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Benzo-hexatomic ring derivative used as DPP-4 inhibitor and application of benzo-hexatomic ring derivative

A solvate, heterocycle technology, applied in the field of medicinal chemistry, can solve the problem of insufficient insulin secretion

Active Publication Date: 2016-05-11
EAST CHINA UNIV OF SCI & TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Dipeptidyl peptidase-4 (Dipeptidylpeptidase-4, DPP-4) has been shown to be an effective target for the treatment of type 2 diabetes, it can rapidly degrade intestinal insulin glucagon-like peptide-1 (glucagon-likepeptide1, GLP-1) and Glucose-dependent insulinotropicpolypeptide (GIP) and other important incretins, leading to insufficient insulin secretion

Method used

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  • Benzo-hexatomic ring derivative used as DPP-4 inhibitor and application of benzo-hexatomic ring derivative
  • Benzo-hexatomic ring derivative used as DPP-4 inhibitor and application of benzo-hexatomic ring derivative
  • Benzo-hexatomic ring derivative used as DPP-4 inhibitor and application of benzo-hexatomic ring derivative

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Experimental program
Comparison scheme
Effect test

Embodiment

[0129] 1. trans-(2RS,3RS)-3-amino-2-(2,4,5-trifluorophenyl)chroman-5-ol (compound-1)

[0130]

[0131] Synthesis of Intermediate 1-1:

[0132] 2,4,5-Trifluorobenzaldehyde (10g, 62.46mmol), nitromethane (4mL), methanol (10mL) were prepared into a solution; methanol (60mL), water (30mL), sodium hydroxide (2.5N , 30mL) into a solution, keeping the temperature at 5°C; adding the former solution dropwise to the latter solution for about 30-60 minutes, and keeping the solution temperature at 5-10°C; Add the above solution dropwise into a mixed solution of zinc chloride (42.6g, 31.25mmol), concentrated hydrochloric acid (13mL), and water (17mL), keep the temperature at 0-10°C during the dropwise addition, and react at room temperature for 2-4h after the dropwise addition; After that, vacuum filtration was performed, and the filter cake was washed several times with 40% methanol solution to obtain 9.8 g of the product with a yield of 77%. GC-MS: 203.

[0133] 1 H-NMR (400MHz, C...

Embodiment 31

[0521] Example 31. DPP4 Inhibitory Activity of Compounds of the Invention

[0522] The inventors have detected the inhibitory activity of the compounds of the present invention to DPP4 at the enzyme level through the following experiments:

[0523] Enzyme level activity evaluation:

[0524] Name: DPP4 (dipeptidyl peptidase 4); alias: CD26; ADABP; ADCP2; DPPIV;

[0525] Screening method:

[0526] Method name: DPP4 activity assay, fluorescence.

[0527] Instrument: microplate reader, Envision (PerkinElmer, USA).

[0528] Material: Human DPP4, which was expressed in insect cells using baculovirus expression system in this experiment. The substrate is Gly-Pro-AMC.

[0529] process:

[0530] DPP4 can specifically hydrolyze the substrate Gly-Pro-AMC to generate the product AMC. AMC is excited by 355nm ultraviolet light to generate 460nm emission light. The linear change of fluorescence value at 460nm wavelength per unit time is dynamically measured, and the DPP4 activity is ca...

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Abstract

The invention relates to a benzo-hexatomic ring derivative used as a DPP-4 inhibitor and application of the benzo-hexatomic ring derivative, in particular to compounds shown as in formula I, medicine compositions with the compounds shown as in the formula I and application of the compounds in preparing medicines for treating diseases related to DPP-4 or inhibiting the DPP-4.

Description

technical field [0001] The invention relates to the field of medicinal chemistry; specifically, the invention relates to a novel benzo six-membered ring derivative, its synthesis method and its application in the preparation of medicines for treating type 2 diabetes and related diseases. Background technique [0002] Diabetes Mellitus (DM) is a metabolic disease characterized by elevated levels of glucose (blood sugar) in the blood. It is a slowly progressive disease caused by the joint action of genetic factors and environmental factors. With the improvement of people's living standards, the number of diabetic patients is increasing rapidly. According to the statistics of the International Diabetes Federation, there were about 371 million diabetic patients in the world in 2012, and the number of diabetics in China reached 90 million, becoming the country with the largest number of patients in the world (Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Diabetes Care. 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/92C07D405/04C07D417/04C07D491/052C07D493/04C07D221/10C07D335/08C07D311/04A61K31/353A61K31/4025A61K31/427A61K31/5377A61K31/382A61K31/4741A61P29/00A61P3/10A61P1/00A61P1/04A61P3/04A61P3/00A61P7/10
CPCC07D221/10C07D311/04C07D311/92C07D335/08C07D405/04C07D417/04C07D491/052C07D493/04A61K31/352A61K31/5377C07D335/04C07D311/60A61P1/00A61P1/04A61P29/00A61P3/00A61P3/04A61P43/00A61P5/48A61P7/10A61P3/10
Inventor 李洪林蒋华良徐玉芳李佳赵振江李静雅徐洪玲李诗良
Owner EAST CHINA UNIV OF SCI & TECH
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