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Thiazolidine derivant with GK and PPAR double excitation activity

A technology of thiazolidinedione and derivatives, applied in the field of thiazolidinedione derivatives, can solve the problems of lack of drug safety and toxicity experimental basis, application prospect to be observed and the like

Inactive Publication Date: 2012-07-11
INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current research results in animals and clinical experiments suggest that PPARα / γ dual agonists or α / δ / γ triple agonists can indeed improve insulin resistance and dyslipidemia, but due to the lack of drug safety and toxicity experimental evidence, this type of The application prospects of the compound remain to be seen

Method used

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  • Thiazolidine derivant with GK and PPAR double excitation activity
  • Thiazolidine derivant with GK and PPAR double excitation activity
  • Thiazolidine derivant with GK and PPAR double excitation activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: (Z)-2-(4-((2,4-thiazolidinedione-5-ylidene)methyl)-2-nitrophenyl)-N-(5-methylisoxan Azol-3-yl)acetamide

[0067]

[0068] 4-Chloro-3-nitrobenzaldehyde

[0069] Put p-chlorobenzaldehyde (14g, 100mmol) into concentrated sulfur (150mL), add sodium nitrate (8.5g, 100mmol) to the above reaction solution in batches under an ice-water bath, control the reaction temperature not to exceed 40°C, and complete the addition , remove the ice-water bath, and react at room temperature for 24h. After the reaction was completed, the reaction solution was poured into 400 g of crushed ice to obtain a milky white solid product, which was filtered and dried to obtain 16.4 g of a white solid. 1 H NMR (CDCl 3 , 300MHz) δppm: 10.05 (s, 1H, CH), 8.37 (s, 1H, ArH), 8.04 (d, 1H, ArH), 7.76 (d, 1H, ArH); MS (FAB): 185 (M+ 1)

[0070] (Z)-5-(4-Chloro-3-nitrophenylmethylene)thiazolidine-2,4-dione

[0071] Put m-nitro-p-chlorobenzaldehyde (6.2g, 33mmol) and thiazolidinedione (3.9g,...

Embodiment 2

[0078] Example 2: (Z)-2-(4-((2,4-thiazolidinedione-5-ylidene)methyl)-2-nitrophenyl)-N-(thiazol-2-yl) Acetamide

[0079]

[0080] Operation is the same as the synthesis of Example 1. The difference is that the dosage of 2-aminothiazole is (100 mg, 1 mmol). Separation on a silica gel column and recrystallization from methanol gave off-white crystals (44 mg, 11.3%): 1 HNMR (DMSO-d 6 , 300MHz) δppm: 12.65(s, 1H, NH), 9.57(s, 1H, NH), 8.32(s, 1H, CH), 7.89(d, 1H, J=6.9Hz, ArH), 7.85(s, 1H, ArH), 7.81(d, 1H, ArH), 7.71(d, 1H, ArH), 7.65(d, 1H, ArH), 4.04(s, 2H, CH 2 ); HRMS (FAB): C 15 h 11 N 4 o 5 S 2 (M+1), measured value: 391.0170(M+1), calculated value: 391.0157(M+1)

Embodiment 3

[0081] Example 3: (Z)-2-(4-((2,4-thiazolidinedione-5-ylidene)methyl)-2-nitrophenyl)-N-(4-methylthiazole- 2-yl)acetamide

[0082]

[0083] Operation is the same as the synthesis of Example 1. The difference is that the dosage of 2-amino-4-methylthiazole is (114mg, 1mmol). Separation on a silica gel column and recrystallization from methanol gave a light yellow solid (73 mg, 18.1%): 1 H NMR (DMSO-d 6 , 300MHz) δppm: 12.77 (s, 1H, NH), 10.72 (s, 1H, NH), 8.30 (s, 1H, CH), 7.81 (s, 1H, ArH), 7.80 (d, 1H, ArH), 7.65(d, 1H, ArH), 6.22(s, 1H, ArH), 4.22(s, 2H, CH 2 ), 2.23 (s, 3H, CH 3 ); HRMS (FAB): C 16 h 13 N 4 o 5 S 2 (M+1), measured value: 405.0333(M+1), calculated value: 405.03273(M+1)

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Abstract

The invention discloses a novel thiazolidine derivant and a preparation method, a medicine combination and a purpose thereof, which specifically relate to the thiazolidine derivant shown as the formula I and the formula II, officinal salt of the derivant, a precursor or a derivant with the same biological function with the thiazolidine derivant, the preparation method of the thiazolidine derivant, the combination of one or a plurality of thiazolidine derivants and the purpose of the compound in treatment on diseases related with glucokinase and a peroxisome proliferators activated receptor, such as diabetes mellitus and obesity.

Description

field of invention [0001] The present invention relates to thiazolidinedione derivatives represented by general formulas I and II, their pharmaceutically acceptable salts, their precursors or derivatives with the same biological function, their preparation methods, and compositions containing one or more of these compounds , and the use of the compounds in treating diseases related to glucokinase and peroxisome proliferator-activated receptors, such as diabetes and obesity. Background of the invention [0002] Sugar is an important energy and carbon source for organisms. The decomposition of sugar produces energy, which can supply the needs of the organism's life activities, and the intermediate products of sugar metabolism can be converted into other carbon-containing compounds, such as amino acids, fatty acids, and nucleosides. Sugar metabolism can be divided into sugar decomposition and sugar synthesis. Sugar catabolism includes glycolysis, the common breakdown pathway ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D277/34A61K31/427A61K31/428A61K31/4439A61K31/4709A61K31/506A61P3/10A61P3/04A61P27/02A61P13/12A61P25/28A61P9/10
Inventor 冯志强申竹芳卢建勋雷蕾金小锋环奕刘泉高丽辉
Owner INST OF MATERIA MEDICA AN INST OF THE CHINESE ACAD OF MEDICAL SCI
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