TW593293B - Substituted benzylthiazolidine-2,4-dione derivatives - Google Patents

Abstract

Substituted benzylthiazolidine-2, 4-dione derivatives of the formula (I), [wherein the bond form of A is -CH2CONH-, -NHCONH-, -CH2CH2CO- and -NHCOCH2-, B is a C1-4 lower alkyl group, a C1-3 lower alkoxy group, a halogen atom, trifluoromethyl group, trifluoromethoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group or an optionally substituted benzyloxy group], or the pharmaceutically acceptable salts and the hydrates thereof, and the process for the preparation thereof are disclosed. These compounds can bond with the receptor as the ligand of PPAR to activate and have the blood sugar reducing effect and lipid reducing effect.

Description

593293 V. Description of the Invention (Technical Field) # @ 明 系 As a peroxisome proliferator drug receptor (PPAR) agonist belonging to the nuclear receptor, especially human PPAR agonist for «I & disease Substituted benzylthiazolidine-2,4-dione derivatives and addition salts thereof which are effective for the prevention and / or treatment of metabolic diseases such as hyperlipidemia and the like, a preparation method thereof and a pharmaceutical composition thereof. BACKGROUND OF THE INVENTION Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that belong to the nuclear receptor superfamily, like steroid receptors, lecithin-like receptors, or adenosine-like receptors. So far, three isoforms (α-type, β-type (or 5) -type, and r-type) with different tissue distributions have been identified in humans and various animals (Proc. Natl. Acad. Sci., 1992, 89, 4653). Among them, PPARa is distributed in liver or kidney with high fatty acid dissimilation ability, especially found in liver (Endocrinology, 1995, 137, 354). Genes related to fatty acid metabolism and intracellular transport (such as fluorenyl CoA synthetase, The performance of fatty acid binding protein and lipoprotein lipase), and apoprotein (AI, AII, CIII) genes related to the metabolism of cholesterol and neutral lipids are controlled positively or negatively. PPAR β is commonly found in various tissues in vivo, centering on nerve cells. The physiological significance of PPARP is still unknown. ppAR 7 is highly found in adipocytes and is related to the differentiation of adipocytes (J. Lip 1C1. Res., 1 9 9 6, 3 7, 9 0 7). In this way, the various isoforms of PPAR have specific functions in specific organs or tissues. Also, the stunned mice with PPARa showed hyperneutrophilic dyslipidemia with increasing age, which was printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs and printed on 5929293 A7 B7. 5. Description of the invention () Obesity mainly due to the increase of white fat cells ( J. Biol. Chem., J 9 9 8, 2 7 3, 2 9 5 7)), strongly suggesting the correlation between the activation of PPARa and the decreasing effect of blood lipids (cholesterol and neutral lipids). In other respects, cellulose ester-based drugs and statin-based drugs have been widely used in the treatment of hyperlipidemia. However, cellulose ester drugs have a weak cholesterol-lowering effect, while statins have a weak effect on reducing free fatty acids or triglycerides. In addition, cellulose ester drugs have reported various side effects such as gastrointestinal disorders, rash, headache, liver dysfunction, renal dysfunction, and gallstones. Cellulose ester drugs have a wide range of pharmacological effects as their possible causes. It is also a series of drugs for the treatment of type II diabetes (non-insulin-dependent diabetes mellitus), and has one of a series of thiazolidine-2,4-dione derivatives such as doxoridazine, which have hypoglycemic effect and improvement of hyperinsulinemia. The main cell internal standard protein of Pioglitazone, Pioclidazon and Rogicladazone is PPAR r, and these pharmacology will increase the transcriptional activation of PPAR r (Endocrinology, 1 9 9 6, 137, 4189, Cell., 1995, 83, 803 , Cell., 1995, 83,813,). Therefore, PPAR r activators (agonists) that increase the transcriptional activation of PPAR τ are extremely important as hypoglycemic agents. In this way, considering the function of PPAR transcription factors on adipocytes and the role of regulating mechanisms of glucose metabolism and lipid metabolism, if it can create compounds that activate PPAR by directly binding PPAR, especially human PPAR ligands, it can be expected to have a reason Medical use of compounds with extremely specific mechanisms for lowering blood glucose and / or lowering blood lipids (both cholesterol and neutral lipids). As a ligand of PPARa, it has an affinity for PPARa. Except for the paper size, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) is applied. ----------------- —Order --------- line (please read the precautions on the back before filling out this page) 593293 5. Description of the invention () In addition to arachidonic acid metabolite LTB4, it is mediated by cytochrome p-4 The arachidic acid of HETE (hydroxyarachidonic acid) and HEPE (hydroxyarachidonic acid) group produced by oxidation of 50, especially 8-HETE, 8-HEPE, etc. (? ^ (:. "丨 1 · A cad S c 1., 119 7, 9 4, 3 1 2). However, these endogenous unsaturated fatty acid derivatives are unstable in metabolism and chemical stability and cannot be used for medicine. Occasionally in Dorocridad Reports of serious side effects on the liver have been requested, so it is required to develop an effective and safe type II diabetes treatment. As for the similar structure of the substituted benzylthiazolidine-2,4-dione derivative of the present invention, it is known that 5 5-2 2 6 3 No. 6, JP Sho 6 0-5 1 1 8 No. 9, JP Sho 6 1-8 5 3 7 No. 2, 'JP Sho 6 1-2 8 6 3 7 6 Kaihei 1-1 3 1 1 6 9 JP-Hira 2-8 3 3 8 4, JP-Hira 5-2 1 3 9 1 3, JP-Hira 8-3 3 3 3 5 5, JP-Hira 9-4 8 7 7 1, Japanese Patent Application Laid-Open No. 9-1 6 9 7 4 6, European Patent Publication No. 0 4 4 1 6 0 5, WO 9 2/0 7 8 3 9 and other thiazolidine-2, 4 -dione derivatives, but These compounds are thiazolidine-2,4-diketone derivatives with different structures from the compounds of the present invention. Patent reports on PPAR α agonism include WO- 97/2 5 04 2 and WO-9 7/3 6 5 7 and 9 etc., but these compounds have different structures from the compounds of the present invention, and the transcriptional activation of PPAR α is by no means satisfactory. Hyperlipidemia and diabetes are both risk factors for arteriosclerosis. For the prevention of diseases, especially coronary sclerosis, it is clinically eager to develop an effective and safe metabolic disease treatment drug. Disclosure of the invention The inventor has created an effective and safe structure for the treatment of metabolic diseases 5929293 A7 B7 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description () Novel drugs, focusing on the lipids of PPAR Thanks to specific roles such as adipocyte differentiation, and repeated thorough investigations, it was found that the following formula (1) substituted benzyl thiazolidine-2,4-dione derivatives have PPAR transcriptional activity, hypoglycemic effect, and lipid-lowering effect And finally complete the present invention. The present invention is to provide a substituted benzyl thiazolyl-2, 4-dione derivative with the following formula (1), a pharmaceutically acceptable salt thereof, and a hydrate thereof:

[In the formula, the combination style of A is _CH2CONH-, -NHCONH-, -CH2CH2CO-, and -NHCOCH2-, B is Ci-4 low radical, Ci.3 low radical oxygen, halogen, trifluoromethyl, trifluoro Methoxy, may be substituted phenyl, may be substituted phenoxy or may be substituted benzyloxy]. The salt of the compound of the formula (1) of the present invention is a user, metal salts, such as salts of alkali metals (such as sodium, gentry, etc.), salts of soil testing metals (such as brocade, magnesium, etc.), pharmacological properties and contents There is a foreign matter in the time structure (1 structure of the different science. Mingguang salt hair Xu Xun this part of the content of the base pyridazolium in its cyclic ketone two in 2 and 2 packages-also mixed with the existing physical structure There are daggers that can be used under the variety of different types. ⅡT} ΛΤ-Β 1 箪 {The format of this paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------ --------- l · --- Order --------- Line * · (Please read the notes on the back before filling this page) 593293 V. Description of the invention ()

NHCONH-, -CH2CH2CO- and 0-3 low alkoxy, halogen, trifluoromethyl [combination sample of A in the formula is ~ CH2c; Qnh -NHCOCH2-, B is Cu low alkyl group, trifluoromethoxy It may be any phenyl group, may have a substituted phenoxy group or may have a substituted benzyloxy group] Within these ranges in the formula (1) above. Fanwei of the invention_ 彳 Wu and its mixtures are also included in the formula (1) of the present invention. "0.4 lower alkyl" is methyl 'ethyl, propyl, isopropyl, butyl and other straight or branched C ^ 4 alkyl. "C ^ 3 lower alkoxy group" is a straight or branched C! .3 group oxy group such as methoxy group, ethoxy group, propoxy group, and isopropoxy group. "Halogen" may be F, Cl, Br, I, "Substituent may be substituted phenyl, may be substituted phenoxy, may be substituted benzyloxy", the substituent may be low alkyl, C! · 3 Low alkoxy and halogen. The combination pattern of A in the formula (1) of the present invention is -NHC0CH2- Compound (la) can be produced according to the following method (Scheme 1) 593293 5. Description of the invention ()

Et > -〇 笫 三 工程

笫 24 project

N Η —► Β Five projects

26 Projects

Scheme 1 is the compound (la) of A in the formula (1). The compound (la) can be obtained from 4-methoxybenzaldehyde (2) and chloro-2- (methylthio) ethyl acetate (Chem. Pharm). Bull., 1 9 8 2, 3 0, 9 1 5) 2 -Methylthio-2-(5 · Methylmethyl-2 -methoxyphenyl) obtained under the reaction of Lewis acid (the first project) ) Ethyl acetate (3) is reacted with thiazolidine-2,4-dione in the presence of a catalyst (second process), and the resulting 2-methylthio-2-[5-[(2, 4-dioxo Thiazidine-5-subunit) methyl] -2 methoxyphenyl] ethyl thio group was removed from the ethyl acetate (4) (third process), and the resulting 2- [5-[(2,4-dioxothiazole) was obtained. Pyridin-5-ylidene) methyl] -2-methoxyphenyl] ethyl acetate (5) ethyl ester partially hydrolyzed (fourth process), resulting in 2-[5-[(2,4 -dioxo Thiazolidine-5-ylidene) methyl] -2-methoxyphenyl] acetic acid (6) is reacted with a compound of the following formula (8) (fifth project)

[Wherein B is Cm low alkyl, Cm low alkoxy, halogen, trifluoromethyl, three 5929293 5. Description of the invention () Fluoromethoxy, may have substituted phenyl, may have substituted benzene instead Benzyloxy], and the compound of the following formula (7) is obtained |

[Wherein B is a Cm lower alkyl group, a Ci.3 lower alkoxy group, a halogen group, a fluoromethoxy group, a substituted phenyl group, and a substituted phenyl group benzyloxy group]. The reaction of the first process can be performed in dichloromethane, chloroform and nitrate. Lewis acid can use aluminum chloride, tin chloride and trifluorination degree -2 0 ~ 150 ° C. It is suitable to perform the second engineering reaction at the reflux temperature of the solvent. It can be used in benzene, toluene, xylene and solvents. Or without solvent. As the catalyst, acetate such as piperidine or pyridine or ammonium acetate can be used. The reaction temperature is 0 ~ 150 ° C, and the flow temperature is performed. The reaction of the third process can be carried out by alloy reaction, zinc-copper alloy reaction in solvents such as acetic acid or hydrochloric acid. The reaction temperature is-from 01 to room temperature. The reaction of the fourth project can be performed under acidic conditions. Acid, sulfuric acid, acetic acid, phosphoric acid and mixtures thereof, and mixtures of these acid solvents. The reaction temperature is from 0.1 to 150 ° C, and the temperature is applied. Oxygen may be reduced by taking the I bond (7) Trifluoromethyl, trioxy or benzene may be used in a solvent such as boron, etc. The reaction temperature is 0. Ethanol, acetic acid and other secondary amines should be in Solvent return and metal zinc, zinc 1 0 ~ 1 01, suitable conditions can be hydrochloric acid and ring mill and other organic solvents in the reflux of solvents printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumer cooperative 53293 A7 _ B7 V. Description of the invention () Fifth Engineering can be carried out by using a carboxyl group or by converting it into a reactive derivative. When using a reactive derivative, it can be used in solvents such as dichloromethane, chloroform, dioxane, N, N-dimethylformamide and the like. The alkali metal hydride such as Na a and other alkali metal hydroxides such as Na Η and alkali carbonate such as potassium carbonate or pyridine and acetoethylamine are used in the presence of organic tests. When the acid is reacted, it is usually carried out in the presence of a condensing agent in a solvent such as dichloromethane, chloroform, dioxane, Ν, Ν-dimethylformamide, and the like with or without a base and or an additive. The condensing agent may be Dicyclohexylcarbodiimide, 1-[3-(dimethylamino) propyl] -3 -ethyl carbon Imine hydrochloride, diethyl cyanophosphate, diphenylphosphine azide, carbonyl diimidazole, etc. The base may be an alkali metal hydroxide such as NaOH, an alkali metal carbonate such as potassium carbonate, or pyridine, triethylamine, etc. Organic base. Additives can be N-methylbenzotrifluorene, N-hydroxydibutyldiimine, 3,4-dihydrohydroxy-4-oxo-1,2,3-benzotrifluorene, and the like. The reaction temperature is -20 ~ 100. (:, Preferably about 0 ~ 50 ° C. The reaction of the sixth process can be in metal catalysts such as palladium-activated carbon, platinum-activated carbon, platinum oxide, rhodium-alumina, etc. In the presence of ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and other solvents, the hydrogen pressure is 1 to 5 kgf / cm2. The reaction temperature is 0 to 100 ° C, preferably at Executed at room temperature to 80 ° C. The binding pattern of A in formula (1) is -NHC0CH2- compound (la) can also be manufactured as follows (Process 2) -1 0-This paper standard applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 public) ------------ install ----- ^ ---- order --------- line (please read the precautions on the back first) Refill this page} 593293 A7 B7 V. Description of the invention (

EtO

〇 The seventh project

EtO

> -〇 The eighth project

> ^ 0 ——► N Ninth Project

> = 0 scheme is that the binding pattern of A in formula (1) is -NHC0CH2- compound (la), which can be selected from [5-[(2,4-dioxothiazol-5-ylidene) methyl] -2- Methoxyphenyl] ethyl acetate (5) reduction (seventh process) [5-[(2,4-dioxothiazol-5-yl) methyl] -2-methoxyphenyl] ethyl acetate (9) 2-[5-[(2,4-dioxothiazol-5-ylidene) methyl] -2 -methoxyphenyl] acetic acid (10) obtained by hydrolysis (eighth project) with the following formula ( 8) Compound reaction (the ninth process) to create chaos

B ⑻ ----------- install ----- ^ ---- order --------- line (please read the precautions on the back before filling this page) Ministry of Economy Printed by the Intellectual Property Bureau employee consumer cooperative [where 6 is (:!. 4 low alkyl, CL3 low alkoxy, halogen, trifluoromethyl, trifluoromethoxy, substituted phenyl, and may be substituted Phenoxy or optionally substituted benzyloxy]. The reaction of the seventh project can be in the presence of metal catalysts such as palladium-activated carbon, platinum-activated carbon, platinum oxide, rhodium-alumina, etc. in ethanol, methanol Tetrahydrofuran 1-This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 593293 A7 B7 5. Description of the invention (), ethyl acetate, N, N-dimethylformamide and other solvents The hydrogen pressure is 1 ~ 5 kgf / c m2. The reaction temperature is 0 ~ 100 ° C, and it should be performed at room temperature ~ 80 ° C. (Please read the precautions on the back before filling this page) Hydrolysis reaction of the eighth project It can be carried out under acidic conditions. For acidic conditions, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, and mixed liquids thereof, and mixed liquids of these acids with organic solvents such as cyclobutane, etc., the reaction temperature is 0 to 5 0 C, it should be carried out at the reflux temperature of the solvent. The ninth project can be carried out by using a carboxyl group or by converting it into a reactive derivative. When using a reactive derivative, in dichloromethane, chloroform, dioxane, N, N -Solvents such as dimethylformamide with or without alkalis, such as alkali metal hydrides such as Na hydrazone, alkali metal hydroxides such as Na O Η, alkali metal carbonates such as potassium carbonate or organic bases such as pyridine, triethylamine If it is reacted with a carboxylic acid, it is usually with or without alkali and or additives in the presence of a condensing agent in a solvent such as dichloromethane, chloroform, dioxane, Ν, Ν-dimethylformamide and the like. The condensing agent printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs can be dicyclohexylcarbodiimide, 1-[3-(dimethylamino) propyl] -3 -ethylcarbodiimide Hydrochloride, diethyl cyanophosphate, diphenylphosphine azide, carbonyl diimidazole, etc. The base may be an alkali metal hydroxide such as NaOH, an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine, triethylamine, etc. The additives can be N-hydroxybenzotriazole, N-hydroxydibutanediimine, 3,4-dihydro-3 Benzyl-4-oxo-1, 2, 3-benzotrifluorene, etc. The reaction temperature is -20 to 100 ° C, preferably about 0 to 50 ° C. The binding pattern of A in formula (1) is -NHCONH- (lb) or -CH2C0NH- (1c) -1 2-The size of this paper applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) 593293 A7 B7 5. The compound of the invention () can be manufactured as follows ( Process 3)

MqO

> -0

> = 〇 UeO (13) The thirteenth project The tenth project B The twelfth project B-jf

Nui · One project household 0 Scheme 3 That is, the compound of A in formula (1) is-NHCONH-(1 b) or -CH2CONH-(1 c) The compound can be 5-[(4 -methoxyphenyl) form -Yl] thiazolidine-2,4-dione (11) Nitrotion (Tenth Project) 5-[(4-methoxy-3 -nitrophenyl) methyl] thiazolidine-2, 4-dione 5-[(3-amino-4 -methoxyphenyl) methyl] thiazolidine-2,4-dione (] 3) obtained by reduction of ketone (1 2) (the eleventh project) with the following formula (26 ) Compound

NCO (26) ----------- · installation ---- l · --- IT --------- line φ (Please read the precautions on the back before filling this page ) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs [where B is Cm low alkyl, (^ -3 low alkoxy, halogen, trifluoromethyl 'trifluoromethoxy, optionally substituted phenyl, Substituted phenoxy or substituted benzyloxy] or compounds of the following formula (2 7) -13- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297) 593293 A7 B7 5 , Description of the invention ()

(27) [wherein 3 is Cm lower alkyl, Ch3 lower alkoxy, halogen, trifluoromethyl, fluorenylmethoxy, may have substituted phenyl, may have substituted phenoxy or may have substituted The benzyloxy] reaction (the twelfth process to the thirteenth process) to manufacture. The reaction of the tenth project can be carried out by reacting with concentrated nitric acid or fuming nitric acid, a mixture of concentrated nitric acid and concentrated sulfuric acid (mixed acid) in a solvent such as dichloromethane or chloroform or without a solvent. The reaction temperature is -20 ~ 12CTC, and it should be carried out at 0 ~ 100 ° C. The reaction of the eleventh project can be carried out in the presence of a catalyst such as palladium-activated carbon, platinum-activated carbon, platinum oxide, etc., in ethanol, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and other solvents. It is applied at a pressure of 1 ~ 5 kgf / c m2. The reaction temperature is from 0 to 100 ° C, and it is preferably performed at room temperature to 80 ° C. The reaction of the twelfth project can be carried out in solvents such as ethyl acetate, tetrahydrofuran, N, N-dimethylformamide. The reaction temperature is -2 0 to 1 5.0 ° C, preferably 0 to 100 ° C. The thirteenth project can be carried out by using a carboxyl group or converting it into a reactive derivative. The "reactive derivative of a carboxyl group" may be fluorenyl chloride, fluorenyl bromide, anhydride, carbonylimidazole, or the like. When using a reactive derivative, with or without alkali in solvents such as dioxane, N, N-dimethylformamide and the like, alkali metal hydrides such as NaH, alkali metal hydroxides such as NaOH, and alkali metals such as potassium carbonate Carbonate, pyridine, triethylamine and other organic 14- This paper size applies to China National Standard (CNS) A4 specification (2) 0 X 297 mm) ----------- pack ----- ^ ---- Order --------- line (Please read the notes on the back before filling out this page) Printed by the Employees 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed 5329293 A7 B7 V. Description of the invention () Implementation in the presence of alkali. When reacting with a carboxylic acid, it is usually carried out in the presence of a condensing agent in a solvent such as dichloromethane, chloroform, dioxane, N, N-dimethylformamide and the like with or without an alkali and or an additive. The condensing agent may be dicyclohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3 -ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphine Nitrogen, carbonyldiimidazole, etc. The base may be an alkali metal hydroxide such as NaOH, an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine. The additive may be N-hydroxybenzotriazole, N-hydroxydibutanediimine, 3,4-dihydro-3-hydroxy-4 -oxo-1,2,3-benzotrifluorene, and the like. The reaction temperature is -2 0 to 100 ° C, preferably about 5 to 5 (TC.) The compound of A in formula (1) is -NHCONH- (lb) or -CH2CONH- (lc). The method can be as follows Manufacturing (Process 4)

(1c) (1b) Process 4 This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) Packing ----- ^-Order --------- line (please first Read the notes on the back and fill in this page) 593293 A7 _B7_ V. Description of the invention () That is, the combination pattern of A in formula (1) is -NHCONH- (lb) or -CH2C0NH- which can be compounded by anti-C ) Keto 4th 5 \ / -2ylpyrimidazole nitrothiazepine 3 fluorenyl 14 oxomethyl benzyl (4 nitro- [-5 3 • derivatized oxygen 'A) 4-way Η tetramidazolidine Ketoamine

Protosylnitropyrimidazolium thiophene 50th 7th (2nd derivation with 6) Chinese formula

B is

C Fluorinated tris, oxymethyl or fluorotrioxo, halogenation of benzoin, oxycoxane, alkoxy) ft 1-3 benzene 26 C C, substituted radicals Like low-coated m,

B

N

6) 2 / VC is B Chinese-based alkane lower alkoxymethylene trifluoride, alkynyl or fluorotrioxo, halogen of benzoin, take oxyalkane, lower 1-3 benzene C1 ϋ ϋ ϋ n-ϋ ϋ n · ϋ I · n H ϋ nn-0 'II ϋ I— nn I n I (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The oxo compound of benzyl compound 7) Take (1 with the following formula: \ ^ / 程 Η

OR ΗΝ

This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 593293 A7 B7 1 V Description of invention () [where 3 is C, -4 low alkyl, C! -3 low alkoxy, Halogen, trifluoromethyl, fluorenylmethoxy, may be substituted phenyl, may be substituted phenoxy or may be substituted benzyloxy] or the double bond of the compound of the following formula (18) is reduced ( The tenth A project) to make Η Η 08) [wherein B is C, .4 lower alkyl, Cw3 lower alkoxy, halogen, trifluoromethyl, trifluoromethoxy, and optionally substituted phenyl, May be substituted phenoxy or may be substituted benzyloxy] The reaction of the fourteenth project can be carried out in solvents such as benzene, toluene, xylene, acetic acid or without solvents. The catalyst can be a secondary amine such as piperidine or pyrrolidine or an acetate such as ammonium acetate. The reaction temperature is 0 ~ 150 ° C, and it should be carried out at the reflux temperature of the solvent. The reaction of the fifteenth project can be carried out by reduction with tin or tin chloride (I I), tin alloy, etc. in a mixed solvent of alcohol such as ethanol or methanol and hydrochloric acid. Response temperature (Please read the notes on the back before filling this page)

> -〇 Β- The bio-productivity of the employees' cooperatives printed by the Intellectual Property Bureau of the Ministry of Economic Affairs should be reversed. Change into OC or ο 5 ~ base temperature carboxyl chambers should be used immediately, the ° c process ο ο Η 11 ~ 6 ο ten is the first. Dissolved oxygen and other ammonia test amines are organic ^: amines and other amines such as ethane, ethane, Na, Tri, IN ', N, S, Pyridoxine, or hydrazone salt diauric acid on alkali carbon, etc. It belongs to the time of gold. The test of NR, such as alkalescence, potassium, acid-free, or carbon, should be used. 7 Paper size applies to China National Standard (CNS) A4 (210 X 297 mm). Intellectual property of the Ministry of Economic Affairs. Printed by the Bureau's Consumer Cooperatives 5929293 A7 B7 V. Description of Invention () Implemented in the absence of existence. When reacting with a carboxylic acid, it is usually carried out in the presence of a condensing agent in a solvent such as dichloromethane, chloroform, dioxane, N, N-dimethylformamide and the like with or without an alkali and or an additive. The condensing agent may be dicyclohexylcarbodiimide, 1-[3- (dimethylamino) propyl] -3 -ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphine Nitrogen, carbonyldiimidazole, etc. The base may be an alkali metal hydroxide such as NaOH, an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine. The additives may be N-hydroxybenzotriazole, N-hydroxydibutanediimine, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3, benzotrifluorene, and the like. The reaction temperature is -20 ~ 100 ° C, preferably about 0 ~ 50 ° C. The reaction of the seventeenth project can be carried out in solvents such as ethyl acetate, tetrahydrofuran, N, N-dimethylformamide. The reaction temperature is -2 0 to 1 5, and is preferably performed at 0 to 100 ° C. The reaction of the eighteenth project can be in the presence of metal catalysts such as palladium-activated carbon, platinum-activated carbon, platinum oxide, rhodium-alumina, etc., in ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-dimethyl Hydrogen pressure in solvents such as methylformamide is 98.1 ~ 49 1kPa. The reaction temperature is 0 ~ 100 ° C, and it should be performed at room temperature ~ 80 ° C. The compound of A in formula (1) is -CH2CH2CO-(1 d). The compound can also be produced according to the following method (Scheme 5) -18- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----------------- „---- Order -------- -Line (Please read the notes on the back before filling this page) 593293 A7 B7

0 Me 0 0 Me 0 • II Η —,% Y Yr r V Nineteenth Engineering § MlV Twentyth Engineering Me ^ MeO (19) 0 0 Qiao (20) 0 0

(21) Twenty-first project

> =-0 (Please read the notes on the back before filling out this page) Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5 That is, the combination of A in formula (1) is -CH2CH2CO- (ld) compound, It is well-known that [Publication No. Hei 1-3 1 6 3 6 3] of 5-methylamino-2 -methoxybenzoic acid (19) reacts with N, 0-dimethylhydroxylamine (nineteenth process) to obtain N -Methoxy-N -methyl-5-methylamidino-2-methoxybenzylamine (20), the methyl group is protected with ethylene glycol (twentyth project), resulting in N -methoxy-N -Methyl- 5- (1,3-difluorenyl-2-yl) -2-methoxybenzylamine (21) is reacted with methyl magnesium iodide (twenty-first project) to obtain 3 '-(1,3-Difluorenyl-2-yl) -2, methoxyacetophenone (22) is reacted with diethyl carbonate in the presence of a base (twenty-second project), and 3 is obtained -[5-(1, 3 -Dipentanyl-2-yl) -2-methoxyphenyl] -3-oxopropanoic acid ethyl ester (23) in the presence of a base with a compound of formula (28) Decarbonation after the reaction (Twenty-third project) -19- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 5 93293 A7 B7 V. Description of the invention (

8 (2 Chinese style fluoro three to take

Physicochemical \ ~ / 4 2, with methyl or methyl trioxo, halogenation of benzoin, take the oxygen with oxoalkane (2 ------------— (Please read first Note on the back, please fill in this page again.) C is B Chinese-based alkane, low-oxymethane, trifluoro, and keto. 1-3 Benzyl C1 Substituted for Oxybenzyl--Two Ϊ Ϊ 第 程 Η Forty Cheng Η Wuying (the original Π bond-the double substance pyridazolium thiazide 5) and (2 and the formula below is as follows The stored medium will touch M in), 2 4 order --------- line ·

Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs as B Chinese-based oxymethyl trifluoro, hexamethyl or trifluoro, halogenated benzoin, oxy-based alkane, low 1-3 benzene C1 The alkoxy group has a low biodegradability, which should be reversed to conversion or carboxyl use. The basis of oxobenzyl is the tenth generation. 2 This paper size applies Chinese national standards (CNS ) A4 size (210 x 297 mm) 593293 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _ — _B7____ V. Description of the invention () OK. When using reactive derivatives, use dioxane, N, N-di Solvents such as methylformamide are used in the absence of an alkali such as an alkali metal hydride such as NaH, an alkali metal hydroxide such as NaOH, an alkali metal carbonate such as potassium carbonate, or an organic base such as pyridine or triethylamine. When reacting with a carboxylic acid, it is usually carried out in the presence of a condensing agent in a solvent such as dichloromethane, chloroform, dioxane, Ν, Ν-dimethylformamide, and the like with or without an alkali and or an additive. The condensing agent may be dicyclohexylcarbodiimide, 1- [3-( Dimethylamino) propyl 3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphine azide, carbonyldiimidazole, etc. The base may be an alkali metal hydroxide such as NaOH, Alkali metal carbonates such as potassium carbonate or organic bases such as pyridine and triethylamine. Additives may be N-hydroxybenzotriazole, N-hydroxydibutanediimine, 3,4-dihydro-3-hydroxy-4 -Oxygen-1, 2, 3-benzotrifluorene, etc. The reaction temperature is -20 ~ 100 ° C, preferably about ◦ ~ 50 ° C. The reaction of the twentieth project can be in solvents such as benzene, toluene, xylene, etc. It is carried out in the presence of an acid catalyst. Sulfuric acid, p-toluenesulfonic acid, phosphonium sulfonic acid, phosphonium chloride, oxalic acid, etc. can be used as the acid catalyst. The reaction temperature is 0 ~ 150 ° C, and it should be performed at the reflux temperature of the solvent. The reaction of the twenty-first project can be carried out in solvents such as diethyl ether, tetrahydrofuran, and dioxane. The reaction temperature is -100 ° C ~ room temperature, and it should be carried out at -8 ° ~ 0 ° C. Engineering reaction can be in ether, tetrahydrofuran, dioxane and other solvents. There are alkalis such as alkali metal hydrides such as NaH, organometallic compounds such as butyl lithium-2 1-Applicable to this paper National Standard (CNS) A4 Specification (210 X 297 mm) ----------------- ^ ---- Order --------- line (please first (Please read the notes on the back and fill in this page) 593293 A7 _ B7 V. Description of the invention, metal amines such as lithium diisopropylamine, metal methoxides such as sodium methoxide and potassium third butoxide. The reaction temperature is -2 0 ~ 150 ° C, preferably at 0 ~ 50 ° C. The reaction of the Twenty-Three Project is an alkylation reaction. Alkali metals such as Na a fluorene can be used in solvents such as ether, tetrahydrofuran and dioxane. Organometallic compounds such as hydride, butyl lithium, metal amines such as lithium diisopropylamine, and metal alkoxides such as sodium methoxide and potassium tert-butoxide. The reaction temperature is -20 to 150 ° C, and it is preferably carried out at the reflux temperature of the solvent. Secondly, the decarbonation reaction can be carried out under acidic conditions. As the acid, p-acid, acetic acid, sulfuric acid, phosphoric acid and the like can be used alone or in a mixed solution. The reaction temperature is from room temperature to 150 ° C, and it should be performed at the reflux temperature of the solvent. The reaction of the twenty-fourth project can be carried out in solvents such as benzene, toluene, xylene, ethanol, acetic acid or without solvents. The catalyst can be a secondary amine such as piperidine or pyrrolidine or an acetate such as ammonium acetate. The reaction temperature is from 0 to 150 ° C, and it should be carried out at the reflux temperature of the solvent. The reaction of the 25th project can be in the presence of metal catalysts such as palladium-activated carbon, platinum-activated carbon, platinum oxide, rhodium-alumina, etc., in ethanol, methanol, tetrahydrofuran, ethyl acetate, N, N-two Hydrogen pressure in solvents such as methylformamide is 9 8. 丨 ~ 4 9 1 k P a. The reaction temperature is 0 ~ 1 00t, and it should be installed at room temperature ~ 8 0t. ---------- Order --------- (Please read the precautions on the back before (Fill in this page) Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, β-granular capsules, non-capsule glue, ingots, injection-type injections or physical and chemical blending, and other new sugar sugar Ming or hair preparations are absorbed into the hair. This is limited to unknown hair copies, but Ming Fa Ben stated that there are specific examples of Shi Jiashi. The following examples show that the application of China National Standard (CNS) A4 (210 X 297) (Centimeter) 593293 A7

V. Description of the invention () Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, 2-methylthio-2- (5-methylfluorenyl-2-methoxyphenyl) acetate 4-methoxy; fe (8.17 g, 60.0 mmol) was dissolved in Erqi Jiayuan (250 ml). Anhydrous tin (IV) chloride (7.02 ml, 60.0_〇1) was added dropwise under ice-cooled stirring in an argon atmosphere. After stirring at room temperature for 10 minutes, ethyl 2-chloro-2- (methylthio) acetate (10.2 g, 60.5 mmol), dichloromethane (50 inl), and carbon tetrachloride (50 m 1) were added dropwise. ) 'S solution. After heating under reflux for 16 hours, it was poured into ice water, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with water, a saturated sodium bicarbonate aqueous solution and a saturated saline solution in this order, dried over anhydrous sodium sulfate, and concentrated. Chromatography on a silica gel column (n-hexane / ethyl acetate = 6/1, v / v) gave the target compound, 7.5 g (47%), as a yellow oil. Mass analysis (EΓ) (m / z): 26 8 (M +) Example 2 2 -Methylthio-2-[5-[(2, 4 -Dioxothiazol-5 -Subunit) methyl]- 2-methoxyphenyl] ethyl acetate mixed 2-methylthio-2- (5-methylmethyl-2-methoxyphenyl) ethyl acetate (7.50g, 28.0_〇1), thiazolidine-2 , 4-diketone (3.95 g, 33.6 mmol), pyridine (2.80 ml, 28.3 mmol) and ethanol (100 ml), and heated under reflux for 14 hours. After leaving to cool, add concentrated hydrochloric acid to acidify under ice-cold stirring, and pour in ice-water and stir for 30 minutes. The crystals were collected, washed with ethanol and water, and dried to obtain 6.18 g (60%) of the target substance as yellow crystals. Mass analysis (EI +) (m / z): 367 (M +) Example 3 2- [5-[(2,4-dioxothiazol-5-ylidene) methyl] -2-methoxyphenyl] Acetic acid-23-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ----------------- ^-Order · ----- --- line (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 593293 A7 ----- B7 V. Description of the Invention () Ethyl Mixture 2-Methylthio-2- [5-[(2, 4 -Dioxothiazol-5-ylidene) methyloxo-2-methoxyphenyl] ethyl acetate (6.18 g, 16.8 — 0)) and acetic acid (100 mi), Add zinc powder (46.0 g, 70.6 mmo 1) with stirring, and stir at room temperature for 24 hours. Zinc was taken, washed with acetic acid, the mash was concentrated, dissolved in ethyl acetate, washed sequentially with water 'saturated brine, dried over anhydrous sodium sulfate, concentrated, and recrystallized from methanol to obtain the target 2 . 7 1 g (50%), yellow powder. Mass analysis (EI +) (m / z): 321 (M +) Example 4 -Dioxothiazol-5-ylidene) methyl] -2 -methoxyphenyl] acetic acid mixed 2-[5-[( 2, 4-dioxothiazolidine-5 -ylidene) methyl] -2-methoxyphenyl] ethyl acetate (1.29g, 4.01_ol), concentrated hydrochloric acid (20ml) and acetic acid (20m 1), Heat and stir for 2.5 hours. After leaving to cool, ice water was added, the crystals were collected by filtration, washed with water, and dried to obtain 1.13 g (9 6%) of the target substance as a yellow powder. Mass analysis (EI +) (m / z): 293 (M +) Example 5 N- [4- (trifluoromethyl) phenylphenyl 2- [5-[(2,4-dioxothiazol-5- Subunit) Methyl] -2-methoxyphenyl] acetamide mixed 2- [5-[(2,4-dioxothiazol-5-ylidene) methyl] -2 -methoxyphenyl] Acetic acid (440mg, 1.50_〇1), 4- (trifluoromethyl) aniline "242L, 1.50mmol), triethylamine (210L, 1.51_01) and dehydrated Ν, Ν -dimethylformamide (5πι1) Add cyano diethyl phosphate (2 8L,]. 50mmo 1) under ice-cooled stirring in an argon atmosphere, stir at room temperature for 1 hour, and leave it for 3 days. Note-24-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ----------------- ^ ---- Order ---- ----- line (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5929293 A7 _ B7 V. Description of the invention () Put it in ice water, take crystals, and use ethyl acetate The ester was washed, dried, and concentrated to give the target compound 472 mg (72%) as yellow crystals. Mass analysis (EI +) (m / z): 4 3 6 (M +) Example 6 N- [4- (trifluoromethyl) phenyl] -2- [5-[(2,4 · dioxothiazole Pyridin-5-yl) methyl] -2 -methoxyphenyl] acetamidamine mixed N-[4-(trifluoromethyl) phenyl 2-[5 _ [(2, 4 _ dioxothiazine · 5. · Subunit) methyl] -2-methoxyphenyl] acetamide (300 mg, 0.687 mm), 10% Pd-C (300 mg), and a mixture of tetrahydrofuran / ethanol (2 / 1 v / v, 40 ml), hydrogenated at an initial pressure of 39.2 kPa at room temperature. After the reaction was completed, the catalyst was filtered off and concentrated, and then subjected to silica gel column chromatography (n-hexane / ethyl acetate :: 2 / 丨 v / v) to obtain the target substance 172 mg (57%) as a colorless powder. Melting point: 194.5 — 196.5 ° C; Mass analysis (EΓ) (πι / ζ): 438 (M +); Elemental analysis: (50C2〇H17F3N204S: Calculated: (%) C, 54.79; H5 3.91; N, 6.39 Measured erbium (%) C, 54 · 62; erbium, 3.81; N, 6.24. Example 7 5 _ [(4-methoxyphenyl) methylene] thiazolidine-2,4-dione Mix 4-methoxybenzaldehyde (20.42,150_〇1) 'thiazolidine-2,4-dione (21.1g, 180mmol), piperidine (12.8g, 150mmol) and ethanol (150ml), and heat to reflux 1 8 hours. After cooling, the crystals were taken out, washed with ethanol, and dried to obtain the target substance, 1.2 g (32%), as yellow crystals. To the filtrate was added concentrated hydrochloric acid-25-Duo Paper Rule National Standard (CNSM4 specification (2) 0 X 297 mm). —Γ — ^ --------- ^ (Please read the precautions on the back before filling out this page) Printed by the Consumer Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 593293 A7 _B7_ V. Description of the invention () Acidification, extraction of crystals, washing with ethanol and water, drying, and then obtaining the target 18.1 g (51%, total 83%), yellow crystals. Mass Analysis (EI +) (m / Z): 2 3 5 (M +) Example 8 5-[([methoxyphenyl) methyl] thiazolidine-2,4 -Diketone 5-[(4-methoxyphenyl) methylene] thiazolidine-2,4-dione (6.00§, 25.5_〇1), 10%? (1-(:( 6.0〇2 ) And a mixture of tetrahydrofuran / ethanol (2/1 v / v, 300 m 1), hydrogenated at an initial pressure of 294 kPa at room temperature. After the reaction was completed, the catalyst was filtered and concentrated to remove the catalyst. Column chromatography (n-hexane / ethyl acetate = 2/1 v / v), to obtain the target product 5.84 g (97%), colorless powder. Mass analysis (EI +) (m / z): 2 3 7 (M +) Example 9 5-[(4-methoxy-3 -nitrophenyl) methyl] thiazolidine-2,4-dione was added slowly to concentrated nitric acid (1000 m 1) [(4-methoxyphenyl) methyl] thiazole Didine-2, 4-dione (3.556 g, 15.0 mm ο 1). After stirring for 3 hours, pour into ice water, and scoop out the crystals After washing with water and drying, 3.04 g (7.2%) of the target substance was obtained as yellow crystals. Mass analysis (EΓ) (m / z): 2 8 2 (M +) Example 1 0 5-[(3- Amino-4-methoxyphenyl) methyl] thiazolidine-2,4-dione mixed 5-[(4-methoxy-3 -nitrophenyl) methyl] thiazolidine-2, 4-di Ketone (3.00g, 10.6mmol), 10% Pd-C (2.00g) and ethyl acetate / ethanol mixed solution (1/1 v / V, 2000 m 1), hydrogenation at an initial pressure of 294 kPa at room temperature. Anti-26-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ---------------- ^ ---- Order ----- --- 1 (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 5929293 A7 B7 V. Description of the invention () After the catalyst is finished, the catalyst is filtered off and concentrated. Chromatography (n-hexane / ethyl acetate: z 1/1 v / V) gave 2.55 g (95%) of the target compound as pale brown crystals. Mass analysis (EI +) (m / z): 252 (M +) Example 1 1 5-[[4 -methoxy-3- [3- [4- (trifluoromethyl) phenyl] ureido] benzene [Methyl] methyl] thiazolidine-2,4-dione mixed 5-[[3-amino-4-methoxyphenyl) methyl ^] thiazolidine-2, 4-dione (3 7 8 g, 1.50mniol) and dehydrated tetrahydrofuran (5ml), 4-trifluoromethyl isocyanate (0.236ml, 1.65mmol) was added under stirring at room temperature in argon atmosphere, and after stirring at room temperature for 6 hours, it was left overnight and concentrated. Dichloromethane was recrystallized to obtain 375nig (57%) of the object as a colorless powder. Melting point: 202.0 — 204.0 ° C; Mass analysis (EΓ) (ει / Z): 439 (M +); Elemental analysis: (%) C19H16F3N304S: Calculate: (¾) C, 51.93; H, 3.67; N, 9.56. Measured erbium (%) C3 51.80; H5 3.60; N3 9.58. Example 1 2 5-[(4-methoxy-3-nitrophenyl) methylene) thiazolidine-2,4-dione mixed 4- Methoxy-3-nitro acetone (4.00g, 22.2mmol), thiazine-2,4-dione (3.10g, 26.5mmol), ammonium acetate (3.40g, 44.1guan), acetic acid (8 m 1) and benzene (120 m 1), while removing the water in the reaction, heat and reflux for 8 hours. After cooling, let the crystals be filtered, washed with benzene and 20% acetone water, and dried to obtain the purpose. 5.50g (88%), yellow powder. -27-This paper size is in accordance with Chinese National Standard (CNS) A4 (2 忉 x 297 mm) (Please read the notes on the back before filling this page)

----- Γ --- Order · ------- • Line V Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 593293 A7 _______ B7 V. Description of the invention () Quality analysis (EI +) (m / z ): 280 (M +) Example I 3 5-[(3-Amino-4-methoxyphenyl) methylene] thiazolidine-2,4-dione mixed 5-[(4-methoxy- 3-Nitrophenyl) methylene] thiazolidine-2,4-dione (841 mg, 3.00 mmol), ethanol (20 ml), and concentrated hydrochloric acid (10 ml), and slowly added with gasification under stirring at room temperature. Tin (II) 2 hydrate (2.26 g, 9.0.1 mm ο 1), stirred at room temperature for 8 hours, poured into ice water, neutralized with saturated sodium bicarbonate water, extracted with ethyl acetate, and washed with water After that, it was dried over anhydrous sodium sulfate and concentrated to obtain 641 mg (85%) of the target substance as yellow-orange crystals. Mass analysis (EI +) (m / z): 250 (M +) Example 1 4 N- [2-methoxy- 5-[(2,4-dioxalidin-5-diene) A Phenyl] phenyl] -2- [4- (trifluoromethyl) phenyl] acetamidine mixed with 5-[(3-amino-4 -methoxyphenyl)] methylene] thiazolidine-2, 4-Dione (561mg, 2.24mmol), 4- (trioxomethyl) phenylacetic acid (460mg, 2.25inmol) and N, N-dimethylformamide (6ml), add under ice-cooled stirring in argon atmosphere Triethylamine (250mg, 2.46mmol) and monoethyl cyanoacetate (0.37ml, 2.44mmol), stirred under ice-cooling for 20 minutes, and after stirring at room temperature for 6 hours, poured into ice water, decanted crystals and washed with water, 87.3 mg (89%) of the target substance was obtained as a yellow powder. Mass analysis (EI +) (m / z): 436 (M +) Example 1 5 N- [2-methoxy- 5-[(2,4-dioxothiazin-5-yl) methyl] phenyl ] -2- -28-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --------- Order --------- Line (Please read first Note on the back, please fill in this page again) 593293 Printed by A7 B7, Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention () [4- (trifluoromethyl) phenyl] acetamide mixed N-[2 -A Oxy-5-[(2,4-dioxothiazol-5-ylidene) methyl] phenyl] -2- [4- (trifluoromethyl) phenyl] acetamidamine (61 mg, 1.40 mmol ), 10% Pd-C (600mg) and a mixture of tetrahydrofuran / ethanol (1/1 v / v, 150ml) 5 Hydrogenated at room temperature with an initial pressure of 3 4 3 k Pa. After the reaction was completed, the catalyst was filtered off and concentrated, and recrystallized from diethyl ether to obtain 598 mg (9.8%) of the target substance as colorless fine powder. Melting point: 147.0— 149.0 ° C; Mass analysis (EΓ) (ηι / ζ): 438 (M +); Elemental analysis: (%) C2〇H17F3N204S: Calculate: (¾) C, 54.79; H? 3.91; N, 6.39. Found 値 (¾) C3 54.71;;, 3.88; N, 6.33. Example 16 N-methoxy-N-methyl-5-methylfluorenyl-2-methoxybenzylamine is well-known for mixing [ Publication No. Hei 1-316313] of 5-methylamido-2-methoxybenzoic acid (6.7〇2, 37'201011101), triethylamine (13.01111, 93.3guan 01) And dichloromethane (200ml), ethyl chlorocarbonate (3.90ml, 40.8mmol) was added under ice-cold stirring, and after stirring for 20 minutes, N, 0-dimethylhydroxylamine hydrochloride (4.35g, 44. (6guan 〇1), and after stirring at room temperature for 6 hours, it was left overnight, washed sequentially with 1 m ο 1/1 hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated. Chromatography on a silica gel column (n-hexane / acetic acid acetate = 2/3, v / v) gave 6.56 g (79%) of the target compound as colorless crystals. Mass analysis (EI +) (m / z): 223 (M +) Example 1 7 -29-This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 public love) --------- --Installation ----------- Order --------- Line · (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 593293 A7 B7 V. Description of the invention () N-methoxy-N-methyl- 5- (1,3-difluorenyl-2-yl) -2 -methoxybenzylamine mixed with N · methoxy- N-methyl-5-methylfluorenyl-2-methoxybenzylamine (6.56g, 29.4mniol), triethylamine (8.20ml, 147mmol), p-toluenesulfonic acid monohydrate (HOrng, 0.578 〇〇1) and toluene (100ml), the generated water was removed with a dehydration device and refluxed for 4 hours, then allowed to cool, ethyl acetate was added, and the mixture was sequentially washed with a saturated sodium bicarbonate aqueous solution and water, and dried over anhydrous sodium sulfate. , Concentrated. Column chromatography on silica gel (n-hexane / ethyl acetate di 1/2, V /, to obtain the target compound 6.60g (84%), colorless oil. Mass analysis (EΓ) (m / z): 2 6 7 (M +) Example 1 8 5 '-(1,3-Difluorenyl-2-yl) · 2'-methoxyacetophenone mixed N-methoxy-N-methyl- 5- ( 1,3 -Diamylpentan-2-yl) -2 -methoxybenzylamine (6.60g, 24.7mmol) and dehydrated tetrahydrofuran (200ml), slowly dripped 3.0M while cooling with stirring in a dry ice-acetone bath in an argon atmosphere. / 1 A solution of methyl magnesium iodide in ether (24.7ml, 74.1 mmol) was stirred under ice-cooling for 1.5 hours, and a saturated ammonium chloride aqueous solution (200ml) was dropped under ice-cooling stirring. The organic layer was separated, and the aqueous layer was separated by Extract with ethyl acetate. Combine the organic layers, wash sequentially with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate. Column chromatography on silica gel (n-hexane / ethyl acetate = 4/1, v / v) to obtain the target product 4.3 I g (79%), colorless crystals. Mass analysis (EI +) (m / z): 267 (M +) Example 1 9 -30-This paper size applies Chinese national standards ( CNS) A4 size (210 X 297 mm) ----------- install ----- j ---- order --------- line (please read the first Please fill in this page again) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy 593293 A7 B7 V. Description of the invention () 3- [5- (1,3-Dioxolane-2-yl) -2 -methoxy Phenyl] -3-oxopropanoic acid ethyl acetate. In dehydrated ether (1 5 m 1) Under cold stirring, sodium hydride (940 mg, 23.5 mmol) was added, followed by diethyl carbonate (1.66 g, 14.1 mmol). After stirring at room temperature for 30 minutes, 5 5-(1, 3-2) was slowly dripped. A mixture of pentamyl-2-yl) -2'-methoxyacetophenone (2.08g, 9.36mnnol), dehydrated tetrahydrofuran (200ml), and ethanol (0.05m1). After dripping was completed, reflux was performed for 7 hours. After standing to cool, a solution of 20 ml of 2 mol / 1 hydrochloric acid and 30 ml of ethyl acetate was slowly dropped under ice-cooling and stirring. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography on a silica gel column (n-hexane / ethyl acetate = 3/1, v / v) gave 1.44 g (52%) of the target compound as a pale yellow oil. Mass analysis (EI +) (m / z): 267 (M +) Example 2 0 3- [4- (trifluoromethyl) phenyl] -1- (5-methylamidino-2-fluorenylphenyl) Propan-1-one was added sodium hydride (190 mg, 4.75 mm ο 1) to dehydrated tetrahydrofuran (7 m 1), and 3-[5-(1, A solution of 3-dioxolan-2-yl-biphenyl-2-methoxyphenyl] -3-oxopropanoic acid ethyl acetate (1.40 g, 4.76 mmol) in dehydrated tetrahydrofuran (100 m 1). Stir at room temperature After 30 minutes, a solution of 4- (trifluoromethyl) benzyl bromide (.30 g, 4.44 mmo 1) in dehydrated tetrafuran (3 m 1) was dropped. After the dripping was completed, refluxed for 18 hours. After cooling, condense and add concentrated hydrochloric acid 3 m 1 and acetic acid 1 〇πι 1 and reflux for 5 hours. After cooling, inject iced paper. Standards apply to Chinese National Standard (CNS) A4 (210 X 297 mm)- ---------- „— Order · -------- line (please read the precautions on the back before filling this page) Printed by the Employee Consumption Cooperative of Intellectual Property Bureau of the Ministry of Economy 593293 A7 B7__ 5 2. Description of the invention () Water, extracted with ethyl acetate, followed by saturated sodium bicarbonate water, water, saturated food The solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography on a silica gel column (n-hexane / ethyl acetate = 6/1, v / v) gave 9 1 1 mg (61%) of the target substance, colorless crystals. Mass analysis (ΕΓ) (ιώ / ζ): 336 (M +) Example 2 1 5-[[3- [3- [4- (trifluoromethyl) phenyl] propanyl] -4 -methoxy Phenyl] methylene] thiazolidine-2,4-dione mixed 3- [4- (trifluoromethyl) phenyl] -1- (5-methylamidino-2-methoxyphenyl) propan- 1-ketone (900mg, 2.68_〇l), 1,3 -Houkou sitting steep-2,4-dione (377mg, 3.2 · _01), azepine (265L, 2.68mmol) and ethanol (10 ml), refluxed for 13 hours. After standing to cool, acidify with concentrated hydrochloric acid under ice-cold stirring. The crystals were collected by filtration, washed with ethanol and water, and dried to obtain 906 mg (78%) of the target substance, yellow crystals. Mass analysis (EI +) (m / z): 435 (M +) Example 2 2 5-[[3- [3- [4- (trifluoromethyl) phenyl] propanyl] -4 -methoxy Phenyl] methyl] thiazolidine-2,4-dione mixed 5-[[3- [3- [4- (trifluoromethyl) phenyl] propanyl] -4 -methoxyphenyl] (Methyl) thiazolidine-2,4-: _ (500nig, 1.15mmol), 10% Pd-C (500 mg) and tetrahydrofuran (50 m 1), in the initial gas 3 9 2 k P a hydrogenated for 8 hours. After the reaction was completed, the catalyst was filtered off and concentrated, and then subjected to silica gel column chromatography (n-hexane / ethyl acetate = 2/1 v / v) to obtain the target substance 4 4 4 g (8.8%) as a colorless powder. -32- This paper uses the Chinese National Standard (CNS) A4 specification (210 X 297 mm1) ----------- install ----- ^ ---- order --- ------ Line 41 ^ (Please read the precautions on the back before filling this page,) 593293 A7 B7_ V. Description of the invention () Melting point 103.0— 104.5 ° C; Quality analysis (EI +) (m / z): 437 (Μ +) 5 · Elemental analysis of thorium (%) C21H18F3N04S: Calculated thorium (%) C, 57.66; H, 4.15; N, 3.20. Measured thorium (° / Q) C, 57.84; thorium, 4.10; Ν, 3.25. Example 2 3 Ν- [4- (phenoxy) phenyl] -2- [5-[(2,4-dioxothiazin-5-yl) methyl] -2-methoxy Phenyl] acetamidate was simulated in Example 6 to obtain the target substance as a colorless powder. Melting point 8 2.0 — 8 4.0 ° C; Mass analysis (EΓ) (πι / ζ): 462 (M +); Elemental analysis (U) C25H22N205S · 1H20: Calculate 値 (%) C5 62.49; Η, 5.03; Ν, 5.83. Measured 値 U) C, 62.21; H5 4.94; N, 6.07. Compound of 1. [Table 1] ----- „— Order --------- Line (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

-33-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 593293 A7B7 V. Description of the invention () Example AB Melting point (° c) Expressive elemental analysis (%) 24 NHCONH 4 a Me 171.5-172.5 Ci9H19N304S B ten calculations; C59.21, H4.97, N10.90 measured 値; C 59.41, Η 4.95, N1 0.84 25 NHCONH 4-C! 236.0-238.0 c18h16cin3o4s calculation 値; C53_2 7 , H3.97, N10.35 Measured 値; C53.66, H3.83, m〇.11 26 NHCONH 4-OC2H5 1 95.0 -1 97.0 C2 〇H2 1 N3O5S Calculated 値; 〇57.82, Post.09 State 0.11 Measured値; G57.57, H5.04, N10.05 (Please read the precautions on the back before filling this page) Example 2 7 N- [2 -Methoxy-5 · [(2,4-dioxothiazole Pyridin-5-yl) methyl] phenyl] -2- (4-chlorophenyl) acetamidamine mixed 5-[(3-amino-4-methoxyphenyl) methyl] 1§ Di-2,4-dione (250 mg, 0.99 1 _ ο 1) and dehydrated dichloromethane (10 m 1), add 1-[3-(dimethylamino) propyl] -3 -Ethylcarbodiimide hydrochloride (228mg, 1 · 19 mm ο 1), stirred for 20 minutes under ice cooling, poured into water, extracted with dichloromethane, and sequentially with 5% hydrochloric acid After washing with a saturated aqueous solution of sodium bicarbonate and saturated brine, and concentrating, recrystallizing from a mixed solution of methanol and isopropyl ether to obtain the target compound 327 mg (82%) as a colorless powder. Melting point 182.0 — 183.0 ° C; Quality analysis (EI +) (m / z): 404 (M +); Analysis of printed elements of consumer cooperatives in the Intellectual Property Bureau of the Ministry of Economic Affairs 値 (¾) C19H17C1N204S: Calculation 値 (%) C5 56.36; Η, 4.23; Ν5 6.92. Measured 値 (%) C, 56.27; Η, 4.16; Ν3 6.88. Example 2 8 ~ 3 6 -34-This paper size is applicable to China National Standard (CNS) A4 specification (2) 0 X 297 mm) 593293 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (Similar to Example 27, compounds of Table 2 are obtained [Table 2]

Example AB Melting point (° c) Elementary analysis of the formula (%) 28 CH2CONH 4-M e 183.0- 185.0 ^ 20 ^ 20 ^ 2 ^ 4 ^ Calculate 値; C62.48.H5.24.N7.29 measured値; C62.32.H5.1 6.N7.21 29 ch2conh 4_0 M e 124.0-125.0 ^ 20 ^ 20 ^ 2 ^ 5 ^ • 1 / 4Η20 Calculate 値; C59.32, H5.10, N6.92 measured値; C59.43, H4.90, N6.89 30 C bu 2CONh · 4-P l ·) (4-0 Μ e) 205.0- 207.0 C26ri24N'205S 1/4 Η 20 calculation 値; C64.S2, bu丨 5.13.N5.S2 Measured 値; C65.15, H5.06, N5.76 31 CH2C〇NH 4-Ph (4-Me) 1 89.ΟΙ 91,0 • 1 / 4Η2〇Calculated 値; C67.15 , H5.31, N6.〇2 Measured 値; C67.36, H5.27, N6.08 32 ch2conh 4-Ph (4-CI) 1 93.〇Ι 95.0 c25h21cin2〇4s 1 / 4Η20 Calculated 値: C61.85 , H4.46.N5.77 Found 値; C61.91.H4.41.N5.72 33 ch2conh 4-〇Ph (4-CI) Amorphous c25h21cin2o5s Calculated 値: C60.42, H4.26.N5. 64 Measured C; C60.12.H4.28.N5.47 34 ch2conh 4-0CH2Ph (4-0Me) 140.0- 141.0 C27H26N206S Calculated 値; C64.02, H5.1 7.N5.53 Measured 値: C64.03 .H5.25, N5.38 35 ch2conh 4-OCH2Ph (4-Me) 1 58.ΟΙ 60.0 c27h26n205s Calculated radon; C66.10.H5.34.N5.71 Measured radon; C66.42.H5.29.N5 .63 36 ch2con h 4-〇Ph (4-Me) 1 86.〇Ι 88.0 〇26 Latch 24 Bu 2S 5S calculation; C65.53, H5.08, N5.88 Found: C65.14.H5.19, N5 .75 Biological activity test example 1: Transcriptional activation test on peroxisome proliferator-activated receptors -35-This paper is in accordance with China National Standard (CNS) A4 (2) 0 × 297 mm)- ---------------- „---- Order --------- line (please read the precautions on the back before filling this page) 593293 Α7 Β7 Description of the invention () CHO cells cultured in 10% Ham, s F-12 medium containing bovine fetal blood sacrifice with free fatty acids removed, combining the DNA binding domain of yeast transcription factors with human PPAR α and r ligands Receptor plastids and their communication plastids (STRATAGENE) in the field (Bi.ochem ist! .Y, 1 9 9 3, 32, 5 5 9 8) and internal standard / 9-galactosidase (Promega) After co-transfection with fatty amines in a blood-free state, the test compound and the control compound (Doparicidazol and Pioclidine Dazol and PPAR α were used as the control drug of PPAR r (8S) _HETE ) Dissolved in DMS. 01% Ham of bovine fetal blood sacrifice with free fatty acids removed, s F-12 culture was tuned to a final concentration of 0.01% DMS0 for culture. After 24 hours, CAT activity and galactosidase activity were measured. The results are shown in Table 3. It can be seen that the compound of the present invention has a strong transcriptional activation effect on peroxisome proliferator-activated receptors α and T. [Table 3] Examples of transcription activation PPARa PPARr EC50 (μπιο / Ι) EC50 (μητϊο / Ι) 6 0-60 3. 30 11 0. 55 0. 43 15 0.86 1. 10 22 0. 80 0. 40 Doroclitazone 1.15 p.Oclidazion — 0. 72 (8S) -HETE 1. 30 a -36- This paper: (degrees apply to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---- --------- 餐 i — (Please read the notes on the back before filling out this page)

Order --------- Line J Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed 5329293 A7 ___ B7 V. Description of the Invention () Industrial utilization possibilities are as described above The substituted benzylthiazolidine-2,4-dione derivative of the present invention is a novel compound having excellent PPAR transcription activation activity. These compounds of the present invention are effective as a combination of the aforementioned hypoglycemic agents and therapeutic agents for hyperlipidemia because of their agonistic activity against human PPAR. This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) ^ --------- ^ ----------------- (please first (Read the notes on the back and fill out this page)

Claims (1)

593293 sa 5. 1 3 VI. Application for Patent No. 89 1 1 6990 "Substituted benzylthiazolidine-2,4-dione derivative" Patent Case 6. Application scope: 1. One of the following formula (1) Substituted benzylthiazolidine-2,4-dione derivatives and pharmaceutically acceptable salts thereof, [Wherein A's bonding style is -CH2CONH-, -NHCONH-, -CH2CH2C0-, and -NHCOCH2-, and B is (V4 lower alkyl, CV3 lower alkoxy, halogen, trifluoromethyl, trifluoromethoxy , Can have 1 substituent of phenyl (substituent is alkyl, C, .3 alkoxy or halogen), can have 1 substituent of phenoxy (substituent is (^ _4 alkoxy or halogen ), Which may have a benzyloxy group (the substituent is a CW4 alkyl group or a G.3 alkoxy group)]. 2 · Such as the substituted benzylthiazolidine-2,4 _ two A ketone derivative and a pharmaceutically acceptable salt thereof, in which the binding pattern of A is -CH2CONH-〇3. Such as the substituted benzylthiazolidine-2,4-dione derivative and a pharmaceutically acceptable salt thereof in the first patent application scope, wherein The binding pattern of A is -NHC0NH_. 4 · As the substituted benzylthiazolidine-2,4-dione derivative and its pharmaceutically acceptable salt in item 1 of the scope of patent application, the binding pattern of A is -NHCOCH2- 593293 6. Scope of patent application 5. If the substituted benzylthiazolidine_2, cardiodionone derivative and its pharmaceutically acceptable salt of item 1 of the scope of patent application, the binding pattern of A is 6. The substituted benzylthiazolidine · 2,4-dione derivative and its pharmaceutically acceptable salt of the first item of the patent scope are: ^ [2_methoxy_5_ [(2,4-dioxothiazol-5 -Methyl) methyl] phenyl] _2_ [4_ (trifluoromethyl) phenyl] acetamidine. 7 • Substituted benzylthiazolidine_2,4_dione derivative as described in item 1 of the patent application Substance and its capacity capacity g noonium salt, which is 5 _ [[4 -methoxy-3- [3- [4- (difluoro / methyl) benzyl] benzyl] benzyl] methyl] thizone Ixidine -2, 4-dione. 8. For example, the substituted benzylthiazolidine_2, renedione derivative and its saccharine-accepting salt in the scope of patent application No. 1 are N_ [4_ (trifluoromethyl) Phenyl group 2_ [5-[(2,4-monooxythiazolidine-yl) methyl group 2-methoxyphenyl] acetamide. 9 • Substituted benzyl thiazole as described in item 1 of the scope of patent application Pyridine 2,4-diketone derivative and its pharmaceutically acceptable salt, which is 5 _ [[3_ [洪 [4_ (trifluoromethyl) phenyl] propanyl-4-methoxyphenyl] methyl] thiazole Pyridine · 2, 1-dione. 1 ··· A pharmaceutical composition of a peroxisome proliferator-activated receptor (PPAR) agonist, which contains a substituted benzylthiazine of formula (1) ^ 2 , 4-monoketone derivatives and their pharmaceutically acceptable salts as active ingredients 593293 VI. Application for patent scope [wherein the combination pattern of A is -CH2C0nh_, -nhc〇nh_, _CH2CH2C〇_, and _NHCOCH2-, B is q low alkyl, ¢: 3 low alkoxy, halogen, Trifluoromethyl, trifluoromethoxy, phenyl with 1 substituent (substituent is c ^ k group, C! .3 alkoxy or halogen), Benzyl group with 1 substituent (Substituent is Cn alkyloxy or halogen), there may be a benzyloxy group (substituent is Ci 4 alkyl or c] 3 alkoxy)]. 1 1 · The pharmaceutical composition of a peroxisome proliferator-activated receptor (PPAR) agonist such as item 10 of the scope of application for a patent, which is a hypoglycemic agent containing a substituted benzine of the following formula (1) Thiathiazolyl-2,4-dione derivatives and their pharmaceutically acceptable salts are the active ingredients: [Wherein the combination of A is —CH2CONH-, —NHCONH-, —CH2CH2C0— and —NHCOCH2-, 6 is (^ .4 lower alkyl, Cl. 3 lower alkoxy, halogen, trifluoromethyl, Trifluoromethoxy, phenyl with 1 substituent (C! _4 alkyl, Ci.3 alkoxy, or halogen), phenoxy with 1 substituent (Ch4 Alkoxy or halogen), benzyloxy with 1 substituent (substituent is (^ .4 alkyl or (^ .3 alkoxy)]. 1 2 · As in the 10th scope of the patent application A pharmaceutical composition of a peroxisome proliferator-activated receptor (PPAR) agonist, which is a hypolipidemic agent and contains a substituted benzylthiazolidine-2,4-dione derivative of the following formula (1) 593293 Sixth, the scope of the patent application Biological and pharmacologically acceptable salts are effective ingredients: [In the formula, the combination style of A is -CH2CONH-, -NHCONH-, -CH2CH2C ¢ ^, and -NHCOCH2-, B is C1_4 lower alkyl, C1.3 lower alkoxy, _ prime, trifluoromethyl, trifluoro Methoxy, phenyl with 1 substituent (substituent is alkyl, G.3 alkoxy or halogen), phenoxy with 1 substituent (substituent is (^ .4 院 oxy) Or halogen), which may have a benzyloxy group (the substituent is Cl4 alkyl or 1-3 alkoxy)].