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tak-875 analogue and its preparation method and application

A TAK-875, 1. The technology of TAK-875 is applied in the field of TAK-875 analogs and its preparation, which can solve the problems of further improvement of drug efficacy and pharmacokinetics

Active Publication Date: 2017-11-10
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its efficacy and pharmacokinetics still need to be further improved.

Method used

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  • tak-875 analogue and its preparation method and application
  • tak-875 analogue and its preparation method and application
  • tak-875 analogue and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] The synthesis of the key intermediate (S)-2-(6-hydroxy-2,3-chroman-3-yl)methyl acetate (8) and the synthesis reference of the reference drug 1 (TAK-875) have been published literature (WO 2012 / 111849 A1).

[0061] 2-((3S)-6-((2',6'-dimethyl-4'-(3-(methylsulfinyl)propoxy)biphenyl-3-yl)methoxy)- Synthesis of 2,3-chroman-3-yl)acetic acid (11):

[0062] (1) Synthesis of 3-(methylthio)propyl 4-benzenesulfonic acid methyl ester (2):

[0063] Weigh p-toluenesulfonyl chloride (11.2g) into a 250mL reaction flask, add 100mL of anhydrous dichloromethane, then add 12mL of triethylamine, add 3-methylthiopropanol (4.0mL) dropwise at room temperature, and react at 30°C overnight. Add a large amount of dichloromethane, wash with 2M hydrochloric acid until acidic, wash twice with saturated sodium chloride solution, dry over anhydrous magnesium sulfate, pass through a flash column with ethyl acetate / petroleum ether system, and evaporate to dryness to obtain 8.0 g of a colorless oily l...

Embodiment 2

[0077] 2-((S)-6-((2',6'-dimethyl-4'-(3-((S)-methylsulfinyl)propoxy)biphenyl-3-yl)methyl Oxy)-2,3-chroman-3-yl)acetic acid (12) and 2-((S)-6-((2',6'-dimethyl-4'-(3- Preparation of ((R)-methanesulfinyl)propoxy)biphenyl-3-yl)methoxy)-2,3-chroman-3-yl)acetic acid (13).

[0078] The chiral preparation of compound 11 was carried out at Daicel Pharmaceutical Chiral Technology Co., Ltd. Chiral preparation conditions: [column, CHIRALPAK ADH, 0.46cm I.D. × 25cm L; mobile phase, CO 2 / MeOH=60 / 40 (V / V); flow rate, 2.0 mL / min; detection, UV 208 nm; temperature, 35°C]. The retention times were 14.2 minutes and 17.6 minutes, respectively. (S,S)-isomer 12, 100.0% de. [Column, CHIRALPAK IA (4.6mm I.D.×250mm.5um); Mobile phase, n-hexane / ethanol / EtOAc / TFA=75 / 10 / 15 / 0.1 (V / V / V / V); Flow rate, 0.8mL / min; detection, UV 286nm; temperature, room temperature]; [α] 25 D +35.93°(c 0.8, acetonitrile).IR(KBr) 3423,2918,2579,1717,1618,1600,1496,1470,1316,1275,1182,1154,1005,826,797,712,632. 1 H NMR (...

Embodiment 3

[0080] 2-((S)-6-((2',6'-dimethyl-4'-(3-((S)-methylsulfinyl)propoxy)biphenyl-3-yl)methyl Oxy)-2,3-chroman-3-yl)acetic acid (16) or 2-((S)-6-((2',6'-dimethyl-4'-(3- Synthesis of ((R)-methylsulfinyl)propoxy)biphenyl-3-yl)methoxy)-2,3-chroman-3-yl)acetic acid (17):

[0081] (1) Synthesis of 3-(methylthio)propyl 4-benzenesulfonic acid methyl ester, with reference to the steps described in Example 1;

[0082] (2) Synthesis of 4'-hydroxy-2',6'-dimethylbiphenyl-3-carbaldehyde, refer to the steps described in Example 1;

[0083] (3) Synthesis of 2',6'-dimethyl-4'-(3-(methylthio)propoxy)biphenyl-3-carbaldehyde, refer to the steps described in Example 1;

[0084] (4) Synthesis of (2',6'-dimethyl-4'-(3-(methylthio)propoxy)biphenyl-3-yl)methanol, refer to the steps described in Example 1;

[0085] (5)(S)-2-(6-((2',6'-dimethyl-4'-(3-(methylthio)propoxy)biphenyl-3-yl)methoxy )-2,3-benzodihydrofuran-3-yl) methyl acetate synthesis, with reference to the steps described in Example 1;

[00...

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Abstract

The invention relates to a TAK-875 analog, and a preparation method and an application thereof, concretely relates to a compound with a structure represented by general formula (I), and various optical isomers, pharmaceutically acceptable salts, solvates and prodrugs thereof, and also relates to a medicinal composition containing the compound of the formula (I), and a pharmacy use thereof.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a TAK-875 analogue, a preparation method thereof, and a medical application in reducing blood sugar. Background technique [0002] According to the report of the International Diabetes Federation (IDF) in 2014, 387 million people in the world suffer from diabetes, and it is estimated that the number of diabetic patients will increase by 205 million in 2035, and 90% of diabetic patients around the world are type 2 diabetic patients. Type 2 diabetes (formerly known as non-insulin-dependent or adult-onset diabetes) results from the body's inability to use insulin effectively. GPR40 is a G protein-coupled receptor (GPCR), mainly expressed in pancreatic β cells and endocrine cells of the small intestine. GPR40 is a novel target for the treatment of type 2 diabetes. The drug TAK-875 (named compound 1 in the present invention) developed by Takeda Pharmaceutical Co., Ltd....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/79A61K31/343A61P3/10A61P25/00A61P35/00
CPCC07D307/79
Inventor 张颖杰闫玉刚徐文方
Owner SHANDONG UNIV