JP2000514041A - Thiazolidinedione compounds having anti-diabetic, hypolipidemic and anti-hypertensive properties, their preparation, and their pharmaceutical compositions - Google Patents

Abstract

  (57) [Summary] Novel thiazolidinedione antidiabetic compounds, their tautomeric forms, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates And pharmaceutically acceptable compositions containing them; methods for preparing the antidiabetic compounds and their uses.

Description

DETAILED DESCRIPTION OF THE INVENTION Thiazolidinedione compounds having anti-diabetic, hypolipidemic, anti-hypertensive properties, those Preparation method and pharmaceutical composition thereofField of the invention   The present invention relates to novel antidiabetic compounds, their tautomeric forms, their derivatives, Their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable To their solvates and pharmaceutically acceptable compositions containing them. I do. The present invention particularly relates to novel thiazolidinedione derivatives of the general formula (I), Tautomeric forms, their derivatives, their stereoisomers, their polymorphs, pharmaceutically acceptable Salts thereof, pharmaceutically acceptable solvates thereof, and containing them Pharmaceutical compositions.   The present invention relates to the novel thiazolidinedione derivatives described above, their tautomeric forms, Their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable Salts thereof, pharmaceutically acceptable solvates, novel intermediates, and pharmaceuticals containing them The preparation of the target composition.   The thiazolidinedione derivative of the present invention represented by the general formula (I) described above has an insulin resistance. Treatment and / or prevention of diseases or conditions in which resistance is a serious pathophysiological mechanism Useful for Examples of these diseases and conditions include type II diabetes, impaired glucose tolerance , Dyslipidaemia, hypertension, coronary heart disease, and atheroma Other cardiovascular diseases, including atherosclerosis. Thiazolidinedione induction of formula (I) The body is useful for the treatment of insulin resistance with obesity and psoriasis. You. Thiazolidinedione derivatives of formula (I) are used to treat diabetic complications Can also be used for polycystic ovarian syndrome (PCOS), sugar Uremic nephropathy, Glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive renal sclerosis, end-stage renal disease Certain renal diseases, including disease and microalbuminuria, and certain Treat and / or prevent other diseases and conditions, such as eating disorders (Aldose Can also be used to improve the cognitive function of dementia.Background of the Invention   Insulin resistance is a study of insulin's biological properties over a wide range of concentrations. The ability to exert a positive effect is diminished. When you become insulin resistant, The body secretes abnormally large amounts of insulin to compensate for the deficiency. This happens If not, plasma glucose levels will necessarily increase, leading to diabetes. Advanced In the country, diabetes is a common problem, obesity, hypertension, hyperlipidemia (J. Clin . Invest., (1985) 75: 809-817; Engl. J. Med. (1987) 317: 350.357; Clin . Endocrinol.Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and And other renal complications (see patent application WO 95/21608) With abnormalities. At present, insulin resistance and relative hyperinsulinemia Contributes to obesity, hypertension, atherosclerosis, and type II diabetes Is gradually being recognized. Obesity, hypertension, and angina With insulin resistance, insulin resistance is associated as a central etiology Syndrome-described as Syndrome X. In addition, polycystic ovary disease Group (patent application WO95 / 07697), psoriasis (patent application WO95 / 35108), dementia (Behavioral Brai) n Research (1996) 75: 1-11) and others suggest that insulin resistance may be the central etiology. unknown.   Many molecular defects are associated with insulin resistance. These include Decreased expression of insulin receptors present in the plasma membrane of insulin-responsive cells Insulin binding to the receptor, including glucose transport and glycogen synthesis. Alterations in signaling pathways that are activated after combining.   The development of non-insulin-dependent diabetes and other related complications It is considered that lack of insulin action is more important than insulin secretion deficiency So anti-diabetic treatment based solely on stimulation of insulin release is not fundamentally appropriate Suspicion has arisen. Recently, Takeda has reported that 5- (4 - Belongs to a new class of derivative books of (alkoxybenzyl) -2,4-thiazolidinedione (See Chem. Pharm. Bull. 1982, 30, 3580-3600). Formula II V represents a substituted or unsubstituted divalent aromatic group, and U represents Represents various groups that have been reported in various patent documents.   As an example, U may represent the following groups:   (i) Group of formula (IIa) (R¹Is a hydrogen or hydrocarbon residue or Is a heterocyclic residue, R^TwoIs hydrogen or lower alkyl which can be substituted with a hydroxyl group. , X is an oxygen or sulfur atom, and Z is a hydroxylated methylene or carboxy group. N, m is 0 or 1, and n is an integer of 1 to 3. These compounds are It is disclosed in state patent application 0,177,353. )   Examples of these compounds are shown in formula (IIb).   (ii) the group of formula (IIc) (where R¹And R^TwoAre the same or different, each Hydrogen or C₁-C_FiveRepresents alkyl, R^ThreeIs hydrogen, an acyl group, (C₁-C₆) Alkoxy carb A carbonyl group or an aralkyloxycarbonyl group;^FourAnd R^FiveAre the same or different And hydrogen and C respectively₁−C_FiveAlkyl or C₁~ C_FiveRepresents alkoxy or R^Four , R^FiveAre both C₁~ C_FourRepresents an alkenedioxy group, n is 1, 2, or 3, and W is CH_Two, C O, CHOR⁶Group (where R⁶Is R^ThreeLists one of the items or groups defined for Then R^ThreeAnd may be the same or different). These compounds The product is disclosed in European Patent Application No. 0,139,421. )   Examples of these compounds are shown in (IId).   iii) Group of formula (IIe) (where A¹Is a substituted or unsubstituted aromatic Represents a multicyclic group, R¹Represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (aryl Moieties may be substituted or unsubstituted) or substituted Represents an unsubstituted aryl group, and n represents an integer in the range of 2 to 6. these The compounds are disclosed in European Patent Application 0,306,228. )   Examples of such compounds are shown in formula (IIf).   (iv) a group of formula (IIg) (where Y is N or CR^Five, R¹, R^Two, R^Three, R^FourAnd R^FiveIs hydrogen , Halogen, alkyl, etc., R⁶Represents hydrogen, alkyl, aryl, etc., and n is 0 Represents an integer of ~ 3. These compounds are disclosed in European Patent Application No. 0,604,98: 3 Have been. ) Examples of such compounds are shown in formula (IIh).   v) Group of formulas (IIia ~ d) (where R¹Is a hydrogen atom, halogen, straight-chain or branched ( C₁~ C₆) Alkyl, (C₁~ C₆) Represents an alkoxy, trifluoromethyl or cyano group X is S, O or NR (where R is H or (C₁~ C₆) Which is an alkyl group). This These compounds are disclosed in European Patent Application 0,528,734. )   Examples of compounds belonging to this class are shown in formula (IIj).  Some of the above-mentioned anti-diabetic compounds known to date have reduced bone marrow function. Has hepatic and cardiotoxicity, or appears to be ineffective, thus treating diabetes. The general use of them to treat and control has limitations and limitations .Summary of the Invention   Has lower toxicity, higher potency and better potency at lower doses Treats less toxic type II diabetes (non-insulin-dependent diabetes mellitus (NIDDM)) In order to develop new compounds for Emphasis on the application and improvement of the efficacy, and as a result Azolidinedione derivatives have been developed.   Therefore, a major object of the present invention is to provide novel thiazolidinedione derivatives, their mutual Mutable forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts A pharmaceutically acceptable solvate thereof, a pharmaceutical composition containing them, or Is to provide a mixture thereof.   It is another object of the present invention to have increased activity, no toxic effects or no toxic effects. Thiazolidinedione derivatives with reduced sexual effects, their tautomeric forms, those Isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable Or their solvates, pharmaceutical compositions containing them, or mixtures thereof. To provide.   Yet another object of the present invention is a novel thiazolidinedione of the above formula (I), Tautomeric forms, their stereoisomers, their polymorphs, pharmaceutically acceptable Or a pharmaceutically acceptable solvate thereof.   Yet another object of the present invention is to provide suitable carriers, solvents, diluents, and such compositions A compound of general formula (I), in combination with other media usually used in the preparation of Tautomers, their stereoisomers, their polymorphs, their salts, their solutions It is to provide a pharmaceutical composition containing a solvate, or a mixture thereof.Detailed description of the invention   The thiazolidinedione derivative of the present invention has the general formula (I).   In the above formula (I), A is a substituted or unsubstituted aromatic group, Substituted or unsubstituted with one heteroatom selected from sulfur, oxygen or sulfur Is an unsubstituted independent or fused 5-membered heterocyclic group, or a substituted Independent or fused 6-membered, unsubstituted or substituted, having one or more nitrogen atoms Ring heterocyclic group (may or may not contain one or more oxo groups on the ring And B and D are a substituted or unsubstituted link between N and X (Which may or may not contain one or more double bonds) X is CH_TwoOr a group selected from the group consisting of nitrogen, oxygen, and sulfur Ar represents any of the optionally substituted divalent aromatic groups or Represents a heterocyclic group, R₁And R_TwoMay be the same or different, and may be a hydrogen atom, a lower Represents a alkyl, halogen, alkoxy, or hydroxyl group, or R¹And R^TwoOne in both Represents one bond, and p is an integer ranging from 0 to 4.   A can be a 6-membered heterocyclic group containing 1-3 nitrogen atoms, and A is substituted Or an unsubstituted independent or fused ring, containing up to 3 oxo groups I can do it.   Suitable aromatic groups represented by A include phenyl, naphthyl, phenanthryl, and Preferably, phenyl and naphthyl groups are included, and a suitable heterocyclic group represented by A is , Furyl, pyrrolyl, thienyl, pyridyl, quinolyl, 4-pyridon-2-yl, Rimidyl, 4-pyrimidone-2-yl, pyridazyl, and 3-pyridazon-2-yl groups; Tarazinyl, phthalazinyl, quinoxalinyl, quinoxalonyl, quinazolinyl , Quinazolinonyl, azaindolyl, naphthalidinyl, carbazolyl, indori Benzofuranyl, pyrimidinyl and the like.   Preferred groups represented by A include pyridyl, quinolyl, indolyl, benzofura And a quinazolinonyl group.   More preferred groups represented by A include pyridyl and quinolyl groups. At A One or more suitable substituents on the aromatic and heterocyclic groups represented include hydroxy, a A mino group, a halogen atom such as chlorine, fluorine, bromine or iodine, substituted or Unsubstituted (C₁~ C₁₂) Alkyl groups, especially methyl, ethyl, n-propyl, Such as isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, etc. Linear or branched (C₁~ C₆) Alkyl group; cyclopropyl, cyclobutyl, cyclo Cycloalkyl groups such as pentyl, cyclohexyl, etc., cyclopropyloxy Such as, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. A cycloalkyloxy group or an aryl group such as phenyl or naphthyl May be substituted), aralkyl such as benzyl or phenethyl (The aralkyl group may be substituted), pyridyl, thienyl, furyl, Loryl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetra Heteroaryl groups such as zolyl, benzopyranyl, benzofuranyl, etc. May be substituted), aziridinyl, pyrrolidinyl, morpho Heterocyclyl groups such as linyl, piperidinyl, piperazinyl, etc. up) (the heterocyclic group may be substituted), phenoxy, naphthyloxy Aryloxy (the aryloxy group may be substituted), methoxy, Alkoxycarbonyl groups such as cycarbonyl or ethoxycarbonyl, if necessary Aryloxycarbonyl, such as optionally substituted phenoxycarbonyl Group, HNC₆H_FiveArylamino groups such as amino (C₁~ C₆) Alkyl, hydroxy (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, thio (C₁~ C₆) Alkyl, (C₁~ C₆) Acyl groups such as alkylthio, acetyl, propionyl, or benzoyl (The acyl group may be substituted), NHCOCH_Three, NHCOC_TwoH_Five, NHCOC_ThreeH₇, NHCOC₆ H_FiveAcylamino group such as NHCOOCH_TwoC₆H_FiveSuch as aralkoxycarbonyl Minoacylamino group, NHCOOC_TwoH_Five, NHCOOCH_ThreeAlkoxycarbonylamido such as No group, CONH_Two, CONHMe, CONMe_Two, CONHEt, CONEt_TwoCarboxylic acids, such as, CONHPh etc Or a derivative thereof such as an amide (the carboxylic acid derivative may be substituted) , OOCMe, OOCEt, OOCPh, etc., an acyloxy group (optionally substituted ), SO_TwoNH_Two, SO_TwoNHMe, SO_TwoNMe_Two, SO_TwoNHCF_Three, SO_TwoSulfonic acid or sulfonic acid derivative such as NHPh Sulfonic acid derivatives may be substituted).   All suitable substituents on group A may be substituted or unsubstituted Good.   When the substituent is further substituted, the substituent is the same as the group that substitutes A. Selected from the group consisting of halogen, hydroxy, or nitro, or alkyl, cyclo Alkyl, alkoxy, silicone alkoxy, aryl, aralkyl, heterocyclic, Teloaryl, heteroaralkyl, acyl, acyloxy, hydroxyalkyl , Amino, acylamino, arylamino, aminoalkyl, aryloxy, Alkoxycarbonyl, alkylamino, alkoxyalkyl, alkylthio, Thioalkyl group, carboxylic acid, or derivative thereof, or sulfonic acid or its derivative It may be selected from optionally substituted groups selected from derivatives.   Substituents on adjacent carbon atoms present in the group represented by A Substituted or unsubstituted, aromatic, saturated or Unsaturated 5- to 7-membered cyclic structures may be formed, which include phenyl, naphthyl, Nil, furyl, oxazolyl, thiazolyl, furyl, imidazolyl, azacyclo Butyl, isoxazolyl, azepinyl and the like, preferably phenyl, furyl, and A carbocycle wherein one or more heteroatoms such as a midazolyl group are selected from N, O and S Or a heterocycle. The substituent on such a cyclic structure is an aromatic represented by A The group may be selected from the same groups as those capable of substituting a heterocyclic group.   Suitable hydrocarbon groups linking between N and X represented by B are 1-4 carbon atoms, preferably Preferably it may contain from 1 to 2 carbon atoms and is a suitable link between N and X represented by D. The group may represent a bond or contain 1-4, preferably 1-2, carbon atoms. The formula (I The compounds described in (1) always have a linking group B and a linking group D. carbon A linking group D having no atoms means that the linking group D represents a bond . B and D may contain no double bonds, or contain 1-2 double bonds But may contain no double bond or contain one double bond preferable. Substituents on B and D are hydroxy, amino, chlorine, fluorine, bromine or Halogen such as iodine, optionally substituted linear or branched Branched (C₁~ C₁₂) Alkyl, especially methyl, hydroxymethyl, aminomethyl, Such as methoxymethyl, trifluoromethyl, ethyl, isopropyl, hexyl, etc. C₁~ C₆) Alkyl group; cyclopropyl, fluorocyclopropyl, cyclobutyl , Cyclopentyl, fluorocyclopentyl, cyclohexyl, fluorocyclo (C such as hexyl_Three~ C₆) Cycloalkyl group, (C₁~ C₆) Alkoxy, (C_Three~ C₆) Aryl such as cycloalkoxy, phenyl, heterocyclic group such as furyl and thienyl , (C_Two~ C₆) Acyl, (C_Two~ C₆) Acyloxy, hydroxy (C₁~ C₆) Alkyl , Amino (C₁~ C₆) Alkyl, mono or di (C₁~ C₆) Alkylamino, cyclo ( C_Three~ C_Five) Alkylamino groups (the two substituents being attached to adjacent carbon Together with an elemental atom form a substituted or unsubstituted 5- to 7-membered cyclic structure And may contain one or more heteroatoms selected from N, O and S, or It is not necessary to have. Such a cyclic structure may contain one or more double bonds. Or may not be contained). Preferred ring structures include phenyl, naph Tyl, pyridyl, thienyl, furyl, oxazolyl, thiazolyl, furyl, iso Xazolyl, azepinyl and the like. Substituents present on such a cyclic structure May be selected from the same groups as those capable of substituting the aromatic or heterocyclic group represented by A .   Suitable X is CH_Two, O, N or S groups, preferably CH_TwoAnd O are included. A preferred ring structure comprising a nitrogen atom, preferred linking groups represented by B and D, And preferred X is pyrrolidinyl, piperidinyl, piperazinyl, aziridini And a morpholinyl group.   A ring structure having a nitrogen atom, a linking group represented by B and D, and X is More preferably, it is a ridinyl group, a morpholinyl group, or an aziridinyl group. .   Ar represented by divalent phenylene, naphthylene, pyridyl, quinolinyl , Benzofuranyl, benzoxazolyl, benzothiazolyl, indolyl, in Including dolinyl, azaindolyl, azaindolinyl, indenyl, pyrazolyl, etc. I will. Substituents present on the group represented by Ar are linear or branched, Optionally halogenated (C₁~ C₆) Alkyl, and optionally halogenated (C₁ ~ C_Three) Alkoxy, halogen, acyl, amino, acylamino, thio, carboxylic acid, Sulfonic acids and their derivatives.   Ar is a substituted or unsubstituted divalent phenylene, naphthylene, benzene Zofuranyl, indolyl, indolinyl, quinolinyl, azaindolyl, azai More preferably, it represents an indolinyl, benzothiazolyl, or benzoxazolyl group. Good.   Ar is more preferably divalent phenylene or naphthylene. It is optionally substituted with a methyl, halomethyl, methoxy, or halomethoxy group. You may.   Proper R¹And R^TwoInclude lower alkyls such as hydrogen, methyl, ethyl, or propyl. A halogen atom such as a kill group, fluorine, chlorine, bromine or iodine, (C₁~ C_Three) Includes alkoxy, hydroxy, or R¹And R^TwoBoth represent one bond and are preferred Ha, R¹And R^TwoIs hydrogen or represents one bond at both.   Suitable p is an integer from 0 to 4, preferably 0 to 2. When p is 0, (CH_Two)_p Represents a bond. The ring structure having N and X, and the linking groups B and D are directly bonded to the oxygen atom Have been.   Pharmaceutically acceptable salts that form part of the present invention include salts such as Li, Na, and K salts. Alkaline earth metal salts such as Lucali metal salts, Ca and Mg salts, lysine, arginine, Salts of organic bases such as guanidine, diethanolamine, choline, etc., ammonium Salts or substituted ammonium salts, preferably aluminum, alkali metals Salt, alkaline earth metal salt, ammonium salt or substituted ammonium salt Such salts of the thiazolidinedione moiety, such as salts of carboxyl groups, are included. Salt , Sulfate, nitrate, phosphate, perchlorate, borate, hydrohalide (hydr ohalide), acetate, tartrate, maleate, succinate, palmoate (pal moate), methanesulfonate, benzoate, salicylate, hydroxynaphthoic acid Salt (hydroxynaphthoate), benzenesulfonate, ascorbate, glyce Acid addition salts, such as lophosphate, ketoglutarate, and the like, may be included. Pharmaceutically acceptable The solvate that can be used can be a hydrate or another crystallization solvent such as an alcohol.   Particularly useful compounds of the present invention include: 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl) piperidin-4-yloxy] phenylmethylene] thia Zolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl) piperidin-4-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione; 5- [4- [2- [4- (pyridin-2-yl) piperazin-1-yl] ethoxy] phenylmethylene] Thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] Thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] Thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Le] j Azolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethylene] thia Zolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione and its salts; 5- [4-[[1- (pyridin-2-yl)-(3R) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione and its salts; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethylene] thia Zolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethylene] thia Zolidine-2,4-dione, hydrochloride; 5- [1-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethyl] thiazo Lysine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethyl] Thiazo Lysine-2,4-dione and its salts; 5- [4-[[1- (pyridin-2-yl)-(3R) -pyrrolidin-3-yloxy] phenylmethyl] Thiazolidine-2,4-dione and salts thereof; 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione and its salts; 5- [4-[[4- (pyridin-2-yl)-(2S) -morpholin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione and salts thereof; 5- [4-[[4- (pyridin-2-yl)-(2R) -morpholin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione and salts thereof; 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione and its salts; 5- [4-[[4- (pyridin-2-yl)-(2S) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione and its salts; 5- [4-[[4- (pyridin-2-yl)-(2R) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione, sodium salt; 5- [4-[[4- (pyridin-2-yl)-(2S) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[4- (pyridin-2-yl)-(2R) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[4- (pyridin-2-yl) aziridin-2-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl) aziridin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl) aziridin-2-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl) aziridin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, and 5- [4-[[4- (quinolin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione.   According to one aspect of the invention,   (a) Compound of general formula (III)                                  A-L¹        (III) (Where A is as defined above and L¹Is like chlorine, bromine or iodine Halogen, thioalkyl such as thiomethyl, or amine nitrogen And a group capable of bonding with) Compound of general formula (IV) (Where B, D, X and p are as defined above, R^aIs a hydroxyl group or a hydroxyl group Or a leaving group such as OMs, OTs, Cl, Br or I). The compound of general formula (V) is reacted by the following method. (Where A, B, D, R^a, X and p are as defined above)   (To obtain the compound of the general formula (V), the compound of the general formula (III) and the general formula (IV) The reaction with the product is carried out without solvent or with DMF, DMSO, acetone, CH_ThreeCN, THF, pyridine Alternatively, it can be performed in the presence of a solvent such as ethanol. With a mixture of solvents Is also good. The reaction may be performed in an inert environment. The inert environment is N_Two, Ar Can be maintained by using an inert gas such as He. The reaction is_TwoCO_Three, N a_TwoCO_Three, KOH, NaOH, NaH, etc. or a mixture thereof. You. The amount of base may range from 1 to 20 equivalents, preferably 1 to 10 equivalents. The reaction is , 20-180 ° C, preferably 50-150 ° C. Reaction time is 1-4 It can range from 8 hours, preferably from 1 to 12 hours. In the reaction, the compound represented by the general formula (III) And the compound of general formula (IV) can range from 1 to 20 equivalents, preferably from 1 to 5 equivalents. You. )   (b) a compound of general formula (V) (where R^aIs a hydroxyl group) and a compound of the general formula (VI)                          R^b−Ar-CHO (VI) (Where Ar is as defined above and R^bIs halo such as chlorine or fluorine Gen atom or R^bIs a hydroxyl group)     Compound of general formula (VII) (Where A, B, D, X, Ar and p are as defined above)   (To obtain a compound of the general formula (VII), a compound of the general formula (V)^aIs hydroxyl Group) and a compound of general formula (VI) (where R^bIs a halogen atom) Can be performed in the presence of a solvent such as THF, DMF, DMSO, DME, or a mixture thereof. You. The reaction may be performed in an inert environment. The inert environment is N_Two, Ar or He Can be maintained by using an inert gas such as The reaction is_TwoCO_Three, Na_TwoCO_ThreeOr in the presence of a base such as NaH and the like. Use a mixture of bases You may. The reaction temperature can be a temperature in the range from 20 to 120C, preferably 30 to 80C. You. Reaction times can range from 1 to 24 hours, preferably 2 to 12 hours.   A compound of general formula (V) (where R^aIs a hydroxyl group) and a compound of the general formula (VI) Where R^bIs a hydroxyl group) with dicyclohexyl urea, PPh_Three/ DEAD etc. Suitable such as a triarylphosphine / dialkylazodicarboxylate This can be done using a smart coupling reagent. The reaction is performed in THF, DME, CH_TwoCl_Two, CHCl_Three Of solvents such as toluene, acetonitrile, carbon tetrachloride or mixtures thereof Can be done in The reaction can be performed in an inert environment. The inert environment is N_Two, Ar Alternatively, it can be maintained by using an inert gas such as He. The reaction is performed with DMAP-H It can be carried out in the presence of OBT, they have 0.05 to 2 equivalents, preferably 0.25 to It can be used in the range of one equivalent. The reaction temperature ranges from 0 to 100 ° C, preferably 20 to 50 ° C. Temperature. The reaction time ranges from 0.5 to 24 hours, preferably from 6 to 12 hours. Can get. )   (c) a compound of the general formula (VII) while removing water produced during the reaction by conventional methods And 2,4 thiazolidinedione to give a compound of general formula (VIII) (Where A, B, D, X, Ar, p are as defined above) To get   (To obtain a compound of general formula (VIII) of step (c), a compound of general formula (VII) The reaction with 2,4 thiazolidinedione is carried out without solvent in the presence of sodium acetate. Or solvents such as benzene, toluene, methoxyethanol or their It can be performed in the presence of a mixture. The reaction temperature ranges from 80 to 140 ° C., depending on the solvent used. Enclosure. Piperidinium acetate or benzoate, or sodium acetate A suitable catalyst such as lium may be used. The water generated during the reaction is Moon Stark (Dean Stark) By using a water separator or by removing water such as molecular sieves It can be removed by using an absorbing material. )   If you want,   (d) reducing the compound of general formula (VIII) obtained in step (c) by a known method And a compound of the general formula (IX) (Where A, B, D, X, Ar and p are as defined above)   (Compound of formula (VIII) obtained in step (c) to obtain a compound of general formula (IX) The return can be carried out in the presence of gaseous hydrogen and a catalyst such as Pd / C, Rh / C, Pt / c and the like. Touch A mixture of media may be used. The reaction is carried out with dioxane, acetic acid, ethyl acetate, etc. A mixture of one solvent that may be performed in the presence of a suitable solvent may be used. Atmospheric pressure ~ 80ps A pressure of i may be used. The catalyst can be 5-10% Pd / C and the amount of catalyst used is 50-30% It can be in the range of 0% w / w. The reaction is carried out with magnesium or methanol in methanol. By using metal solvent reduction such as sodium amalgam in Is also good. The reaction is performed with CoCl_TwoCobalt salts and ligands, preferably 2,2'- Existence of bidentate ligands such as pyridyl, 1,10-phenanthroline, pisoximes, etc. At present, LiBH_Four, NaBH_Four, KBH_FourAlkali metal borohydrides (boro, etc.) hydride). )   If you want,   (e) separating the compound of the general formula (VIII) and the compound of the general formula (IX) into their stereoisomers And if you want   (f) the compound of general formula (VIII) obtained in steps (c) and (d), respectively, ), Or their resolved stereoisomers, by conventional methods. To their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates. Thiazolidinedione derivatives of formula (I), their stereoisomers Body, that Their polymorphs, their tautomeric forms, their pharmaceutically acceptable salts, their pharmaceutically acceptable Methods of preparing those solvates are provided.   In one embodiment of the present invention, the compound of general formula (VII) is a compound of general formula (V) Is a compound of the general formula (X) (Where A, B, D, X and p are as defined above;^TwoIs chloride, bromide, Or halide groups such as iodide, or methanesulfonate, p-toluene Is a leaving group such as sulfonate and trifluoromethanesulfonate) And a compound of general formula (X) and a compound of general formula (VI) (Ar is as defined above) R^bIs a hydroxyl group).   Compounds of general formula (V) include thionyl chloride, CBr_Four/ PPh_Three, CCl_Four/ PPh_Three, Phosphorus halogen Using a halogenating reagent such as chloride, or without solvent, or pyridine, DM P-Toluenesulfonyl in the presence of a base such as AP, triethylamine, etc. Chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride Can be converted to a compound of the general formula (X) by using an anhydride. Mixing bases An object may be used. These reagents may be used in 1-4 equivalents, preferably 1-2 equivalents. You. Temperatures in the range of -10 to 100C, preferably 0 to 60C may be used. The reaction is 0.5 For up to 24 hours, preferably 1 to 12 hours.   A compound of the general formula (X) and a compound of the general formula (VI) to obtain a compound of the general formula (VII) (R^b= OH) is a reaction with a solvent such as THF, DMF, DMSO, DME, or a mixture thereof. Can be performed in the presence of an object. The reaction may be performed in an inert environment. Inert ring The border is N_TwoMay be maintained by using an inert gas such as Ar, He or He. The anti Response is K_TwoCO_Three, Na_TwoCO_ThreeOr in the presence of a base such as NaH or a mixture thereof Can be implemented. The reaction temperature is a temperature in the range of 20 to 120C, preferably 30 to 80C. obtain. The reaction time can be between 1 and 24 hours, preferably between 2 and 12 hours.   In another embodiment of the present invention, the compound of general formula (VII) is a compound of general formula (XI)(Where B, D, X, Ar and p are as defined above) And a compound of the general formula (III).   The reaction of the compound of the general formula (XI) with the compound of the general formula (III) is carried out without solvent or Solvents such as MF, DMSO, acetone, acetonitrile, ethanol and so on It can be performed in the presence of these mixtures. The reaction may be performed in an inert environment. Unfortunate The active environment is N_TwoCan be maintained by using an inert gas such as, Ar or He. You. The reaction is carried out without solvent or with K_TwoCO_Three, Na_TwoCO_ThreeSuch as, KOH, NaOH, NaH etc. It can be carried out in the presence of a group or a mixture thereof. The amount of the base is 1-20 equivalents, preferably Preferably it can range from 1 to 10 equivalents. Reaction temperature in the range of 20-180 ° C, preferred Or at a temperature in the range of 50 to -150 ° C. The reaction time is 1 to 48 hours, preferably 1 to 48 hours. It can range from ~ 12 hours. The amount of the compounds of the general formulas (III) and (XI) is from 1 to 20 equivalents, Preferably it can range from 1 to 9 equivalents.   Next, the compound of the general formula (XI) is a compound of the general formula (XII) (Where B, D, X, Ar and p are as defined above;^ThreeIs a protecting group, R^aIs Leaving group) And the general formula (VI) (R^b= OH), and then N-protected using conventional methods It can be prepared by removing the group.   General formula (VI) (R^b= OH) and the compound of general formula (XII) are reacted with THF, DMF , DMSO, DME, etc. or mixtures thereof. The reaction is , Under an inert environment. The inert environment is N_TwoInactive, like Ar, He Can be maintained by using a neutral gas. The reaction is_TwoCO_Three, Na_TwoCO_ThreeLike NaH It can be carried out in the presence of a suitable base or a mixture thereof. The reaction temperature ranges from 20 to 120 ° C. Ambient temperature, preferably in the range of 30-80 ° C. Reaction time is 1 It can range from -12 hours, preferably 2-6 hours. N-protecting group R^ThreeIs usually acid treated Or by hydrogenation, or of a suitable base depending on the nature of the protecting group used. It is removed either in the presence.   In yet another embodiment of the present invention, compounds of general formula (I), their tautomeric forms: , Their stereoisomers, their polymorphs, pharmaceutically acceptable salts thereof, and drugs The solvates which are chemically acceptable are the compounds of the above formula (V) Here R^aIs an OH group) and a compound of the general formula (XIII) (Where R¹, R^TwoAnd Ar are as defined above, and R^FourIs an acyl group or triary Hydrogen or nitrogen protecting group such as methyl group) Can also be prepared by reaction with To obtain a compound of the general formula (I), a compound of the general formula (V) The reaction between the compound and the compound of the general formula (XIII) is performed by dicyclohexylurea, PPh_Three/ DEAD Like triarylphosphine / dialkylazadicarboxylate such as Using any suitable coupling reagent. The reaction is performed in THF, DMF, CH_TwoCl_Two, CH Cl_ThreeCan be performed in the presence of a solvent such as toluene, acetonitrile, carbon tetrachloride, etc. You. The reaction may be performed in an inert environment. The inert environment is N_Two, Ar or He Can be maintained by using an inert gas such as The reaction is based on the DMAP-HOBT May be carried out in the presence, they range from 0.05 to 2 equivalents, preferably from 0.25 to 1 equivalent. Can be used with The reaction temperature is a temperature in the range of 0 to 100 ° C, preferably 20 to 80 ° C. obtain. The reaction time can be 0.5 to 24 hours, preferably 6 to 12 hours.   In yet another embodiment of the present invention, compounds of general formula (I), their tautomeric forms: , Their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutical The solvates acceptable for the compound of the above general formula (X) obtained and the above It can also be prepared by reaction with a compound of general formula (XIII).   A compound of the general formula (X) and a compound of the general formula (XIII) for obtaining the compound of the general formula (I) Reaction with a solvent such as THF, DMF, DMSO, DME or the like, or a mixture thereof. Can be done in the presence. The reaction may be performed in an inert environment, and the inert environment is N_TwoMay be maintained by using an inert gas such as Ar, He or He. The reaction is Alkalis such as sodium hydroxide or potassium hydroxide; sodium carbonate or potassium carbonate Alkali metal carbonates such as lium, alkali metal water such as sodium hydride Halides; organometallic bases such as n-butyllithium; alkaloids such as zodaamide It may be carried out in the presence of a base such as a metalloid amide, or a mixture thereof. Duplicate A number of solvents and bases can be used. The amount of the base is 1-5 equivalents, preferably 1 It can be in the range of ~ 3 equivalents. The reaction temperature ranges from 0 to 120 ° C, preferably from 20 to 100 ° C. Temperature. The reaction time ranges from 0.5 to 24 hours, preferably from 2 to 12 hours. Can get.   In yet another embodiment of the present invention, the compound of general formula (I) is Compound of formula (XIV) (Where B, D, R¹, R^Two, R^Four, X, Ar and p are as defined above) and one of the above It can be obtained by reacting with a compound of the general formula (III).   Compounds of the general formula (XIV) and the general formula (III) for obtaining the compound of the general formula (I) The reaction with the product is carried out without solvent or in DMF, DMSO, acetone, acetonitrile, ethanol And a solvent such as THF or a mixture thereof. The The reaction may be performed in an inert environment. The inert environment is N_Two, Like Ar or He The temperature can be maintained by using an active gas. The reaction is_TwoCO_Three, Na_TwoCO_Three, KOH , NaOH, NaH, and the like, or a mixture thereof. Base The amount may range from 1 to 20 equivalents, preferably 1 to 6 equivalents. The reaction is carried out at 20-180 ° C. And preferably at a temperature in the range of 50 to 150 ° C. Reaction time is 1 ~ 48 hours, preferred Or between 1 and 12 hours. The amount of the compounds of the general formulas (III) and (XIV) is from 1 to 20 equivalents, preferably in the range of 1-5 equivalents,   According to one aspect of the present invention, a compound of general formula (XIII) and a compound of general formula (XV) (Where B, D, R^Three, X, L^TwoAnd p are as defined above) And then removing the protecting group by a conventional method after reacting A method for the preparation of a new intermediate of formula (XIV) is provided.   The reaction between the compound of the general formula (XIII) and the compound of the general formula (XV) is performed in THF, DMF, DMSO, DME And the like, or a mixture thereof. The reaction is inert It may be performed in an environment. The inert environment is N_TwoUse inert gas such as, Ar or He Can be maintained by The reaction is_TwoCO_Three, Na_TwoCO_Three, A base such as NaH or It can be carried out in the presence of a mixture thereof. Reaction temperature is in the range of 20-120 ° C, preferred Alternatively, the temperature may range from 30 to 80C. The reaction time is 1 to 12 hours, preferably 2 to It can be 6 hours.   According to another embodiment of the present invention, a compound of general formula (XIV) wherein R¹And R^TwoIs both Represents one bond) is a compound of the general formula (XVI) (Where B, D, Ar, X and p are as defined above;^ThreeIs A- (CH_Two)_k-O-C (= Y)- Wherein A represents an aryl or heteroaryl group, and k is 1 Y is O, S or NR (where R is hydrogen or lower alkyl or Or a hetero atom selected from) and 2,4-thia After reacting zolidinedione, the N-protecting group is removed by conventional methods. Therefore, it can also be prepared.   The reaction of the compound of the general formula (XVI) with 2,4 thiazolidinedione is carried out with sodium acetate. Solvent-free in the presence or like benzene, toluene, methoxyethanol In the presence of a suitable solvent. Mixtures of solvents may be used. The reaction temperature used Depending on the solvent used, it can range from 80 to 140 ° C. Piperidinium acetate Kuha A suitable catalyst such as benzoate or sodium acetate may be used. In reaction Generated by, for example, using a Teen Stark water separator, or It can be removed by using a water-absorbing substance such as a molecular sieve.   In another embodiment of the present invention, there is provided a compound of general formula (I) wherein A, B, D, X, p and Ar is as defined above) is a compound of general formula (XVII) (Where A, B, D, X, p and Ar are as defined above, and J is chlorine, bromine, or Is a halogen atom such as iodine, and R is a lower alkyl group) And thiourea, followed by treatment with an acid.   The reaction of general formula (XVII) with thiourea is usually carried out with methanol, ethanol, Alcohol, isobutanol, 2-methoxybutanol, etc., or DMSO or Is carried out in the presence of a sulfonate. The reaction is carried out at a temperature between 20 ° C. and the reflux temperature of the solvent used. It can be performed at temperatures between. Use bases such as NaOAc, KOAc, NaOMe, NaOEt, etc. Can be. After the reaction, it is usually treated at 20 to 100 ° C. with a mineral acid such as hydrochloric acid.   The compound of the general formula (XVII) (where J is a halogen atom) is an alkali metal Using nitrite, an amino compound of the general formula (XVIII)(Where all symbols are as defined above) followed by halogenation In the presence of hydrogen acid and a catalytic amount of copper oxide or copper halide, And by treating with   Next, the compound of the general formula (XVIII) is a new intermediate (XIX) (Where all symbols are as defined above) in a conventional manner Can be prepared.   The novel intermediate of the general formula (XIX) is a compound of the general formula (V) (Where A, B, D, X and p are as defined above;^aIs a hydroxyl group or a leaving group And the compound of general formula (XX) (Where R^bIs a halogen atom such as chlorine or fluorine or a hydroxyl group, and Ar Is as defined above).   The reaction of a compound of formula (V) with a compound of formula (XX) to obtain a compound of formula (XIX) Can be performed in the presence of a solvent such as THF, DMF, DMSO, DME, or a mixture thereof . The reaction may be performed in an inert environment,_TwoInert gas such as, Ar or He An inert environment is maintained by using The reaction is_TwoCO_Three, Na_TwoCO_Three, Young Or in the presence of a base such as NaH or a mixture thereof. The reaction temperature is , 20-120 ° C, preferably 30-100 ° C. Reaction time is 1-12 hours , Preferably in the range of 2 to 6 hours.   In another embodiment of the present invention, the compound of general formula (XIX) has the general formula (XXI) Compound (Where B, D, X, Ar and p are as defined above) and a compound of general formula (III) Can also be prepared by reacting   The reaction between the compound of the general formula (XXI) and the compound of the general formula (III) is carried out without solvent or in DM. In the presence of a solvent such as F, DMSO, acetone, acetonitrile or ethanol Can be done. A mixture of solvents may be used. The inert environment is N_Two, Ar or He It can be maintained by using an active gas under such conditions. The reaction is carried out without solvent, or K_TwoCO_Three, Na_TwoCO_Three, In the presence of a base such as KOH, NaOH, NaH, or a mixture thereof. Can be implemented. The amount of the base ranges from 1 to 20 equivalents, preferably from 1 to 10 equivalents. obtain. The reaction may be carried out at a temperature in the range from 20 to 180C, preferably 50 to 150C. Anti The reaction time can be between 1 and 48 hours, preferably between 1 and 12 hours. The general formula (III) and the general formula ( The amount of the compound of XXI) may range from 1 to 20 equivalents, preferably 1 to 9 equivalents.   The compound of the general formula (XXI) is a compound of the general formula (XII) (Where B, D, X, Ar and p are as defined above, R3 is a protecting group, Ra is A leaving group) and the general formula (XX) (R^b= OH), and then use the conventional method. And by removing the N-protecting group.   Formula (XX) (R^b= OH) and the compound of the general formula (XII) are reacted with THF, DMF, It can be performed in the presence of a solvent such as DMSO, DME and the like. A mixture of solvents may be used . An inert environment may be used, wherein the inert environment is N_TwoInert, like Ar, He It can be maintained by using gas. The reaction is_TwoCO_Three, Na_TwoCO_ThreeOr NaH In the presence of a base such as The reaction temperature is 20-120 ° C, preferably 30-80 ° C. ° C range. The reaction time can be 1-12 hours, preferably 2-6 hours . N-protecting group R^ThreeAre usually protected by acid treatment or by hydrogenation or by using protection It is removed in the presence of a suitable base depending on the nature of the group.   Conventional deprotection methods include acids such as hydrochloric acid, trifluoroacetic acid, or KOH, NaOH, N a_TwoCO_Three, NaHCO_ThreeOr K_TwoCO_ThreeAnd the like. these The reagent may be used as an aqueous solution or a solution in an alcohol such as methanol or ethanol. Can be used. When the protecting group is benzyl or a substituted benzyl group, Deprotection can be by gaseous hydrogen in the presence of a catalyst such as Pd / carbon, or By the transfer hydrogenation method Can also be.   Pharmaceutically acceptable salts include compounds of formula (I) and ethers, THF, methanol, t-butyl. NaOH hydroxide in solvents such as tanol, dioxane, isopropanol and ethanol Lium, sodium methoxide, sodium hydride, potassium t-butoxide, water Reaction with 1-4 equivalents of a base such as calcium oxide, magnesium hydroxide, etc. And is prepared by A mixture of solvents may be used. Lysine, arginine, di Uses organic bases such as ethanolamine, choline, guanidine and their derivatives May be. Alternatively, acid addition salts include ethyl acetate, ether, alcohol, Hydrochloric acid, hydrobromic acid, nitric acid, in a solvent such as ton, THF, dioxane, etc. Sulfuric acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, Leic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid Treatment with acids such as succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid, etc. And is prepared by A mixture of solvents may be used.   Stereoisomers of the compounds that form part of the invention may, where possible, be included in the process. By using a single enantiomeric form of the reactant, or a single enantiomer By performing the reaction in the presence of a type of reagent or catalyst, or by conventional methods It can be prepared by resolving a mixture of stereoisomers. The preferred method is microbiota Physical resolution, such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc. Lal acids or brucine, cinchona alkaloid and their Resolving diastereomeric salts formed with chiral bases such as derivatives Is included.   The various polymorphs of the compounds of the general formula (I) which form part of the present invention, under various conditions, It can be prepared by crystallizing the compound of I). For example, for recrystallization, Use of various commonly used solvents or their mixtures, crystallization at different temperatures Crystallization, from very fast to very slow cooling during crystallization The use of a cooling mode. Polymorphs gradually develop after heating or melting a compound. Alternatively, it can be obtained by rapid cooling. The presence of polymorphism NMR spectroscopy, IR spectroscopy, differential scanning calorimetry (DSC), powder X-ray data or Can be determined by other techniques.   The present invention provides compounds of the above general formula (I), their tautomeric forms, their steric Isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable Re Pharmaceuticals containing ordinary pharmaceutically usable carriers, diluents, etc. together with these solvates Composition comprising type II diabetes, impaired glucose tolerance, lipemic disorder, hypertension, coronary Like arterial heart disease and other cardiovascular diseases including atherosclerosis Treatment of diseases in which insulin resistance is the underlying pathophysiological mechanism and / or Is useful for the treatment and / or prevention of insulin resistance with obesity and psoriasis Yes, diabetic complications and polycystic ovary syndrome (PCOS), diabetic nephropathy, glomerulonephritis, Glomerular sclerosis, nephrotic syndrome, hypertensive renal sclerosis, end-stage renal disease and microprotein Treat certain renal diseases, including urinary disorders, as well as other diseases such as certain eating disorders (As an aldose reductase inhibitor) and cognitive function in dementia Also provided are pharmaceutical compositions that are useful for improving the following.   The pharmaceutical composition may be a tablet, capsule, powder, syrup, solution, suspension, etc. It can be in any commonly used form and may be in any suitable solid or liquid carrier or diluent. Or in a suitable sterile solvent to form an injectable solution or suspension. Sweeteners may be included. Such compositions are typically 1-2 weight percent. It contains 5%, preferably 1-15%, of the active compound and the balance of the composition is pharmaceutically acceptable. Carrier, diluent, or solvent.   A typical tablet preparation method is exemplified below. Example of tablet preparation   a) 1) Active ingredient 30g       2) lactose 95g       3) 30g corn starch       4) Carboxymethyl cellulose 44g     5) Magnesium stearate 1g                   200g for 1000 tablets   Ingredients 1-3 are uniformly mixed with water, dried under reduced pressure and granulated. Ingredient 4 and 5 is mixed well with the particles and compressed with a tablet machine, 1000 tablets each containing 30 mg of active ingredient A tablet is prepared.   b) 1) Active ingredient 30g       2) Calcium phosphate 90g       3) Lactose 40g       4) Corn starch 35g       5) 3.5 g of polyvinylpyrrolidone     6) Magnesium stearate 1.5g                  200g for 1000 tablets     Components 1 to 4 are uniformly moistened with an aqueous solution of component 5, dried under reduced pressure, and then granulated. To Add ingredient 6, compress with tablet press, 1000 tablets containing 30mg of active ingredient 1 Prepare the agent.   The compounds of formula (I) above may be clinically administered by either the oral or parenteral route of administration. Thus, it is administered to mammals including humans. More convenient and possible pain and administration Administration by the oral route is preferred because there is no irritation. But disease or other If the patient is unable to swallow the drug due to abnormalities in If there is a disorder, the drug must be administered parenterally. By any route Even so, the dose may be about 0.10-200 mg / kg of patient body weight / day, or preferably about 0.10-50 m It is in the range of g / kg of body weight of the patient / day and is administered alone or in divided doses. But, The optimal dose for each patient receiving treatment is determined by the person responsible for treatment and To begin with a smaller dose and then gradually increase to determine the optimal dose .   Suitable pharmaceutically acceptable carriers include solid filters or diluents. Excipients and sterile aqueous or sterile organic solutions. Active compounds are such In a pharmaceutical composition in an amount sufficient to provide the desired dose within the above range. Exist. Thus, for oral administration, the compound can be a capsule, tablet, powder, A solid or liquid carrier or diluent suitable to form a syrup, solution, suspension, etc. Can be combined with excipients. If desired, the pharmaceutical composition may include flavors, sweeteners, excipients, Components such as excipients and the like may be further contained. For parenteral administration, the compound is In combination with a sterile aqueous solution or a sterile organic solvent to form a sprayable solution or suspension. I can do it. For example, solutions in coma oil or peanut oil, aqueous propylene glycol Pharmaceutically acceptable acid addition salts or salts of the compounds, which are soluble in liquids and the like, and water. Potash or An aqueous solution of an alkaline earth metal salt can be used. Prepared in this way Injectable solutions can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly. Although possible, intramuscular administration is preferred in humans.   The following examples illustrate the invention in more detail, but for illustrative purposes only. It is described and should not be construed as limiting the scope of the invention. Synthesis 1 (S) -2-hydroxymethyl-1- (pyridin-2-yl) pyrrolidine  Under nitrogen gas and stirring, 2-chloroviridine (118 g) and L-prolinol (70 g )) Was heated at 160 ° C. for 4 hours. The mixture is cooled to room temperature, poured into water and the solution The liquid was repeatedly extracted with chloroform. The organic extracts were collected, dried (Na_TwoSO_Four) And concentrated. CHCl as eluent_ThreeColumn chromatography using 2% MeOH in water Purify the crude product by chromatography to obtain 67.3 g (54.5%) of the title compound. Obtained as a liquid in the form of a pump. Synthesis 2 1- (pyridin-2-yl) -4-piperidinol   By the same operation as described in Synthesis 1, 2-chloropyridine (6.7 g) and 4- Peridinol (4 g) gave the title compound (3.5 g, 50%) as a semi-solid. Synthesis 3 4-hydroxymethyl-1- (pyridin-2-yl) piperidine  By the same operation as described in Synthesis 1, 2-chloropyridine (7.8 g) and 4-hydroxypyridine were used. From the droxymethylpiveridine (2 g), the title compound (2.7 g, 80%). Synthesis 4 1- (pyridin-2-yl) piperidin-4-ylmethanesulfonate   The product from Synthesis 2 (3.25 g) and triethylamine (30 mL) in dichloromethane (30 mL) Methanesulfonyl chloride (1.7 mL) was added to an ice-cooled solution (about 0 ° C.) of 8 mL). . At room temperature, the mixture was stirred for 12 hours. After this is completed, the reaction mixture is Wash, dry (CaCl 2_Two) And concentrated to give 4.7 g (100%) of the title compound (mp 66 6868 ° C.). Synthetic 5 [1- (pyridin-2-yl) piperidin-4-yl] methylmethanesulfonate  By the same operation as in Synthesis 4, the 4-hydroxymethyl obtained in Synthesis 3 1- (pyridin-2-yl) piperidine (1.8 g) and methanesulfonyl chloride (0.8 mL) The title compound (2.1 g, 83%) was synthesized as a semi-solid. Synthetic 6 4- [1- (ethoxycarbonyl) piperidin-4-yloxy] benzaldehyde   1- (ethoxycarbonyl) piperidin-4ylmethanesulfur in dry DMF (75 mL) Konate (10 g) and 4-hydroxybenzaldehyde (5.8 g) in a mixture_TwoCO_Three(11g) Was added and the mixture was stirred at 80 ° C. for 12 hours. After this is completed, the reaction mixture Was cooled, water was added and extracted with EtOAc. 5% Na_TwoCO_ThreeThe Et with aqueous solution followed by brine The OAc extract was washed and dried over anhydrous sodium sulfate. Next, steam under reduced pressure The solvent was removed by distillation to give 7 g (63.6%) of the title compound as a semi-solid. Obtained, Synthetic 7 4- (piperidin-4-yloxy) benzaldehyde  A mixture of the compound (4.5 g) obtained in Synthesis 6 and concentrated hydrochloric acid (40 mL) was stirred at 100 ° C. for 12 hours. . The reaction mixture was concentrated under vacuum. Dilute the residue with water and add saturated NaHCO_ThreeIn aqueous solution Neutralize and CHCl_ThreeAnd dried (CaCl 2_Two) And concentrate under vacuum to afford the title compound ( 3g, 90%) as a semi-solid. Synthesis 8 (S) -4-[[1- (pyridin-2-yl) pyrrolidin-2-yl] methoxy] benzaldehyde   While cooling, a suspension of 16.1 g of sodium halide in 300 mL of DMF (60% w / w Dispersion), a solution of 40 g of the product obtained in Synthesis 1 in 300 mL of DMF is added dropwise. Was. Next, the mixture was stirred at room temperature for 1 hour before adding 4-fluorobenzene in 200 mL of DMF. 47.7 mL of zaldehyde was added dropwise at room temperature. Subsequently, the reaction mixture is The mixture was stirred at 80 ° C for 4 hours. After this was completed, water was added to the reaction mixture. EtOAc Then, the mixture was extracted and dried over anhydrous sodium sulfate. Under reduced pressure, the solution The medium was evaporated to dryness. 5-10% EtOAc in petroleum ether (gradient (Elution), chromatograph the crude product on silica gel, 42.5 g (67%) of the title compound were obtained as a semi-solid.Synthesis 9 4- [1- (pyridin-2-yl) piperidin-4-yloxy] benzaldehyde Method A:   1- (Pyridin-2-yl) piperidin-4ilme obtained in Synthesis 4 in dry DMF (30 mL) To a mixture of tansulfonate (4.5 g) and 4-hydroxybenzaldehyde (2.5 g), K_TwoCO_Three(9.7 g) was added and the mixture was stirred at 80 ° C. for 10 hours. After this is done, The reaction mixture was cooled, water was added and extracted with EtOAc. 5% Na_TwoCO_ThreeAqueous solution, then The EtOAc extract was washed with brine and dried over anhydrous sodium sulfate. next The solvent was removed by distillation under reduced pressure, 1.8 g (36.3%) of the title compound (Mp 114-116 ° C). Method B   The title compound (0.6 g, 43%) was prepared by a procedure similar to that described in Synthesis 1. 4- (4-piperidinyloxy) benzaldehyde (1.0 g) obtained in Synthesis 7 and 2-chloro It was also synthesized as a pale yellow solid (mp 114-116) from pyridine (3.6 mL). Synthetic 10 4-[[1- (pyridin-2-yl) piperidin-4-yl] methoxy] benzaldehyde  [1- (pyridyl) obtained in Synthesis 5 by the same operation as described in Method A of Synthesis 9. 2-Nyl) piperidin-4-yl] methylmethanesulfonate (2.0 g) and 4-hydroxy The title compound (1.0 g, 45%) was synthesized as a semi-solid from benzaldehyde (1.1 g). . Synthesis 11 4- [2- [4- (pyridin-2-yl) piperazin-1-yl] ethoxy] benzaldehyde   By an operation similar to that described in Method A of Synthesis 9, 2- [4- (pyridin-2-yl) Piperazin-1-yl] ethyl chloride, HCl salt (2g) and 4-hydroxybenzaldehyde The title compound (2.0 g, 84%) was synthesized as a thick liquid from the solvent (1.4 g). Synthetic 12 (S) -2-hydroxymethyl-1- (quinolin-2-yl) pyrrolidine  By the same operation as described in Synthesis 1, 2-chloroquinoline (4 g) and L-prolyl were used. The title compound (6 g, 100%) was synthesized from knol (14.8 g) as a syrupy liquid. . Synthesis 13 (S) -4-[[1- (quinolin-2-yl) pyrrolidin-2-yl] methoxy] benzaldehyde   By an operation similar to that described in Synthesis 8, the (S) -2-hydroxymethine obtained in Synthesis 12 was obtained. Tyl-1- (quinolin-2-yl) pyrrolidine (3 g) and 4-fluorobenzaldehyde (2.8 mL ) Was synthesized from the title compound (1.6 g, 37%) as a thick liquid. Synthetic 14 (S) -4-[[1- (quinolin-2-yl) pyrrolidin-2-yl] methoxy] nitrobenzene  Suspension of 5.2 g of sodium halide in DMF (50 mL) (50% w / w dispersion), a solution of 16.5 g of the product obtained in Synthesis 12 in DMF (100 mL) was added dropwise. Added. After stirring the mixture at room temperature for 0.5 hour, 12.3 g of 1-fluoro-4-nitro Benzene was added dropwise, then the mixture was stirred at the same temperature for 12 hours. this After the addition, water was added and the resulting solid was filtered, washed with excess water and dried. Drying afforded 9 g (30%) of the title compound (118-120 ° C). Synthetic 15 (S) -4-[[1- (Quinolin-2-yl) pyrrolidin-2-yl] methoxy] aniline   (S) -4-[[1- (Quinolin-2-yl) obtained in Synthesis 14 in EtOH (40 mL) and concentrated HCl (40 mL). A small amount of iron powder (9.6 g) was added to a solution of pyrrolidin-2-yl] methoxy] nitrobenzene (6 g). Was added. The reaction mixture was stirred at room temperature for 1 hour. The solution is filtered and the filtrate Was evaporated to dryness. The residue was water and neutralized (pH 7) NaHCO_ThreeIn aqueous solution Dilute and CHCl_ThreeAnd dried (CaCl 2_Two), Concentrated to 5.5 g (100%) of the title compound Was obtained as a black solid (mp 138-140 ° C).Synthetic 16 Ethyl 2-bromo-3- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy [Phenyl] propanate   The (S) -4-[[1- (quinolin-2-yl) pyrrolidine-2- obtained in Synthesis 15 was stirred and cooled with ice. Yl] methoxy] aniline (5 g), aqueous HBr (48%, 8.5 mL), MeOH (15 mL) and acetoacetate (37 mL) in a solution of NaNO in water (2.1 mL) at no more than 5 ° C._Two(1.2 g) solution was added dropwise. Was added. The solution was stirred at 5 ° C. for 30 minutes, ethyl acrylate (10 mL) was added, The temperature was raised to 60C. To the vigorously stirred mixture, add Cu_TwoO powder (140mg) Added N_TwoAfter gas evolution ceased, the reaction mixture was concentrated in vacuo. The rest After diluting the distillate with water, concentrated NH_FourIt was made alkaline with OH and extracted with EtOAc. EtOAc extraction The effluent is washed with brine, dried (Na_TwoSO_Four), Concentrated under vacuum. In chloroform The crude product was purified on silica gel using methanol 0-10% (gradient elution). Chromatography of the product to give 2.6 g (34%) of the title compound as a thick liquid. Obtained. Synthetic 17 (S) -2-hydroxymethyl-1- (lepidin-2-yl) pyrrolidine  By the same operation as described in Synthesis 1, 2-chlorolepidine (17.3 g) and L-pro The title compound (22 g, 94%) was synthesized from corinol (59 g) as a thick liquid. Synthetic 18 (S) -4-[[1- (Lepidin-2-yl) pyrrolidin-2-yl] methoxy] benzaldehyde   (S) -2-Hydroxymethyl-1 obtained in Synthesis 17 in the same manner as described in Synthesis 8. -(Lepidin-2-yl) pyrrolidine (0.5 g) and 4-fluorobenzaldehyde (0.33 mL) Synthesized the title compound (0.25, 35%) as a thick liquid. Synthetic 19 (S) -4-[[1- (Lepidin-2-yl) pyrrolidin-2-yl] methoxynitrobenzene  (S) -2-Hydroxymethine obtained in Synthesis 17 was prepared in the same manner as in Synthesis 14. Tyl-1- (lepidin-2-yl) pyrrolidine (10 g) and 1-fluoro-4-nitrobenzene (5.3 mL) to give the title compound (8 g, 53%) as a yellow solid. Synthetic 20 (S) -4 [[1- (Lepidin-2-yl) pyrrolidin-2-yl] methoxy] aniline   (S) -4 [[1- (Lepidin-2-yl) pyrrolidin-2-yl] methoxynitro obtained in Synthesis 19 Dissolve benzene (5 g) in EtOAc (20 mL) and store 10% palladium on activated carbon (0.5 g). Use hydrogen (50 psi) at room temperature until hydrogen uptake ceases (approximately 16 hours) Reduced. The solution is filtered through a layer of celite and the filter pad is Washed thoroughly with EtOAc. The filtrate was collected and evaporated under reduced pressure to dryness . Silica using 1-10% methanol in chloroform (gradient elution) Chromatography of the crude product on a gel yields 4.6 g (100%) of the title compound. Was obtained as a thick liquid.Synthetic 21 Ethyl-2-chloro-3- [4-[[1- (lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy [S] phenyl] propanoate   An operation similar to that described in Synthesis 16 except that HCl was used instead of HBr. (S) -4 [[1- (Lepidin-2-yl) pyrrolidin-2-yl] methoxy obtained in Synthesis 20 The title compound (15 g, 85%) was synthesized from [shi] aniline (13.7 g) as a thick liquid. . Equation 22 Ethyl-2-bromo-3- [4-[[1- (lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy [S] phenyl] propanoate  By an operation similar to that described in Synthesis 16, (S) -4 [[1- ( N-2-yl) pyrrolidin-2-yl] methoxy] aniline (4.6 g) to give the title compound (1.5 g) , 23%) as a thick liquid. Synthetic 23 (3R) -hydroxy-1- (pyridin-2-yl) pyrrolidine   By the same operation as described in Synthesis 1, 2-chloropyridine (40 g) and L-pro The title compound (2.9 g, 15%) was synthesized from linol (10 g) as a thick liquid. Synthetic 24 (3R) -1-pyridin-2-yl) -3-pyrrolidine methanesulfonate  By a procedure similar to that used in Synthesis 4, the (3R) -3-hydroxy- obtained in Synthesis 23. 1- (pyridin-2-yl) pyrrolidine (0.2 g) and methanesulfonyl chloride (0.18 mL) Synthesized the title compound (0.3 g, 100%) as a thick liquid. Synthetic 25 (3S) -4- [1- (pyridin-2-yl) pyrrolidin-3-yloxy] benzaldehyde   (3R) -1-pi obtained in Synthesis 24 by the same operation as described in Method A of Synthesis 9. (Lysin-2-yl) -3-pyrrolidine methanesulfonate (0.2 g) and 4-hydroxyben The title compound (0.15 g, 68%) was synthesized as a thick liquid from duzaldehyde (0.12 g). Was. Synthetic 26 2-hydroxymethyl-4- (pyridin-2-yl) morpholine  By a procedure similar to that described in Synthesis 1, 2-chloropyridine (54.32 g) and 2-hydroxypyridine were used. Add the title compound (33.0g, 72%) from droxymethylmorpholine (28.0g) Was synthesized. Synthetic 27 4-[[-(pyridin-2-yl) morpholin-2-yl] methoxy] benzaldehyde   By a procedure similar to that described in Synthesis 8, the 2-hydroxymethyl 4- (pyridin-2-yl) morpholine (33.5 g) and 4-fluorobenzaldehyde (27.8 From 5 g), the title compound (39.0 g, 76%) was synthesized as a sylobic liquid. Example 1 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] thiazolidine-2,4-dione  Synthesis 8 in toluene (300 mL) containing piperidine (1.5 g) and benzoic acid (1.8 g) (S) -4-[[1- (pyridin-2-yl) pyrrolidin-2-yl] methoxy] benzure obtained in Add a solution of aldehyde (33.5 g) and 2,4 thiazolidinedione (16.7 g) to Dean-Stark water. The mixture was heated for 1 hour under reflux using a separator. Cool and filter the reaction mixture The filtrate was washed with water, dried (Na_TwoSO_Four) And evaporated under reduced pressure. Methaneau The crude product was triturated with a filter and filtered to give 27.5 g (60%) of the title compound (mp 164 ° C).         [α]_D ²⁷= -73.6 (c.1.0, DMSO) Example 2 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione   To a stirred suspension of the product from Example 1 (10 g) in methanol (250 mL) At room temperature, magnesium turning (10.8 g) was added to the reaction. The mixture was stirred at room temperature for 4 hours. The reaction mixture was added to ice water (100 mL) and hydrochloric acid was added. The pH is adjusted to 6.5 to 7.0 using an aqueous solution, and the solution is extracted with cocoloform (3 × 150 mL). Issued. The combined organic extracts are washed with water, dried (CaCl 2_Two), Remove the solvent under reduced pressure Leave Was. The residue was chromatographed on silica gel using 0.5% methanol in chloroform. Chromatography gave 6.5 g (65%) of the title compound (mp 79-80 ° C).         [α]_D ²⁷= -107.9 (c.1.0, CHCl_Three) Example 3 5- [4-[[1- (pyridin-2-yl) piperidin-4-yloxy] phenylmethylene] thia Zolidine-2,4-dione   By a similar operation to that described in Example 1, 4- [1- (pyridine-2) obtained in Synthesis 9 was used. -Yl) -4-piperidinyloxy] benzaldehyde (1.5 g) from the title compound (1.5 g, 74%) was synthesized (melting point: 218-220 ° C). Example 4 5- [4-[[1- (pyridin-2-yl) piperidin-4-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione  By a similar operation to that described in Example 1, the 4- [1- (pyridine-2) obtained in the synthesis 10 was obtained. -Yl) piperidin-4-yl] methoxy] benzaldehyde (0.55 g) to give the title compound (0.46 g, 63%) was synthesized (melting point: 233.4 ° C.). Example 5 5- [4- [2- [4- (pyridin-2-yl) piperazin-1-yl] ethoxy] phenylmethylene] Thiazolidine-2,4-dione   By a similar operation to that described in Example 1, the 4- [2- [4- (pyridyl) obtained in Synthesis 11 was obtained. N-2-yl) piperazin-1-yl] ethoxy] benzaldehyde (1.0 g) A compound (0.85 g, 64%) was synthesized (melting point: 158-160 ° C). Example 6 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] Thiazolidine-2,4-dione, maleate   A solution of the product obtained in Example 1 (50 g) and maleic acid (16.7 g) in dry acetone (2 L) Was stirred at room temperature for 20 hours. After this is completed, the resulting solid is filtered and the cold Wash with seton (2 × 200 mL) and dry under reduced pressure to give 52 g (80%) of the title compound ( 132 ° C).         [α]_D ²⁷= -77.3 (c.1.0, DMSO) Example 7 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] thiazolidine-2,4-dione, hydrochloride   Dry HCl gas was added to a solution of the product (40 g) obtained in Example 1 in dry acetone (2 L). Aerated at 0 ° C. for 30 minutes. Filter the resulting solid and wash with cold acetone (2 x 200 mL) And dried under reduced pressure to give 33 g (78%) of the title compound as a white solid, mp 241 243243 ° C.).         [α]_D ²⁷= -131.9 (c.1.0, DMSO)Example 8 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ren] thiazolidine-2,4-dione, sodium salt   5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy obtained in Example 1 To a solution of [phenyl] methylene] thiazolidine-2,4-dione (1 g) was added MeOH (10 mL) at room temperature. NaOMe in () synthesized in situ by dissolving Na (66 mg) in MeOH (5 mL) ]. After stirring the reaction mixture at room temperature for 1 hour, Et2_TwoDiluted with O (10 mL). The resulting solid is filtered, and P_TwoO_Five400 mg (38%) of the title product Was obtained as a white solid (mp 254-256 ° C).         [α]_D ²⁷= -85.2 (c.1.0, DMSO) Example 9 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate  By the same operation as described in Example 6, the 5- [4-[[1- (pyri) obtained in Example 2 was obtained. Zin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine The title compound (2 g, 76%) was obtained from -2,4-dione (2 g) as a white solid, mp 58-60. ° C).         [α]_D ²⁷= -80.5 (c.1.27, DMSO) Example 10 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt   By the same operation as described in Example 8, the 5- [4-[[1- (pyri) obtained in Example 2 was obtained. Zin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine The title compound (0.7 g, 25%) was obtained from -2,4-dione (2.7 g) as a white solid (mp 26 0-262 ° C).         [α]_D ²⁷= -63.0 (c, 0.5, DMSO) Example 11 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] thiazolidine-2,4-dione   By the same operation as described in Example 1, the 4-[[1- (quinoline- 2-yl)-(2S) -pyrrolidin-2-yl] methoxy] benzaldehyde (1.5 g) The compound (2 g, 100%) was obtained as a pale yellow solid (mp 260-262 ° C).         [α]_D ²⁷= +49.2 (c.1.0, DMSO) Example 12 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione   Ethyl 2-bromo-3- [4-[[1- (quinolin-2-yl)-(2S) -pyrroli obtained in Synthesis 16 Zin-2-yl] methoxy] phenyl] propanoate (2.5 g), thiourea (0.76 g), A mixture of NaOAc (0.82 g) and EtOH (25 mL) was stirred at reflux for 4 hours, And dried (Na_TwoSO_Four), Concentrated and 2-imino-5- [4-[[1- (quinolin-2-yl)- (2S) -Pyrrolidin-2-yl] methoxy] benzyl] -4-thiazolidinedione was obtained. Used in the next step without further purification.   Stir a mixture of the above product, 2N HCl (15 mL) and EtOH (30 mL) at reflux for 12 hours did. The reaction mixture was concentrated under vacuum. Dilute the residue with water and add saturated NaHCO_ThreeWater soluble The mixture was neutralized and extracted with ethyl acetate. The EtOAc extract was washed with brine, dried ( Na_TwoSO_Four), Concentrated under vacuum. CHCl as eluent_ThreeSilicate using 0-10% MeOH in The residue was purified by chromatography on Kagel to give the title compound (1.6 g, 68%). Obtained as a yellow solid (mp 81-83 ° C)         [α]_D ²⁷= -13.8 (c.1.0, DMSO) Example 13 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate   By the same operation as described in Example 6, the 5- [4-[[1- (quino) obtained in Example 12 was obtained. Phosphorus-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine- The title compound (0.85 g, 70%) was synthesized from 2,4-dione (1.0 g) as a yellow solid ( 84-86 ° C).         [α]_D ²⁷= -458 (c.1.0, DMSO) Example 14 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride   By the same operation as described in Example 7, the 5- [4-[[1- (quino) obtained in Example 12 was obtained. Phosphorus-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine The title compound (0.9 g, 83%) was synthesized from -2,4-dione (1.0 g) as a yellow solid ( 144-146 ° C).         [α]_D ²⁷= -100.6 (c.1.0, DMSO) Example 15 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium saltBy the same operation as described in Example 8, the 5- [4-[[1- (quinolini) obtained in Example 12 was obtained. 2-Nyl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine-2 The title compound (0.27 g, 72%) was obtained from, 4-dione (0.36 g) as a pale yellow solid. ( 248-250 ° C).         [α]_D ²⁷= +1.4 (c.1.0, DMSO) Example 16 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] thiazolidine-2,4-dione   By the same operation as that described in Example 1, 4-[[1- (lepidin- 2-yl)-(2S) -pyrrolidin-2-yl] methoxy] benzaldehyde (1.8 g) The compound (1.78 g, 77%) was obtained as a pale yellow solid. Example 17 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione Method A:   Ethyl-2-chloro-3- [4-[[1- (lepidin-2) obtained from synthesis 21 in sulfolane (20 mL). -Yl)-(2S) -pyrrolidin-2-yl] methoxy] phenyl] propanoate (15 g) Mix urea (5 g) with N_TwoStirred at 120-130 ° C under gas for 4 hours. The reaction mixture The mixture was cooled to room temperature and 2-methoxyethanol (192 mL), water (50 mL), and concentrated HCl (2 mL) 6 mL) was added. The temperature was raised to 80 ° C. and stirred for 15 hours. Cool the reaction mixture And diluted with EtOAc, NH_ThreeAfter washing with an aqueous solution, wash with water, dry (Na_TwoSO_Four) And concentrated. 10-40% ethyl acetate in pet ether as eluent (Gradient elution)) and chromatograph the crude product on silica gel. Roughening afforded the title compound (14 g, 95%) as a white solid (mp 95-97 ° C). ). Method B:   By the same operation as described in Example 12, the ethyl-2-bromo- obtained in Synthesis 22 was obtained. 3- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenyl] pro The title compound (0.12 g, 15%) was synthesized from panoate (1.5 g) as a white solid (mp 95 9797 ° C.).         [α]_D ²⁷= -31.5 (c.1.0, CHCl_Three) Example 18 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate   By the same operation as described in Example 6, the 5- [4-[[1- (repi) obtained in Example 17 was obtained. Zin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine The title compound (0.21 g, 78%) was synthesized from -2,4-dione (0.22 g) as a white solid ( Mp 68-70 ° C).         [α]_D ²⁷= -72.0 (c.1.0, DMSO) Example 19 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride   By the same operation as described in Example 7, the 5- [4-[[1- (repi) obtained in Example 17 was obtained. Zin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine The title compound (0.2 g, 86%) was obtained from -2,4-dione (0.22 g) as a white solid (mp 1 20 ° C).         [α]_D ²⁷= -1205 (c, 1.0, DMSO) Example 20 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt   By the same operation as described in Example 8, the 5- [4-[[1- (repi) obtained in Example 17 was obtained. Zin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl] thiazolidine The title compound (0.28 g, 53%) was synthesized as a pale yellow solid from -2,4-dione (0.5 g). (Mp 229 ° C).         [α]_D ²⁷= -5.3 (c.1.0, DMSO) Example 21 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione   By the same operation as described in Example 1, 4 [[1- (pi) Table from (lysin-2-yl)-(3S) -pyrrolidin-3-yloxy] benzaldehyde (0.7 g) The title compound (0.5 g, 52%) was obtained as a pale yellow solid (mp 204-206 ° C).         [α]_D ²⁷= -20.4 (c, 0.5, DMSO) Example 22 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione, maleate   By a similar operation to that described in Example 6, the 5- [4- [ [1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene] thia The title compound (0.25 g, 78%) was obtained from zolidine-2,4-dione (0.25 g) as a pale yellow solid. (Mp 176-178 ° C).         [α]_D ²⁷= -15.0 (c.1.0, DMSO) Example 23 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione, hydrochloride  By a similar operation to that described in Example 7, the 5- [4- [ [1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene] thia The title compound (0.13 g, 78%) from zolidine-2,4-dione (0.15 g) as a white solid (Melting point 256-258 ° C.).         [α]_D ²⁷= -20.44 (c.0.45, DMSO) Example 24 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethyl] Thiazolidine-2,4-dione   By a procedure analogous to that described in Example 2, the 5- [4- [ [1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene] thia The title compound (0.25 g, 35%) from zolidine-2,4-dione (0.7 g) as a white solid (Mp 78-80 ° C). Example 25 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethylene] thio Azolidine-2.4-dione   By a procedure similar to that described in Example 1, the 4-[[4- ( Pyridin-2-yl) morpholin-2-yl] methoxy] benzaldehyde (16.0 g) The title compound (19 g, 89%) was obtained as a pale yellow solid (mp 188 ° C). Example 26 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione   By a procedure analogous to that described in Example 2, the 5- [4- [ [4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethylene] thiazoly Gin-2,4-dione (17.0 g) gave the title compound (5.0 g, 30%) as a white solid ( 139-142 ° C).Example 27 5- [4-[[4-pyridin-2-yl] morpholin-2 yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione, sodium salt   By the same operation as described in Example 8, the 5- [4- [ [4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethyl] thiazolidi 2,4-dione (3.1 g) gave the title compound (2.9 g, 89%) as a white solid (mp 272 ° C).   Mutations in laboratory animal colonies and variable susceptibility to dietary programs Gender leads to non-insulin dependent diabetes with obesity and insulin resistance It has become possible to develop an affected animal model. Understand the pathophysiology of the disease, To test the efficacy of new anti-diabetic compounds, mice were tested for db / db and ob / ob (Di abetes, (1982) 31 (1): 1-6), and fa / fa and zucker rat Genetic models such as have been developed by various laboratories (Diabetes, (1 983) 32: 830-838; Annu.Rep.Sankyo Res.Lab. (1994) 46: 1-57). Jackson Labora Tree, homozygous developed by the United States (Jackson Laboratory, US) The combined animal, C57 BL / KsJ-db / db mouse, is obese, hyperglycemic, hyperinsulinemic, And insulin resistance (J. Clin. Invest., (1990) 85: 962-967). In contrast, heterozygous animals are lean and have normal blood glucose levels. In db / db model Indicate that mice gradually develop hypoinsulinism with age, When sugar levels are poorly controlled, the terminal stage of human type II diabetes This is a feature commonly observed on floors. The state of the pancreas and its changes depend on the model. Various. Since the motel resembles type II diabetes, the compounds of the present invention will A test was conducted for the activity of lowering blood and triglycerides.   The compounds of the present invention improve glycemic and glucose levels by improving insulin resistance. It showed an activity of lowering glyceride. This is demonstrated by the following in vivo experiments. It was proved.   Jackson Laboratory, obtained from the United States, weighs in the range of 35-60 grams Male C57BL / KsJ-db / db mice, aged 8-14 weeks, were used in the experiments. The mouse Use standard diet (National Nutrition Research Institute, Hyderabad, India) and acidified water I gave it to you. Animals with blood glucose greater than 300 mg / dL were used for testing. Each glue The number of animals in the group was four.   Using heparinized tubules, orbital sinus into tubes containing EDTA By collecting blood (100 μL) and centrifuging it to obtain plasma, random Blood glucose and triglyceride levels were measured. Plasma glucose levels and triglycerides Celide levels were measured for glucose oxidase and glycerol-3-phosphate, respectively. Spectrophotometrically measured by the oxidase / peroxidase enzyme method (Dr. Reddy ' s Lab. Diagnostic Division Kits, Hyderabad, India). On the sixth day, the biological activity One hour after administration of the test compound / vehicle to evaluate The pull was collected.   Test compound is 0.25% carboxymethylcellulose or water (for water-soluble compounds) ) And by oral gavage at a dose of 10-30 mg / kg daily for 6 days. It was administered to a strike group. The control group received the vehicle (10 mL dose /kg). Troglitazone (100 mg / kg, daily dose) as standard drug Used, but this reduced random blood glucose levels by 28% on day 6.   The activity of a nuclear test compound in lowering blood glucose and triglycerides has the formula: Blood glucose / triglyceride lowering activity (%) = 1− (DT / DC) / (TC / ZC) × 100   ZC = value of control group on day 0   DC = value of treated group on day 0   TC = control group value on test day   DT = value of treated group on test day Calculated according to   In the above test, by-products of any of the compounds of the present invention indicated. No use was observed.   The experimental results from db / db mice show that the novel compound of the present invention is obese, hypertensive and hyperlipidemic. It is also useful in the prevention or regular treatment of cardiovascular diseases such as Suggest that you Because, according to the literature, such diseases are mutually exclusive. This is because it is known that Subacute toxicity in rats   Group of 20 rats consisting of 10 males and 10 females weighing 120-140 grams Then, 100 mg / kg of the compound of Example 6 was orally administered for 28 days. Behavioral changes and weight Monitored daily. Rats were sacrificed on day 29 for hematological and biochemical measurements. Blood was collected for All major reservoirs were examined visually and microscopically.   At the 100 mg / kg dose, the compound of Example 6 did not cause any death. 28th day At the end of treatment, hematological and biochemical parameters No significant difference from the control was observed. Heart, lung, bone marrow, kidney, There were no overall macroscopic and microscopic changes in the spleen.

[Procedure of Amendment] Article 184-8, Paragraph 1 of the Patent Act [Submission date] August 10, 1998 (1998.8.10) [Correction contents] Examples of such compounds are shown in formula (IIh).   v) Group of formulas (IIia ~ d) (where R¹Is a hydrogen atom, halogen, straight-chain or branched ( C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, trifluoromethyl or cyano groups X is S, O or NR (where R is H or (C₁~ C₆) Which is an alkyl group). These compounds are disclosed in European Patent Application No. 0,528,734. )   Examples of compounds belonging to this class are shown in formula (IIj).  Formula (IIk) or their tautomeric forms, pharmaceutically acceptable salts thereof, pharmaceutically acceptable Their acceptable solvates (where A¹Is substituted or unsubstituted Represents an aromatic heterocyclic group, R¹Represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group (A The reel portion may or may not be replaced) or has been replaced Or an unsubstituted aryl group,^TwoAnd R^ThreeDoes each represent hydrogen Or R^TwoAnd R^ThreeRepresents one bond between the two, and A^TwoIs a ben having up to 5 substituents in total Represents a zen group, and n represents an integer in the range of 2 to 6). Drugs containing such compounds Compositions and the use of such compounds and compositions in medicine are disclosed in US Pat. No. 5,002,953. ).   Examples of compounds of this class are shown in formula (III).   Group of formula (IIm) (where the dashed line represents a bond of 1 or 0, V is CH = CH, N = CH, CH = N or S, W is CH_Two, CHOH, C = O, C = NOR, CH = CH, and X is S, O, NR¹, CH = N, N = CH, Y is CH or N, Z is hydrogen, (C₁~ C₇) Alkyl, (C_Three~ C₇) Chloroalkyl, phenyl, naphthyl, pyridyl, furyl, thienyl, or (C₁~ C_Three ) Alkyl, trifluoromethyl, (C₁~ C_Three) Alkoxy, fluoro, chloro, or Is the same or different groups that are bromo, mono- or di-substituted phenyl, Z¹Is Hydrogen or (C₁~ C_Three) Alkyl, R is hydrogen or methyl, n is 2 or 3 ) Are disclosed in European Patent Application No. 0,332,: 332.   Examples of compounds of this class are shown in formula (IIn).   A group of formula (IIo), its salts and pharmaceutical compositions containing them, wherein R¹ , R^Two, And R^ThreeIs independently hydrogen, halogen, optionally halogenated lower alkyl Killed or lower alkoxy, hydroxy, nitro, amino, lower acylamino, No or di (lower alkyl) amino, carboxy, lower alkoxycarbonyl, shea No, 2-oxazolyl, thiazolidine-2,4-dione-5-ylidenemethyl or thiazolyl Gin-2,4-dione-5-ylmethyl, R¹And R^TwoAre bonded to form an alkylene chain -(CH_Two)_p-(Where p represents 3, 4 or 5) or an alkylenedioxy chain -O (CH_Two)_q O- (where q represents 1, 2 or 3) to form a ring Well, R^FourAnd R^FiveEach independently represents hydrogen or lower alkyl, and X represents carbon or nitrogen. Represents Y, Y represents oxygen or imino, A and B each represent lower alkylene , M represents 0 or 1, and "------" may be a double bond). No. 0,645,387.   Examples of compounds of this class are shown in formula (IIp).  A group of formula (IIq) wherein R is an alkyl group and X is oxygen or sulfur , Y is a hydrogen atom or A-COOH (A is an alkylene group), and Ar is aryl or Substituted aryl groups) are disclosed in European Patent Application No. 590,793 .   Examples of compounds of this class are shown in formula (IIr).   A group of the formula (IIs), wherein n represents an integer of 1 to 3, and A represents an aromatic 5-membered heterocyclic ring Residue (having at least one nitrogen atom as a ring atom, Wherein the residue A is a carbon atom adjacent to the nitrogen atom of the residue. Rukokin group (A- (CH_Two)_n-O-), where "------" is a single bond or a double bond. Is disclosed in European Patent Application No. 605,228.   Examples of this class of compounds are shown in formula (IIt).  The group of formula (IIu) (where R¹Is alkyl, sicccoalkyl, phenylal One or two heteroatoms selected from kill, phenyl, nitrogen, oxygen, and sulfur A 5- or 6-membered heterocyclic group containing^Three-N-R^FourGroup (where R^ThreeAnd R^FourIs Identical or different, each being lower alkyl, or R^ThreeAnd R^FourAre each other Or directly by a heteroatom selected from N, O or S. To form a 5- or 6-membered ring), R^TwoIs one bond or low Lower alkylene group; L¹And L^TwoAre the same or different and are each lower alkyl, or L¹And L^TwoAre linked to form an alkylene group (R¹Is other than alkyl Is L¹And L^TwoCan also be a hydrogen atom) in European Patent Application No. 0,008,203. It is shown.   Examples of compounds of this class are shown in formula (IIv).   Chem. Pharm. Bull; 30, 3580-3600 (1992) Are disclosed.     The group of formula (IIw) (where R¹And R^TwoAre the same or different and are each hydrogen or Represents a lower alkyl group, R^ThreeIs hydrogen or an acyl group, and n is 0 or 1. And their salts exhibiting blood glucose and blood lipid lowering activity are disclosed in European Patent Application No. 155,845. Is disclosed.  Examples of compounds of this class are shown in formula (IIx).   International application WO 94/25026 discloses compounds of formula (IIy), wherein A¹Is replaced Represents a substituted or unsubstituted aromatic heterocyclic group, R¹Is a hydrogen atom, an alkyl group , An acyl group, an aralkyl group (the aryl moiety is substituted or unsubstituted Or a substituted or unsubstituted aryl group;^Two And R^ThreeEach represents hydrogen or R^TwoAnd R^ThreeRepresents a single bond, and A^TwoIs the sum Represents a benzene group having up to 5 substituents, and n represents an integer in the range of 2 to 6. )   Examples of compounds of this class are shown in formula (IIz).   J. Med.Chem 37, 3977-3985 (1995). Has already been disclosed. Some of the compounds in the literature are described in European Patent Application 0,295,82. It is described in No. 8.   European Patent Application No. 0,295,828 wherein R represents hydrogen or alkyl;¹Is A alkyl group or a substituted or unsubstituted aryl group;^Twoas well as R^ThreeEach represents hydrogen or R^TwoAnd R^ThreeRepresents one bond between the two, A is a total of five X represents oxygen, sulfur, or NR^FourPart (where , R^FourRepresents hydrogen or alkyl) n represents an integer in the range of 2 to 6) is a compound of the formula (I) Disclosure.   Examples of compounds of this class are represented by the formula: Shown in   Exp.Opin.Invest.Drugs (1995) 4 (12): 1299-1309 are non-insulin dependent sugars. Thiazolidinedione in the treatment of urine (NIDDM) is described. The reference is: It also describes in vitro and in vivo activities in various animal models. You. The literature specifically mentions four molecules (ie, ciglitazone, pio Glitason (Pioglitazone), troglitazone (Troglitazone), and englitazo (Englitazone).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/5377 A61K 31/5377 A61P 3/06 A61P 3/06 3/10 3/10 5/50 5 / 50 9/10 9/10 9/12 9/12 13/12 13/12 25/28 25/28 C07D 213/74 C07D 213/74 401/04 401/04 417/12 417/12 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, SD, SZ, UG), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AL, AM, AT, AU, AZ, BA, B , BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK , TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU (72) Inventors Lorai, Bidya Boothhan India, Andhra Pradesh, Hydra Rabad 500 033, Jubilee Hills, Road Number 50, Plot 986 (72) Inventors Lorai, Bly Boothan, India, Andhra Pradesh, Hydra Labad 500 033, Jubilee Hills, Road Number 50, Plot 986 (72) Inventor Ara, Karl Lady India, Andhra Pradesh, Hydra Rabad 500 050, Myarpur, Bolalam Road, JP N Nagar, Plot 19 (72) Inventor Paraselli, Lao Bemah India, Andhra Pradesh Hyde Rabad 500 050, Myapur, Deepisuri Nagar, H No. 5-8 (72) Inventor Ramanyam, Rajagopalan India, Andhra Pradesh, Hyde Rabad 500 873, Yeladi Guda, Nabodaya Colony 8-3 -682, Bistial Towers 28 (72) Inventor Chakravarti, Ranyam India, Andhra Pradesh, Hyde Rabad 500 038, Nagar, Rabi Teja Apartments 283/3 RT, Flat Number 104

Claims (1)

[Claims]   1. A compound of formula (I), Their tautomeric forms, their stereoisomers, their polymorphs, pharmaceutically acceptable A salt thereof, or a pharmaceutically acceptable solvate thereof, wherein A is substituted Selected from aromatic or unsubstituted aromatic groups, oxygen, nitrogen, or sulfur. Substituted or unsubstituted, independently, having three heteroatoms or Fused five-membered heterocyclic group, or one or more substituted or unsubstituted An independent or fused 6-membered heterocyclic group having a nitrogen atom of B and D Is a substituted or unsubstituted hydrocarbon group linking N and X, respectively. Where X is CH_TwoRepresents a group or a heteroatom selected from nitrogen, oxygen, or sulfur , Ar represents a substituted or unsubstituted divalent aromatic or heterocyclic group;₁ And R_TwoMay be the same or different and include hydrogen, lower alkyl, halogen, alcohol Represents xy or hydroxy, or R¹And R^TwoRepresents one bond, and p is 0 Is an integer in the range of ~ 4).   2. The compound of claim 1, wherein A is substituted or unsubstituted. A 6-membered heterocyclic group which is independent or fused and has one or more oxo groups in a ring. Compounds.   3. 2. The compound according to claim 1, wherein the group B connecting N and X is saturated. Or a compound containing one or more double bonds.   4. 2. The compound according to claim 1, wherein the group D connecting N and X is saturated. Or a compound containing one or more double bonds.   5. 2. The compound according to claim 1, wherein the group represented by B connecting N and X is 1-4. And the group represented by D connecting N and X contains from 1 to 4 carbon atoms Or a compound that represents one bond.   6. The compound according to claim 1, wherein the groups represented by B and D connecting N and X are saturated. Compounds that are unified or contain 1-2 double bonds.   7. The compound according to claim 1, wherein the hydrocarbon linking group is represented by B and D. And a compound wherein the heterocycle comprising N and X is a three-membered to five-membered ring.   8. The compound according to claim 1, wherein the aromatic group represented by A contains one to two rings. The compound you are doing.   9. The compound of claim 1, wherein A is selected from nitrogen, oxygen, or sulfur. The compound is a five-membered heterocyclic group containing one hetero atom.   10. 2. The compound according to claim 1, wherein A is a substituted aromatic group, A 5- or 6-membered heterocyclic group, wherein the substituent is hydroxy or a Mino, substituted or unsubstituted (C₁~ C₁₂) Alkyl, (C_Three~ C₆) Cycloalkyl group, cycloaminoalkyl, aryl, aralkyl, heteroaryl , Alkoxy, aryloxy, alkoxycarbonyl, aryloxyca Rubonyl, amino (C₁~ C₆) Alkyl, hydroxy (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, thio (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylthio, acyl group , A compound selected from carboxylic acid derivatives, acyloxy, or sulfonic acid derivatives object.   11. 11. The compound according to claim 10, wherein the substituent is halogen, lower alkyl. A compound substituted by a lower alkoxy, lower alkoxy, hydroxy, or amino group.   12. The compound according to claim 10, wherein the carbon atom adjacent to the group represented by A The substituent on the member is one of a substituted or unsubstituted 4- to 7-membered ring structure; And the cyclic structure is an aromatic or saturated or unsaturated carbocycle, aromatic or saturated Or an unsaturated heterocycle, wherein the heteroatom is selected from nitrogen, oxygen, or sulfur Compound.   13. The compound according to claim 12, wherein the substituent on the cyclic structure is hydroxy. C, amino, halogen, substituted or unsubstituted (C₁~ C₁₂) Alkyl group , (C_Three~ C₆) Cycloalkyl, cycloaminoalkyl, aryl, aralkyl, Aralkyl, heteroaryl, alkoxy, aryloxy, alkoxycarbo Nil, aryloxycarbonyl, amino (C₁~ C₆) Alkyl, hydroxy (C₁ ~ C₆) Alkyl, thio (C₁~ C₆) Alkyl, (C₁~ C_Two) Alkylthio, acyl, carbo Acid-derived compounds selected from the group consisting of book, acyloxy, or sulfonic acid derivatives Compound.   14． The compound according to claim 1, wherein the substituent on the linking group represented by B and D is , Hydroxy, amino, halogen, optionally substituted linear or branched (C₁~ C₁₂) Alkyl group, (C_Three~ C₆) Cycloalkyl group, (C₁~ C₆) Alkoxy , (C_Three~ C₆) Cycloalkoxy, aryl, heterocyclic, (C_Two~ C₆) Acyl, ( C_Two~ C₆) Acyloxy, hydroxyl (C₁~ C₆) Alkyl, amino (C₁~ C₆A) Lucil, mono or di (C₁~ C₆) Alkylamino, cyclo (C_Two~ C₆) Alkylam Groups (two substituents, with adjacent carbon atoms attached to them, Or an unsubstituted 5- to 7-membered ring structure, wherein the ring structure is An aromatic or saturated or unsaturated carbocycle wherein the terrorist atom is selected from N, O, or S, Or an aromatic or saturated or unsaturated heterocyclic ring, and substitution on the cyclic structure. If the group is hydroxy, amino, halogen, substituted or unsubstituted (C₁~ C₁₂ ) Alkyl group, (C_Three~ C₆) Cycloalkyl group, cycloaminoalkyl group, ant Aralkyl, heteroaryl, alkoxy, aryloxy, alcohol Xycarbonyl, aryloxycarbonyl, amino (C₁~ C₆) Alkyl, hydr Roxy (C₁~ C₆) Alkyl, (C₁~ C₆) Alkoxy, thio (C₁~ C₆) Alkyl, (C₁~ C₆) Alkylthio, acyl groups, carboxylic acid derivatives, acyloxy groups, and A compound selected from the group consisting of sulfonic acid derivatives.   15. A thiazolidinedione derivative of the formula (I) according to claim 1, Tautomeric forms, their stereoisomers, their polymorphs, pharmaceutically acceptable Or a pharmaceutically acceptable solvate thereof, comprising:   (a) Compound of general formula (V)(Where A, B, D, X and p are as defined in claim 1;^aIs a hydroxyl group) And of the general formula (VI)   And a compound of the general formula (VI)                          R^b−Ar-CHO (VI) (Where Ar is as defined in claim 1, R^bIs a hydroxyl group or a halogen group) And react with     Compound of general formula (VII) (Where A, B, D, X, Ar and p are as defined above) and (b) Reacting the compound of general formula (VII) obtained in step (a) with 2,4 thiazolidinedione, Compound of general formula (VIII) (Where A, B, D, X, Ar, and p are as defined above) A preparation method comprising:   16. 16. The method according to claim 15, wherein the method is obtained in step (b) of claim 15. Reducing the compound of general formula (VIII)(Where A, B, D, X, Ar and p are as defined in claim 15) A method to further prepare.   17． 16. The method according to claim 15, wherein the compound of formula (VIII) is separated into stereoisomers. A method further comprising splitting.   18. 17. The method according to claim 16, wherein the compound of formula (IX) is separated into stereoisomers. A method further comprising:   19. A thiazolidinedione derivative of the formula (I) according to claim 1, Tautomeric forms, their stereoisomers, their polymorphs, pharmaceutically acceptable Or a pharmaceutically acceptable solvate thereof, comprising: Compound of formula (V) (Where A, B, D, X and p are as defined in claim 1;^aIs a hydroxyl group) Or a compound of formula (X) (Where A, B, D, X and p are as defined in claim 1;^TwoIs a leaving group) And a compound of formula (XIII)(Where R¹, R^TwoAnd Ar are as defined in claim 1;^FourIs a hydrogen or nitrogen protecting group ).   20. A thiazolidinedione derivative of the formula (I) according to claim 1, Tautomeric forms, their stereoisomers, their polymorphs, pharmaceutically acceptable Or a pharmaceutically acceptable solvate thereof, comprising: a) Compound of formula (V) (Where A, B, D, X and p are as defined in claim 1;^aIs a hydroxyl group) Or a compound of formula (X) (Where A, B, D, X and p are as defined in claim 1;^TwoIs a leaving group) And a compound of formula (XX) (Where R^bIs a halogen atom or a hydroxyl group, and Ar is as defined in claim 1 ) To give a compound of formula (XIX)(Here, all symbols are as defined in claim 1) b) reducing the compound of formula (XIX) obtained in step (a) above to obtain a compound of formula (XVIII) And (All symbols are as defined in claim 1) c) After diazotizing the compound of formula (XVIII), acrylate / hydrogen halide Treatment with an acid gives a compound of formula (XVII) (Where A, B, D, X, p and Ar are as defined in claim 1, and J is a halogen atom And R is a lower alkyl group), after treatment with thiourea, followed by treatment with an acid. And d) reacting the compound of formula (XVII) obtained in step (c) above with thiourea, The compound of formula (I) according to claim 1 wherein R¹Passing And R^TwoEach represents a hydrogen atom).   21. A process for preparing intermediate (VII), comprising:(Where A, B, D, X, Ar and p are as defined in claim 1), a) Compound of formula (XI) (Where B, D, X, Ar and p are as defined above) and a compound of formula (III)                                  A-L¹        (III) (Where A is as defined above and L¹Is a leaving group) Or b) a compound of formula (X) (Where A, B, D, X and p are as defined above;^TwoIs a leaving group) and the formula ( VI) Compound                          R^b−Ar-CHO (VI) (Where Ar is as defined above and R^bIs a hydroxyl group) A preparation method comprising:   22. Type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart Disease and other cardiovascular diseases including atherosclerosis, obesity and psoriasis Pathophysiological mechanisms underlying insulin resistance, such as insulin resistance Composition useful for treatment and / or prevention of diseases having diabetes, diabetic complications and polycapsules Ovarian syndrome (PCOS), diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrosis Certain renal diseases, including syndrome, hypertensive renal sclerosis, end-stage renal disease and microproteinuria Pharmaceutical compositions useful for treating other diseases, such as certain eating disorders ( Aldose reductase inhibitor), as well as improving cognitive function in dementia A pharmaceutical composition useful in a pharmaceutically acceptable carrier, diluent, or solvate. A pharmaceutical composition comprising the compound of the formula (I) according to claim 1 together with a product.   23. The following groups: 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl) piperidin-4-yloxy] phenylmethylene] thia Zolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl) piperidin-4-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione; 5- [4- [2- [4- (pyridin-2-yl) piperazin-1-yl] ethoxy] phenylmethylene] Thiazolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Len] Thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (quinolin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (quinolin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[1- (Lepidin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl)-(2S) -pyrrolidin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl)-(2R) -pyrrolidin-2-yl] methoxy] phenylmethyl Le] j Azolidine-2,4-dione, sodium salt; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethylene] thia Zolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione and its salts; 5- [4-[[1- (pyridin-2-yl)-(3R) -pyrrolidin-3-yloxy] phenylmethylene ] Thiazolidine-2,4-dione and its salts; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethylene] thia Zolidine-2,4-dione, maleate; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethylene] thia Zolidine-2,4-dione, hydrochloride; 5- [4-[[1- (pyridin-2-yl) pyrrolidin-3-yloxy] phenylmethyl] thiazo Lysine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(3S) -pyrrolidin-3-yloxy] phenylmethyl] Thiazolidine-2,4-dione and salts thereof; 5- [4-[[1- (pyridin-2-yl)-(3R) -pyrrolidin-3-yloxy] phenylmethyl] Thiazolidine-2,4-dione and salts thereof; 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione and its salts; 5- [4-[[4- (pyridin-2-yl)-(2S) -morpholin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione and salts thereof; 5- [4-[[4- (pyridin-2-yl)-(2R) -morpholin-2-yl] methoxy] phenylmethyl [Lens] thiazolidine-2,4-dione and salts thereof; 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione and its salts; 5- [4-[[4- (pyridin-2-yl)-(2S) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione and its salts; 5- [4-[[4- (pyridin-2-yl)-(2R) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl) morpholin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione, sodium salt; 5- [4-[[4- (pyridin-2-yl)-(2S) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[4- (pyridin-2-yl)-(2R) -morpholin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, sodium salt; 5- [4-[[4- (pyridin-2-yl) aziridin-2-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione; 5- [4-[[1- (pyridin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl) aziridin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[4- (pyridin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl) aziridin-2-yl] methoxy] phenylmethylene] thio Azolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl [Len] thiazolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl) aziridin-2-yl] methoxy] phenylmethyl] thia Zolidine-2,4-dione; 5- [4-[[4- (quinolin-2-yl)-(2S) -aziridin-2-yl] methoxy] phenylmethyl Ru] thiazolidine-2,4-dione, and 5- [4-[[4- (quinolin-2-yl)-(2R) -aziridin-2-yl] methoxy] phenylmethyl Le] j Azolidine-2,4-dione 2. The compound of claim 1, wherein the compound is selected from the group consisting of:   24. Claim 2 in the form of a tablet, capsule, powder, syrup, solution or suspension. 3. The pharmaceutical composition according to 2.   25. A compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier, Administering a diluent or solvate to a patient in need thereof. Method for preventing or treating diseases in which insulin resistance is a fundamental pathophysiological mechanism .   26. 24. The compound according to claim 23 as an active ingredient, and a pharmaceutically acceptable carrier. A pharmaceutical composition comprising a body, diluent or excipient.   27. The compound of formula (1) according to claim 1 and a pharmaceutically acceptable carrier, Blood glucose, blood triglycerides and blood free fatty acids with diluent or solvate How to reduce.   28. 26. The method of claim 25, wherein the disease is type II diabetes, glucose. Impaired tolerance, lipemic disorder, hypertension, coronary heart disease, cardiovascular disease, athero Atherosclerosis, insulin resistance with obesity and psoriasis, diabetic complications, polycapsular Ovarian syndrome (PCOS), diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrosis Syndrome, hypertensive renal sclerosis, end-stage renal disease, microproteinuria, eating disorders, or dementia The way that is.   29. Type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart Disease and other cardiovascular diseases including atherosclerosis, obesity and psoriasis Pathophysiological mechanisms underlying insulin resistance, such as insulin resistance For treating and / or preventing diseases that are: diabetic complications and polycystic ovarian symptoms Group (PCOS), diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, high Certain renal diseases, including blood pressure renal sclerosis, end-stage renal disease and microproteinuria, (Aldose reductase inhibition to treat other diseases such as eating disorders 15. An agent according to any one of claims 1 to 14 for improving cognitive function of dementia. A use of the compound according to claim 23.   30. Type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart Disease and other cardiovascular diseases including atherosclerosis, obesity and psoriasis Pathophysiological mechanisms underlying insulin resistance, such as insulin resistance For treating and / or preventing diseases that are: diabetic complications and polycystic ovarian symptoms Group (PCOS), diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, high Certain renal diseases, including blood pressure renal sclerosis, end-stage renal disease and microproteinuria, (Aldose reductase inhibition to treat other diseases such as eating disorders For the manufacture of a medicament for improving the cognitive function of dementia. 24. Use of a compound according to any one of claims 1 to 14 or claim 23.   31. Type II diabetes, impaired glucose tolerance, dyslipidemia, hypertension, coronary heart Disease and other cardiovascular diseases including atherosclerosis, obesity and psoriasis Pathophysiological mechanisms underlying insulin resistance, such as insulin resistance For treating and / or preventing diseases that are: diabetic complications and polycystic ovarian symptoms Group (PCOS), diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, high Certain renal diseases, including blood pressure renal sclerosis, end-stage renal disease and microproteinuria, (Aldose reductase inhibition to treat other diseases such as eating disorders And a medicament for improving cognitive function of dementia; A medicament comprising the compound according to any one of claims 14 to 23 or a compound according to claim 23.