon atoms is preferable. Optimal is a linear or branched alkyl group having 1 to 3 carbon atoms. R If is a linear or branched acyloxy group having 1 to 6 carbon atoms, it may be, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, Hexanoyloxy and the like can be given. It is preferably a linear or branched acyloxy group having 1 to 5 carbon atoms. Optimal is an acyloxy group having 1 to 3 carbon atoms. More optimally, it is an acetoxy group. R When is an aralkyloxy group having 7 to 13 carbon atoms which may have a substitution, the aralkyl moiety has a linear or branched alkyl moiety having 1 to 3 carbon atoms. , The alkyl moiety is substituted with one or two aryls. Suitable linear or branched alkyl having 1 to 3 carbon atoms is methyl, ethyl, propyl or isopropyl. And these are replaced with one or two aryls such as phenyl, naphthyl. Examples of the aralkyloxy group having no substitution include benzyloxy, phenethyloxy, 1-phenylethoxy, 3-phenylpropoxy, naphthylmethoxy and the like. In the case of an aralkyloxy group having 7 to 13 carbon atoms which may have a substitution component, the number of substitution components is not particularly limited, but is usually preferably 1 to 5 and optimally 1 to 3. It is an aralkyloxy group having a substitution component. Substitutions of aralkyloxy groups with substitutions include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, preferably fluorine atom, chlorine atom, bromine atom; methyl, ethyl, propyl, butyl. Linear or branched alkyl with 1 to 4 carbon atoms such as, isopropyl, t-butyl; linear chain with 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy. Alternatively, branched alkoxy; nitro; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-Dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyl, Haloalkyl having 1 to 4 carbon atoms in a linear or branched chain such as 4-fluorobutyl and preferably having 1 to 3 halogen atoms of the same or different, preferably 1 to 3 Haloalkyl with 1 to 3 carbon atoms with the same 2 or 3 halogen atoms, more preferably 1 to 3 fluorine atoms, methyl or ethyl with chlorine atoms, optimally Are trifluoromethyl, trichloromethyl, difluoromethyl, 2-fluoroethyl, especially trifluoromethyl; or hydroxy ;. Examples of the aralkyloxy group having a substituent include o-, m- or p-fluorobenzyloxy, o-, m- or p-chlorobenzyloxy, o-, m- or p-methylbenzyloxy, o-, m- or p-methoxybenzyloxy, o-, m- or p-nitrobenzyloxy, o-, m- or p-trifluoromethylbenzyloxy, o-, m- or p-hydroxybenzyloxy, 3,5 -Di-t -Butyl-4-hydroxybenzyloxy, 3,4,5-trimethoxybenzyloxy. Preferably, a halogen atom as a substitution material in the aryl moiety, a linear or branched alkyl having 1 to 4 carbon atoms, a linear or branched alkoxy having 1 to 3 carbon atoms, An aralkyloxy group which may have 1 to 3 trifluoromethyls or hydroxys, which may be the same or different. Optimal is a benzyloxy group which may have one or two fluorine atoms, chlorine atoms, methyl or methoxy as substitutions in the aryl moiety, which may be the same or different. R In the case of an aryloxy group having 6 to 10 carbon atoms which may have a substitution, the number of substitutions is not particularly limited, but is usually preferably 1 to 5, and optimally 1 to 3. It is an aryloxy group having a substitution of. Examples of the aryloxy group having no substitution component include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like. Substitutions of aryloxy groups with substitutions include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, preferably fluorine atom, chlorine atom, bromine atom; methyl, ethyl, propyl, butyl. Linear or branched alkyl with 1 to 4 carbon atoms such as, isopropyl, t-butyl; linear chain with 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy. Alternatively, branched alkoxy; nitro; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-Dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyl, Haloalkyl having 1 to 4 carbon atoms in a linear or branched chain such as 4-fluorobutyl and preferably having 1 to 3 halogen atoms of the same or different, preferably 1 to 3 Haloalkyl with 1 to 3 carbon atoms with the same 2 or 3 halogen atoms, more preferably 1 to 3 fluorine atoms, methyl or ethyl with chlorine atoms, optimally Are trifluoromethyl, trichloromethyl, difluoromethyl, 2-fluoroethyl, especially trifluoromethyl; or hydroxy ;. Examples of the aryloxy group having a substituent include o-, m- or p-fluorophenoxy, o-, m- or p-chlorophenoxy, o-, m- or p-methylphenoxy, o-, m- or p-Methoxyphenoxy, o-, m- or p-nitrophenoxy, o-, m- or p-trifluoromethylphenoxy, o-, m- or p-hydroxyphenoxy, 3,5-di-t-butyl- 4-Hydroxyphenoxy and 3,4,5-trimethoxyphenoxy. Preferably, the aryl moiety is a halogen atom, a linear or branched alkyl having 1 to 4 carbon atoms, a linear or branched alkoxy having 1 to 3 carbon atoms, and the like. It is an aryloxy group that may have 1 to 3 trifluoromethyl or hydroxy groups that are the same as or different from each other. Optimal is a phenoxy group which may have one or two fluorine atoms, chlorine atoms, methyl, methoxy or trifluoromethyl as substitutions in the aryl moiety, which may be the same or different. R In the case of an aryl group having 6 to 10 carbon atoms which may have a substitution, the number of substitutions is not particularly limited, but is usually preferably 1 to 5, and optimally 1 to 3. It is an aryl group having a substitution component. Examples of the aryl group having no substitution component include phenyl, 1-naphthyl, 2-naphthyl and the like. Substitutions of aryl groups with substitutions include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom, preferably fluorine atom, chlorine atom, bromine atom; methyl, ethyl, propyl, butyl, Linear or branched alkyl having 1 to 4 carbon atoms such as isopropyl and t-butyl; linear or branched alkyl having 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and isopropoxy. Branched chain alkoxy; nitro; trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2 , 2-Dibromoethyl, 3-chloropropyl, 3,3,3-trifluoropropyl, Haloalkyl having 1 to 4 carbon atoms in a linear or branched chain such as 4-fluorobutyl and preferably having 1 to 3 halogen atoms of the same or different, preferably 1 to 3 Haloalkyl with 1 to 3 carbon atoms with the same 2 or 3 halogen atoms, more preferably 1 to 3 fluorine atoms, methyl or ethyl with chlorine atoms, optimally Are trifluoromethyl, trichloromethyl, difluoromethyl, 2-fluoroethyl, especially trifluoromethyl; or hydroxy ;. Aryl groups having a substituent include, for example, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylphenyl, o-, m- or p-. Methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-trifluoromethylphenyl, o-, m- or p-hydroxyphenyl, 3,5-di-t -butyl-4- Hydroxyphenyl, 3,4,5-trimethoxyphenyl. Preferably, as a substituent, a halogen atom, a linear or branched alkyl having 1 to 4 carbon atoms, a linear or branched alkoxy having 1 to 3 carbon atoms, or trifluoromethyl. Alternatively, it is an aryl group which may have 1 to 3 hydroxy groups, which are the same as or different from each other. Optimal is a phenyl group which may have one or two fluorine atoms, chlorine atoms, methyl, methoxy or trifluoromethyl as substitutions, which may be the same or different. R When is a linear or branched haloalkyl group having 1 to 4 carbon atoms, it preferably has 1 to 3 halogens of the same or different. For example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2,2-dibromoethyl, Examples include 3-chloropropyl, 3,3,3-trifluoropropyl and 4-fluorobutyl. It preferably has a linear or branched alkyl having 1 to 3 carbon atoms and has 1 to 3 halogen atoms (and the same 2 or 3 halogen atoms) that are the same or different. A haloalkyl group, more preferably one to three fluorine atoms, a methyl or ethyl group having a chlorine atom, preferably trifluoromethyl, trichloromethyl, difluoromethyl, 2-fluoroethyl, especially trifluoromethyl. R When is a halogen atom, for example, it is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom, and optimally, a fluorine atom or a chlorine atom. R When is a linear or branched alkoxy group having 1 to 5 carbon atoms, it may include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and the like. A linear or branched alkoxy group having 1 to 3 carbon atoms is preferable. Optimal is a methoxy group. R If is a linear or branched alkyl group with 1 to 5 carbon atoms, it is, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, s-butyl, t-butyl, 2 -Pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, etc. can be mentioned. A linear or branched alkyl group having 1 to 4 carbon atoms is preferable. Optimal is a linear or branched alkyl group having 1 to 3 carbon atoms. R When is a halogen atom, for example, it is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom, a chlorine atom, or a bromine atom, and optimally, a fluorine atom or a chlorine atom. R When is a linear or branched alkoxy group having 1 to 5 carbon atoms, it may include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy and the like. A linear or branched alkoxy group having 1 to 3 carbon atoms is preferable. Optimal is a methoxy group. R If is a linear or branched alkyl group with 1 to 5 carbon atoms, it is, for example, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, s-butyl, t-butyl, 2 -Pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, etc. can be mentioned. A linear or branched alkyl group having 1 to 4 carbon atoms is preferable. Optimal is a linear or branched alkyl group having 1 to 3 carbon atoms. Especially a methyl group. The compound having the general formula (I) can be salted according to a conventional method. Such salts include, for example, alkali metal salts such as lithium, sodium, potassium; alkaline earth metal salts such as calcium, barium; magnesium salts; aluminum salts; inorganic salts such as ammonia, methylamine, dimethyl. Organic base salts such as amine salts such as amines and dicyclohexylamines; basic amino acid salts such as lysine and arginine; can be mentioned. Alternatively, such salts include, for example, salts of hydrohalogen acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; nitrates; perchlorates; sulfates; phosphates; etc. Inorganic acid salts or salts of lower alkane sulfonic acids such as methane sulfonic acid, trifluoromethane sulfonic acid, ethane sulfonic acid; salts of allyl sulfonic acid such as benzene sulfonic acid, p-toluene sulfonic acid; Salts of amino acids such as; salts of carboxylic acids such as fumaric acid, succinic acid, citric acid, tartrate acid, sulphonic acid, maleic acid; and organic acid salts such as. It is preferably a pharmacologically acceptable salt. The compound having the general formula (I) has various isomers. That is, equation (A) [0057] [Chemical 9] (In the formula, R , R , R , R , X and Ar have the same meaning as described above. ), R If is a hydrogen atom, at least two asymmetric carbon atoms (* and* ) Have and R If is a methyl or hydroxymethyl group, at least 3 asymmetric carbon atoms (*) and* ) Have. In the general formula (I), the steric isomers based on these and the equal and non-equal mixtures of these isomers are all represented by a single formula. Therefore, the present invention also includes all of these isomers and mixtures of these isomers. In the compound having the general formula (I), the suitable absolute coordination of the asymmetric carbon is the asymmetric carbon atom *. and* Is a compound with an (R) -configuration. (1) In the compound having the general formula (I), R Indicates a hydrogen atom, a methyl group or a hydroxymethyl group. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is the basis (II) [0063] [Chemical 10] (In the formula, R Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxy group, a linear or branched alkyl group having 1 to 5 carbon atoms, an acetoxy group, and a nitro group. Shows a group, a cyano group, a benzyloxy group, a phenoxy group, a phenyl group or a trifluoromethyl group. R Indicates a linear or branched alkyl group or nitro group having a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a methoxy group, and 1 to 5 carbon atoms. R Indicates a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a methyl group. ) Or group (III) [0066] [Chemical 11] (In the formula, R , R And R Shows the same meaning as described above. ) Is shown. Alternatively, it is a salt of these compounds. (2) In the compound having the general formula (I), R Indicates a hydrogen atom or a methyl group. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is the basis (II) [0072] [Chemical 12] (In the formula, R Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxy group, a linear or branched alkyl group having 1 to 4 carbon atoms, an acetoxy group, and a nitro group. Shows a group, a benzyloxy group, a phenoxy group, a phenyl group or a trifluoromethyl group. R Indicates a linear or branched alkyl group having a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a methoxy group or 1 to 4 carbon atoms. R Indicates a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxy group, a methoxy group or a methyl group. ) Or group (III) [0075] [Chemical 13] (In the formula, R , R And R Shows the same meaning as described above. ) Is shown. Alternatively, it is a salt of these compounds. (3) In the compound having the general formula (I), more preferably R Indicates a hydrogen atom or a methyl group. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is the basis (II) [0081] [Chemical 14] (In the formula, R Is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a hydroxymethyl group, a methoxy group, an ethoxy group, a linear or branched alkyl group having 1 to 4 carbon atoms, an acetoxy group, and a nitro group. Shows a group, a benzyloxy group, a phenoxy group, a phenyl group or a trifluoromethyl group. R Indicates a linear or branched alkyl group having a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a methoxy group or 1 to 4 carbon atoms. R Indicates a hydrogen atom, a hydroxy group, a methoxy group or a methyl group. ) Or group (III) [0084] [Chemical 15] (In the formula, R , R And R Shows the same meaning as described above. ) Is shown. Alternatively, it is a salt of these compounds. (4) In the compound having the general formula (I), more preferably R Indicates a hydrogen atom. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is the basis (II) [0090] [Chemical 16] (In the formula, R Indicates a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, a linear or branched alkyl group having 1 to 4 carbon atoms, a phenoxy group or a trifluoromethyl group. R Indicates a linear or branched alkyl group having a hydrogen atom, a chlorine atom, a methoxy group or 1 to 4 carbon atoms. R Indicates a hydrogen atom, a hydroxy group or a methoxy group. ) Or group (III) [0093] [Chemical 17] (In the formula, R , R And R Shows the same meaning as described above. ) Is shown. Alternatively, it is a salt of these compounds. (5) In the compound having the general formula (I), more preferably R Indicates a hydrogen atom. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-bromophenyl group, 3-fluorophenyl group, 3-phenoxyphenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 3,5-Dichlorophenyl group, 3,5-di-t -butyl-4-hydroxyphenyl group, 3,4,5-trimethoxyphenyl group, 3-trifluoromethylphenyl group, 3-chloro-4-fluorophenyl Indicates a group, 1-naphthyl group or 2-naphthyl group. Alternatively, it is a salt of these compounds. (6) In the compound having the general formula (I), more preferably R Indicates a hydrogen atom. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar is a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-bromophenyl group, 3-fluorophenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 3,5-di- It indicates t-butyl-4-hydroxyphenyl group, 3-trifluoromethylphenyl group, 3-chloro-4-fluorophenyl group or 2-naphthyl group. Alternatively, it is a salt of these compounds. (7) In the compound having the general formula (I), more preferably R Indicates a hydrogen atom. R Indicates a 2,4-dioxothiazolidine-5-ylmethyl group. R And R Indicates a hydrogen atom. X indicates an oxygen atom. Ar represents a phenyl group, a 3-chlorophenyl group, a 3-bromophenyl group, a 3-trifluoromethylphenyl group, a 3-chloro-4-fluorophenyl group or a 2-naphthyl group. Alternatively, it is a salt of these compounds. Specific examples of the compound having the general formula (I) include the compounds listed in the table below. [Chemical 18] [table 1] Compound Ar R R R R number 1 3-Cl-Ph- H 4- (2,4- (O =)) -Thiz) CH --HH 2 2-Np- H 4-(2,4- (O =)) -Thiz) CH --HH 3 3-Tfm-Ph- H 4- (2,4- (O =)) -Thiz) CH --HH 4 3-Cl-4-F-Ph- H 4- (2,4- (O =)) -Thiz) CH --HH 5 3,5- (tBu) -4-HO-Ph- H 4- (2,4- (O =) -Thiz) CH --HH 6 3-MeO-Ph- H 4- (2,4- (O =)) -Thiz) CH --HH 7 Ph- -Me 4- (2,4- (O =)) -Thiz) CH --HH 8 Ph--CH OH 4- (2,4- (O =) -Thiz) CH --HH [0113] However, the abbreviations in the table have the following meanings. Ph = phenyl, Np = naphthyl, Me = methyl, tBu = t-butyl, Tfm = trifluoromethyl, 2,4- (O =) -Thiz = 2,4-dioxothiazolidine-5-yl. In the above compound table, it is preferably Exemplified Compound Nos. 1 and 3 or a salt thereof. The compound having the general formula (I) produced using the intermediate of the present invention can be produced by the method described below. Manufacturing method 1. The compound having the general formula (I) has a general formula. [0115] [Chemical 19] (In the formula, R And Ar have the same meaning as described above. Halo represents a halogen atom such as a chlorine atom or a bromine atom. ) With halohydrin and general formula [0116] [Chemical 20] (In the formula, R , R , R And X have the same meaning as described above. ) Is reacted with an amino compound having). The reaction is carried out in the presence or absence of a deoxidizing agent such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine and the like. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. Classes; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; alcohols such as methanol, ethanol, isopropanol; sulfoxides such as dimethyl sulfoxide; Alternatively, a mixed solvent of these is preferably used. The reaction temperature is room temperature or warm. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to several days. It is preferably carried out in a solvent of alcohols, amides, sulfoxides, for 3 hours to 3 days at room temperature to 60 ° C. The compound having the general formula (V) is produced by the following method. [Chemical 21] However, Boc = t-butoxycarbonyl group, Z = benzyloxycarbonyl group, Ms = mesyl group, Ts = shows a tosyl group. R , R , R And X have the same meaning as described above. Compound (c) is prepared by subjecting compound (b) to N-Boc-aminoalcohol or NZ-aminoalcohol (a) according to the usual Mitsunobu reaction (O. Mitsunobu, Synthesis, p. 1 (1981)). Manufactured by That is, the reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. Classes; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; or a mixed solvent thereof are preferably used. The reaction temperature is ice-cooled or warm, preferably ice-cooled or 60 ° C. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually several hours to several days, preferably 5 hours to 3 days. Compound (c) can also be obtained by reacting compound (d) with compound (e). The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as ethyl ether, tetrahydrofuran and dioxane; dimethylformamide, Amides such as dimethylacetamide, hexamethylphosphoric acid triamide; or a mixed solvent thereof are preferably used. The reaction temperature is under ice cooling or heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to several days. It is preferably carried out in the presence of a solvent for 1 hour to 1 day under ice cooling or at 60 ° C. In addition, compound (d) is obtained by mesylating or tosylating compound (a). The reaction is carried out in the presence or absence of a deoxidizing agent such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine, pyridine and the like. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. Classes; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; sulfoxides such as dimethyl sulfoxide; or a mixed solvent thereof are preferably used. The reaction temperature is under ice cooling or heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to several days. It is preferably carried out in the presence of triethylamine for 1 hour to 1 day under ice cooling or at 60 ° C. Then, the compound having the general formula (V) can be de-Boc or de-Z from the compound (c) by the usual method (for example, TWGreen, Protective Groups in Organic Synthesis), John Wiley & Sons; Obtained according to JFWMcOmie, Protective Groups in Organic Chemistry, Plenum Press. The compound having the general formula (V) of the optically active substance can be obtained by using the compound (a) of the optically active substance. When the compound having the general formula (IV) and the compound having the general formula (V) are optically active substances, * of the general formula (A) and* Each steric isomer based on a carbon atom can be obtained. Manufacturing method 2. The compound having the general formula (I) has a general formula. [0128] [Chemical 22] (In the formula, R And Ar have the same meaning as described above. ) And the above general formula [0129] [Chemical 23] (In the formula, R , R , R And X have the same meaning as described above. ) Is reacted with an amino compound having). The reaction is carried out in the presence or absence of an acid catalyst such as hydrochloric acid, sulfuric acid, boron trifluoride, aluminum chloride or basic alumina. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. Classes; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; alcohols such as methanol, ethanol, isopropanol; sulfoxides such as dimethyl sulfoxide; Nitrives such as acetonitrile; water; or a mixed solvent thereof are preferably used. The reaction temperature is under ice cooling or heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 1 hour to several days. It is preferably carried out at 30 ° C to 120 ° C for 1 hour to 1 day in the presence of a solvent. When the compound having the general formula (V) and the compound having the general formula (VI) are optically active substances, * of the general formula (A) and* Each steric isomer based on a carbon atom can be obtained. Manufacturing method 3. The compound having the general formula (I) has a general formula. [0132] [Chemical 24] (In the formula, R And Ar have the same meaning as described above. Z'indicates a hydrogen atom or hydroxyl protecting group. Here, the protecting group for the hydroxyl group is a commonly used protecting group, and examples thereof include tetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl, trimethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl. .. ) Is reacted with the amino compound having the general formula (V) to carry out the general formula. [0133] [Chemical 25] (In the formula, R , R , R , R , X, Ar and Z'have the same meaning as described above. ) Is produced (step [A]) and then reduced (step [B]). [0134] [Chemical 26] (In the formula, R , R , R , R , X, Ar and Z'have the same meaning as described above. ) Is produced, and if necessary, it is obtained by subjecting it to a deprotecting group reaction when Z'is a protecting group for a hydroxyl group. The step [A] is a step of producing a compound having the general formula (VIII), and is usually preferably carried out in the presence of a solvent. The reaction is carried out in the presence or absence of a dehydrating agent such as anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium sulfate, anhydrous calcium chloride, anhydrous magnesium sulfate, and molecular sieve. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride. Classes; ethers such as ethyl ether, tetrahydrofuran, dioxane; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphate triamide; alcohols such as methanol and ethanol; sulfoxides such as dimethyl sulfoxide; sulfolane; Alternatively, a mixed solvent of these is preferably used. The reaction temperature is under ice-cooling or heating under reflux. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 0.5 hours to 10 It's time. It is preferably carried out in a solvent of hydrocarbons and alcohols for 1 to 5 hours under ice-cooling or heating under reflux. More preferably, it is carried out by heating under reflux in benzene for 1 to 3 hours and dehydrating. The step [B] is a step of producing a compound having the general formula (IX), and is a reaction of reducing the compound having the general formula (VIII). The reaction is usually carried out by hydrogenation in the presence of a reducing agent or in the presence of a catalyst. When the reaction is carried out in the presence of a reducing agent, the reducing agent used includes, for example, metallic hydrogen such as lithium borohydride, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and diisobutylaluminum hydride. A compound is used. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as ethyl ether, tetrahydrofuran and dioxane; dimethylformamide. , Dimethylacetamide, amides such as hexamethylphosphate triamide; alcohols such as methanol, ethanol, isopropanol; or a mixed solvent thereof are preferably used. The reaction temperature is under ice cooling or heating. The reaction time varies depending on the reaction reagent, reaction temperature, etc., but is usually 0.5. Time or days. It is preferably carried out in an alcohol solvent in the presence of sodium borohydride or sodium cyanoborohydride for 1 hour to 1 day under ice cooling or at 50 ° C. When the hydrogenation reaction is carried out in the presence of a catalyst, the reaction is carried out in the presence of a catalyst. As the catalyst used, for example, a catalytic hydrogenation catalyst such as palladium-carbon or platinum oxide is preferably used. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, ethers such as ethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; methanol, ethanol and isopropanol. Alcohols; organic acid esters such as methyl acetate and ethyl acetate; or a mixed solvent thereof are preferably used. When using a palladium-based catalyst, medium to high pressure hydrogen gas, preferably 1-5 kg / cm Hydrogen gas is used. When using a platinum-based catalyst, hydrogen in atmospheric pressure can be used if desired. The reaction is preferably carried out in alcoholic solvents, especially methanol and ethanol, at room temperature to 50 ° C. The deprotecting group reaction, which is then performed as needed, when Z'is a protecting group for the hydroxyl group, is carried out in the usual manner (eg, TWGreen, Protective Groups in Organic Synthesis), Obtained by performing at John Wiley & Sons; JFWMcOmie, Protective Groups in Organic Chemistry, Plenum Press. Here, in the compound having the general formula (VII), R Compound (X) where is a hydrogen atom [0140] [Chemical 27] Is manufactured as follows. [Chemical 28] (In the formula, Ar and Z'have the same meaning as described above. R represents a lower alkyl group.) That is, compound (f) is used in the usual way, eg Organic Syntheses, Volume I, 336. The compound (g) is produced by processing according to the method described on page. The reaction is usually carried out, for example, by reacting compound (f) with hydrogen cyanide in the presence or absence of a solvent to give cyanohydrin, or reacting trimethylsilylnitrile in the presence of zinc iodide to give cyanohydrin, and then acid-catalyzed hydrolysis. It is carried out by subjecting it to a decomposition reaction. The cyanohydrinization reaction is usually carried out under ice cooling or heating, preferably at room temperature to 100 ° C. Acid-catalyzed hydrolysis reactions typically use common acids, such as hydrochloric acid, inorganic acids such as sulfuric acid; or organic acids such as p-toluenesulfonic acid, acetic acid; at room temperature or in the presence of excess water. It is carried out in tens of minutes to tens of hours under reflux. It is preferably carried out by heating under reflux for 30 minutes to 10 hours in the presence of hydrochloric acid or sulfuric acid. Next, the obtained compound (g) is subjected to, for example, an usual acid-catalyzed esterification method, a diazoalkane esterification method, an alkali-alkyl halide esterification method, or the like to produce compound (h). To do. Acid-catalyzed esterification methods include, for example, adding excess alcohol in the presence or absence of a solvent at room temperature or in the presence of an inorganic acid such as hydrogen chloride, sulfuric acid; or an organic acid such as p-toluenesulfonic acid; It is obtained by reacting at warm temperature for several hours to several days. The esterification method with diazoalkane is a common solvent such as alcohols such as methanol and ethanol; hydrocarbons such as benzene, toluene, xylene, hexane and heptane; ethers such as ethyl ether, tetrahydrofuran and dioxane; or These mixed solvents are preferably used. The reaction temperature is ice-cooled or warm, preferably ice-cooled or 60 ° C. Examples of the alkali used in the esterification method using an alkali and an alkyl halide include potassium carbonate and sodium carbonate. The reaction is carried out in conventional solvents such as alcohols such as methanol and ethanol; ethers such as ethyl ether, tetrahydrofuran and dioxane; hydrocarbons such as benzene, toluene, xylene, hexane and heptane; dimethylformamide, dimethylacetamide, Amides such as hexamethylphosphoric acid triamide; or a mixed solvent thereof are preferably used. The reaction is usually carried out at room temperature or warming for several hours to several days. Next, the obtained compound (h) is protected with a normal hydroxyl-protecting group to produce compound (i). The reaction is protected with a hydroxyl protecting group such as tetrahydropyranyl, methoxymethyl, diphenylmethyl, trityl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl (eg TWGreen, Protective Groups in Organic Synthesis (Protective)). Groups in Organic Synthesis), John Wiley & Sons; JFWMcOmie, Protective Groups in Organic Chemistry, Plenum Press. The resulting compound (i) was then combined with diisobutylaluminum hydride in a conventional manner, eg, in a hydrocarbon solvent such as hexane, heptane, benzene, toluene, xylene, under cooling in a dry ice / acetone bath. By reacting, a compound having the above general formula (X) can be obtained. Alternatively, the compound having the general formula (X) is also produced by the following method. [Chemical 29] (In the formula, Ar, Z'and R have the same meaning as described above.) That is, compound (i) is reacted with a conventional method, for example, a metal hydride such as lithium aluminum hydride or diisobutylaluminum hydride. To produce compound (j). The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, and is preferably carried out in the presence of ethers such as ethyl ether, tetrahydrofuran and dioxane. Next, the obtained compound (j) is subjected to a normal oxidation reaction, for example, pyridine-SO. A compound having the general formula (X) can be obtained by subjecting it to a complex, an oxidation reaction using a chromic acid-based oxidizing agent, a Swern oxidation reaction, or the like. When the compound having the general formula (VII) is an optically active substance, * of the general formula (A) A three-dimensional isomer based on a carbon atom can be obtained. That is, the amino compound having the general formula (V) is an optically active substance, and R If is a hydrogen atom, depending on the combination (* R, * R) body, (* R, * S) body, (* S, * R) body, (* S, * S) The body can be obtained independently. In addition, compound (g) uses optically active amines used in conventional optical resolution, such as (+)-or (-)-ephedrine, (d)-or (l) -1-phenylethylamine, etc. It can be divided into (R) -g) and ((S) -g). Manufacturing method 4. In the compound having the general formula (I), R A compound in which is a 2,4-dioxothiazolidine-5-ylmethyl group is obtained by reducing the corresponding compound which is a 2,4-dioxothiazolidine-5-ylmethylene group. The reduction reaction is accomplished by a hydrogenation reaction in the presence of a catalyst. As the catalyst used, for example, a catalytic hydrogenation catalyst such as palladium-carbon or platinum oxide is preferably used. The reaction is usually preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not affect the reaction, for example, ethers such as ethyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; methanol, ethanol and isopropanol. Alcohols; organic acid esters such as methyl acetate and ethyl acetate; or a mixed solvent thereof are preferably used. When using a palladium-based catalyst, medium to high pressure hydrogen gas, preferably 1-5 kg / cm Hydrogen gas is used. When using a platinum-based catalyst, hydrogen in atmospheric pressure can be used if desired. The reaction is preferably carried out in alcoholic solvents, especially methanol and ethanol, at room temperature to 50 ° C. After completion of the reaction, the target compound obtained by the above-mentioned production methods 1 to 4 can be purified by a conventional method, for example, column chromatography, recrystallization method, reprecipitation method or the like, if necessary. For example, a solvent is added to the reaction mixture for extraction, and the solvent is distilled off from the extract. The obtained residue can be purified by subjecting it to column chromatography using silica gel or the like to obtain a pure product of the target compound. [Action] The compound having the general formula (I) or a salt thereof has a hypoglycemic effect, an obesity-improving effect, a glucose intolerance-improving effect, a glucose tolerance-suppressing effect in the liver, and a lipid-lowering effect. It is useful as a prophylactic and / or therapeutic agent for hyperglycemia, diabetic complications such as retinopathy, nephropathy, neuropathy, cataracts, coronary artery disease, arteriosclerosis, obese hypertension, osteoporosis and the like. Furthermore, since the compound having the general formula (I) or a salt thereof has extremely low toxicity, it is useful as a prophylactic and / or therapeutic agent for the above diseases. The compound having the general formula (I) is administered in various forms. Examples of the administration form include oral administration with tablets, capsules, granules, powders, syrups and the like, or parenteral administration with injections (intravenous, intramuscular, subcutaneous), drip infusions, suppositories and the like. .. These various preparations are usually used in the field of pharmaceutical formulation technology such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizing agents, suspending agents, coating agents, etc. in accordance with the conventional method. It can be formulated with known additives. The dose varies depending on the symptoms, age, body weight, administration method, dosage form, etc., but usually 0.01 mg to 2000 mg can be administered daily to adults. [Example] Next, the present invention will be described in more detail with reference to Examples and Reference Examples. Example 1.5- (4-acetoxybenzyl) -3-triphenylmethylthiazoli Gin-2, 4-Zeon (1) 5- (4-acetoxybenzylidene) thiazolidine-2,4-dione A mixture of p-hydroxybenzaldehyde (200 g), thiazolidine-2,4-dione (229 g), sodium acetate (280 g) and dimethylacetamide (660 ml) was stirred at 150 ° C for 1 hour. After cooling the reaction mixture, dimethylacetamide (540 ml) and acetic anhydride (370 ml) were added, and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was poured into water, the precipitated solid was collected by filtration, washed with water, and dried to give 5- (4-acetoxybenzylidene) thiazolidine-2,4-dione. (2) 5- (4-acetoxybenzyl) thiazolidine-2,4-dione 90 ° C to the mixture of 5- (4-acetoxybenzylidene) thiazolidine-2, 4-dione (2.0 g), acetic acid (80 ml) and 10% palladium-carbon (2.0 g) obtained in (1) above. Hydrogen gas was introduced at normal pressure and a hydrogenation reaction was carried out for 5 hours. The catalyst was filtered off from the reaction mixture, toluene was added to the filtrate, acetic acid was azeotropically distilled off, toluene and hexane were further added, and the precipitated crystals were collected by filtration and dried. -2,4-Zeon was obtained. (3) 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione Triethylamine (3.43 g) was added to methylene chloride (70 ml) containing 5- (4-acetoxybenzyl) thiazolidine-2,4-dione (9.0 g) obtained in (2) above, and triphenylmethyl chloride (triphenylmethyl chloride) ( Methylene chloride (30 ml) containing 9.45 g) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then left at the same temperature overnight. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent is distilled off from the organic layer, the precipitated crystals are washed with a mixed solvent of hexane-ethyl acetate, and then dried to reach the melting point. 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione having a temperature of 169 to 178 ° C was obtained. Example 2.5- (4-Hydroxybenzyl) -3-triphenylmethylthiazoli Gin-2, 4-Zeon Toluene (70 ml) containing 5- (4-acetoxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione (7.86 g) obtained in Example 1 was mixed with 28% sodium methoxide under ice-cooling. Methanol solution (2.99 g) and methanol (10 ml) were added dropwise. The reaction mixture was stirred at room temperature for 1 hour and then left at the same temperature overnight. After adjusting the pH to 4 by adding 1N hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off from the ethyl acetate layer, the precipitated crystals were washed with hexane, and when dried, they had a melting point of 139 to 148 ° C. 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4- Zeon was obtained. Reference example 1.3-Chloromandelic acid 3-Chlorobenzaldehyde (158 g), trimethylsilylnitrile (111.6 g) ) And zinc iodide (catalytic amount) were heated and stirred at 90 ° C for 2 hours. The reaction mixture was ice-cooled, concentrated hydrochloric acid (350 ml) was added, and the mixture was heated under reflux for 1 hour. Water and ethyl acetate were added to the reaction mixture to separate the ethyl acetate layer, a 30% aqueous sodium hydroxide solution was added, and the aqueous layer was washed 3 times with ethyl acetate. Concentrated hydrochloric acid was added to the aqueous layer to make it acidic, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous sodium sulfate. When ethyl acetate was distilled off from the extract, the target compound having a melting point of 110 to 114 ° C was obtained. Reference example 2. (R) -3-chloromandelic acid and (S) -3-chloromandelic acid The mixture of 3-chloromandelic acid (100 g) and (R)-(+)-1-phenethylamine (32.7 g) obtained in Reference Example 1 was recrystallized from a mixed solvent of methanol and ether, and the crystals and filtrate were recrystallized. Divided into. The crystals were recrystallized three more times with a mixed solvent of methanol and ether, and then hydrochloric acid was added and the crystals were extracted with ethyl acetate. When the ethyl acetate solution is dried over anhydrous sodium sulfate and the solvent is distilled off, the melting point is 102 to 105 ° C and the optical rotation is [α]. D -153.7 ° (C = 1.026, CHCl ) To (R) -3-chloromandelic acid was obtained. Further, after adding hydrochloric acid to the above filtrate to make it acidic, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and ethyl acetate was distilled off. When (S)-(-)-phenethylamine (32.7 g) was added to the obtained residue and recrystallized three times with a mixed solvent of methanol and ether, the melting point was 101 to 104 ° C and the optical rotation was [α]. D + 151.9 ° (C = 1.008, CHCl ) Was obtained (S) -3-chloromandelic acid. Reference example 3. Methyl (R) -3-chloromandelate Trimethylsilyldiazomethane (18.3 g; 10% hexane solution) was added to the solution of (R) -3-chloromandelic acid (28 g) obtained in Reference Example 2 in methanol (300 ml) and benzene (700 ml) at room temperature. The mixture was added dropwise and stirred for 1 hour. When the solvent was distilled off from the reaction mixture, the Rf value = 0.36 (silica gel TLC; ethyl acetate: hexane = 1: 5) and the optical rotation [α]. D -119.3 ° (C = 1.00, CHCl ) Was obtained. Reference Example 4. (R) -α-t-Butyldimethylsilyloxy-α- (3-Chlorophenyl) Methyl Acetate To a solution of methyl (R) -3-chloromannerate (28 g) and imidazole (28.5 g) obtained in Reference Example 3 in dimethylformamide (300 ml) under ice-cooling, t-butyldimethylsilyl chloride (31.6 g). ) Dimethylformamide (200 ml) solution was added dropwise, and the mixture was stirred at the same temperature for 30 minutes and then left overnight at 40 ° C. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, the ethyl acetate layer was separated, and the mixture was dried over anhydrous sodium sulfate. When ethyl acetate was distilled off from the ethyl acetate layer and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 15), the melting point was 36 to 38 ° C and the optical rotation was [α]. D -39.1 ° (C = 1.014, CHCl ) Was obtained. Reference example 5. (R) -α-t-butyldimethylsilyloxy-α- (3-chlorophenyl) acetaldehyde A solution of (R) -α-t-butyldimethylsilyloxy-α- (3-chlorophenyl) methyl acetate (26 g) obtained in Reference Example 4 in anhydrous hexane (1000 ml) and anhydrous toluene (500 ml) was used. After cooling to -60 ° C, diisobutylaluminum hydride (1 molhexane solution) (124 ml) was added dropwise. After stirring at the same temperature for 3 hours, water (10 ml) was added to gradually raise the temperature to room temperature, water and ethyl acetate were added, and the mixture was stirred for 30 minutes. The insoluble material was filtered off from the reaction mixture with Celite, the ethyl acetate layer of the filtrate was separated, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the ethyl acetate layer, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 60). Rf value = 0.36 (silica gel TLC; ethyl acetate: hexane = 1: 60). ) Was obtained. Reference Example 6.5-{4- [2 (R) -t-butoxycarbonylaminopropoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione Azodicarboxylic acid diethyl ester (13.2 g) was added dropwise to a benzene (300 ml) solution containing triphenylphosphine (20.7 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Next, 5- (4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione (35.0 g) obtained in Example 2 was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour, and then (R). -2-t-Butoxycarbonylamino-1-propanol (13.2 g) was added and the mixture was left overnight. Then, triphenylphosphine (total 40.9 g), azodicarboxylate diethyl ester (total 23.68 ml) and (R) -2-t-butoxycarbonylamino-1-propanol (total 33 g) were sequentially added to the reaction mixture 3 to 4 It was added in batches and stirred for 2 days. After completion of the reaction, benzene was distilled off from the reaction mixture, and then the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 3) to have a melting point of 153 to 157. ° C and specific rotation [α] D + 19.5 ° (C = 1.000, CHCl ) Was obtained. Reference Example 7.5- [4- (2 (R) -amino-1-propoxy) benzyl] thiazolidine-2,4-dione / trifluoroacetate Methylene chloride containing 5- {4- [2 (R) -t-butoxycarbonylaminopropoxy] benzyl} -3-triphenylmethylthiazolidine-2,4-dione (85.5 g) obtained in Reference Example 6. Trifluoroacetic acid (500 ml) was added dropwise to the 700 ml) solution under ice-cooling, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, methylene chloride and trifluoroacetic acid were distilled off from the reaction mixture under reduced pressure, benzene and a small amount of ethyl acetate were added to the obtained residue, and the produced crystals were filtered off. When this crystal is recrystallized from a mixed solvent of methanol-ethyl acetate, it has a melting point of 162 to 166 ° C and a specific rotation [α]. D The target compound at -13.0 ° (C = 0.885, MeOH) was obtained. Reference example 8. 5- {4- [2 (R)-(2 (R)-(3-chlorophenyl) -2-t-butyldimethylsilyloxyethylamino) propoxy] benzyl} thiazolidine-2,4-dione 5- [4- (2 (R) -Aminopropoxy) benzyl] thiazolidine-2,4-dione-trifluoroacetate (36.5 g) obtained in Reference Example 7., obtained in Reference Example 5 ( A mixture of R) -α-t-butyldimethylsilyloxy-α- (3-chlorophenyl) acetaldehyde (98.4 g) and anhydrous methanol (400 ml) was stirred at room temperature for 2.5 hours, then cooled in an ice-salt bath and hydrogen. Sodium cyanoborohydride (29.0 g) was added in small portions. The reaction mixture was allowed to stand at room temperature overnight, and then methanol was distilled off under reduced pressure. Then, water and ethyl acetate were added to the obtained residue, and the ethyl acetate layer was separated. The separated ethyl acetate solution was washed with brine and dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off from this solution under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 2: 1) to show specific rotation [α]. D -26.3 ° (C = 0.988, CHCl ) Was obtained. Reference Example 9.5-{4- [2 (R)-(2 (R)-(3-chlorophenyl) -2-hydroxyethylamino) propoxy] benzyl} thiazolidine-2,4-dione (Example Compound No. 1) 5- {4- [2 (R)-(2 (R)-(3-chlorophenyl) -2-t-butyldimethylsilyloxyethylamino) propoxy] benzyl} thiazolidine-2, obtained in Reference Example 8. Tetrahydrofuran-n-butylammonium (88 g) was added to a solution of 4-dione (46.2 g) in tetrahydrofuran (500 ml) under ice-cooling. After stirring the reaction mixture at room temperature for 15 hours, tetrahydrofuran was distilled off under reduced pressure, water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off from the extract under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: ethanol = 5: 1). When the obtained crude crystals were further recrystallized from a mixed solvent of ethyl acetate and ethanol, they had a melting point of 100 to 112 ° C and a specific rotation [α]. D 27.1 g of the target compound at -4.4 ° (C = 1.005, methanol) was obtained. [Effect of Examples] Test Example 1. Aldose reductase inhibitory action The aldose reductase of bovine crystalline lens is S. Hyman and JHKinoshita [J. Biol. Chem., Vol. 240, p. 877 (1965)] and K. Inagaki, I. Miwa and J. Okuda [Arch. Biochem. Biophys. , 316, 337 (1982)], and separated and partially purified by the method described. The activity was then measured photometrically by the method described in Varma et al. [Biochem.Pharmac., Vol. 25, p. 2505 (1976)]. Inhibition of enzyme activity was measured at a concentration of 5 μg / ml of the compound of the present invention. The results are shown in Table 2. [Table 2] At 5 μg / ml Inhibition rate (%) Compound 47.5 of Reference Example 9 [0166] The compound of Reference Example 9 showed an excellent aldose reductase inhibitory effect. Test example 2. Toxicity Male ddY mice were used as experimental animals. Three animals in a group were used in the experiment. The test compound was orally administered to each animal at a body weight of 300 mg / kg. The test compound used was obtained in Reference Example 9. Animals were observed for 1 week after administration. And, during that period, no anomaly caused by the test compound was observed. All animals were alive during the observation period. From the point of view of the parenchymal dose to each animal, a mortality rate of 0 indicates that the compound having the general formula (I) has very low toxicity. [Effect of the invention] The compound having the general formula (I) or a salt thereof produced by using the intermediate of the present invention has a hypoglycemic effect, an obesity improving effect, a glucose intolerant improving effect, a hepatic gluconeogenesis inhibitory effect, and a lipid on humans. Has a lowering effect. Therefore, prophylactic and / or therapeutic agents for hyperglycemia, obesity, hyperlipidemia, obese hypertension, osteoporosis, diabetic complications such as retinopathy, nephropathy, neuropathy, cataracts, coronary artery disease, arteriosclerosis, etc. It is useful as.

JP3899147

PRODUCTION OF OPTICALLY ACTIVE COMPOUND

Yuichiro Haramoto

JP2005504043A

June 29, 2006

March 22, 2004

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Nippon Chemical Industry Co., Ltd.
Yuichiro Haramoto

C07C217/18; C07C209/12; C07C213/08; C09K19/16; C09K19/38; G03G5/06; H01L51/50

JPS568350A	1981-01-28
JPS5674154A	1981-06-19
JPH09316442A	1997-12-09
JP2001351786A	2001-12-21

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