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Target mitochondrion antioxidant as well as preparation method and application of target mitochondrion antioxidant

A technology of nitrogen oxides and compounds, applied in the field of biochemistry, can solve problems that cannot delay the progress of diseases and cannot be cured

Active Publication Date: 2017-06-20
XW LAB INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disease is currently incurable
Currently, doctors can only give patients antidepressants or compounds that reduce the loss of motor coordination, neither of which can slow the progression of the disease

Method used

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  • Target mitochondrion antioxidant as well as preparation method and application of target mitochondrion antioxidant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1 prepares compound I

[0064] one, Synthesis of intermediate 13:

[0065] First, intermediate 13 was synthesized according to the following synthetic route:

[0066]

[0067] Step 1: Synthesis of Compound 5

[0068] Compound 4 (10 g, 37.6 mmol) was dissolved in methanol (150 mL), cooled to 0°C, and thionyl chloride (22 g, 0.19 mmol) was added dropwise thereto.

[0069] Under stirring, the reaction solution was gradually raised to room temperature, and the stirring was continued for 12 h. The reaction solution was concentrated under reduced pressure to obtain compound 5 (11.7 g), with a yield of 98%.

[0070] Step 2: Synthesis of Compound 2

[0071] Compound 1 (6.45 g, 30 mmol) and D-Valine methyl ester hydrochloride (5.53 g, 33 mmol) were dissolved in dichloromethane (200 mL), cooled to 0°C. To the above solution were added 1-hydroxybenzotriazole (4.46 g, 33 mmol), carbodiimide (6.3 g, 33 mmol) and DIEA (8.51 g, 66 mmol).

[0072] The reaction sol...

Embodiment 2

[0149] Embodiment 2 physical and chemical properties are measured

[0150] 1. Investigation of pH stability

[0151] Prepare pH 1.2 and 8.0 buffer solutions as follows:

[0152] pH = 1.2 hydrochloric acid solution: take 765ul of concentrated hydrochloric acid in a volumetric flask, dilute to 100ml, and obtain.

[0153] pH=8.0 Phosphate buffer solution: 0.2mol / L potassium dihydrogen phosphate solution (solution A): take 2.722g of potassium dihydrogen phosphate, add water to dissolve, and dilute to 100ml; 0.2mol / L sodium hydroxide solution (solution B) : Take 800mg of sodium hydroxide, add water to dissolve, and dilute to 100ml; take 25ml of solution A, 23.05ml of solution B, add water to dilute to 100ml, and obtain.

[0154] The incubation was designed and implemented as follows:

[0155] Compound I stock solution preparation: 1 g of Compound I prepared in Example 1 was dissolved in a volumetric flask, and acetonitrile was added to 10 ml to obtain a standard solution with a ...

Embodiment 3

[0162] Example 3 Compound I has inhibitory effect on Erastin-induced HT 1080 cell ferroptosis (Ferroptosis)

[0163] After the diluted cells were added to the 96-well plate for adherent growth, 10 μM Rastin was added to induce the state of ferroptosis (Ferroptosis) in HT1080 cells, and then compound I was added at different concentrations. After 6 wells of each concentration were incubated for 24 h, the cells were incubated with CTG ( CellTiter-Glo) method was used to detect cell viability, and the half maximum effective concentration of compound I was obtained as EC50=275.2nM.

[0164] The experimental results show that compound I can inhibit the ferroptosis induced by Erastin in HT1080 cells, indicating that our compound I can target mitochondria and can eliminate free radicals generated in cells (see image 3 ).

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Abstract

The invention discloses a compound. The compound is a compound shown as a formula I or a stereoisomer, a geometric isomer, a tautomer, nitrogen oxide, hydrate, a solvate, a metabolite and a pharmaceutically acceptable salt of the compound shown as the formula I, wherein Cbz represents benzyloxycarbonyl; Bn represents benzyl; Boc represents tert-butoxycarbonyl. The compound has stable physiochemical properties; compared with XJB-5-131, the compound has the advantages of improved water solubility, stable physiochemical properties, good bioactivity, small medicinal dosage, improved in-vivo stability, high bioavailability, small side effect and prominent target anti-oxidization property; the compound can be used for effectively repairing oxidization injuries of mitochondria, and preventing or treating neurodegenerative diseases including age-related macular degeneration and the like. The formula I is shown in the description.

Description

[0001] priority information [0002] This application claims the priority and benefit of the patent application No. 201510922167.8 filed with the State Intellectual Property Office of China on December 11, 2015, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to the technical field of biochemistry, specifically, the present invention relates to the field of compound preparation, more specifically, the present invention relates to a novel compound (Formula I) and its preparation method and application. Background technique [0004] Mitochondrial oxidative damage and neurodegenerative diseases including dry age-related macular disease (Dry-AMD), glaucoma (Glaucoma), traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and many other neurodegenerative diseases. Among them, Huntington's disease is a genetic disease in whic...

Claims

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Application Information

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IPC IPC(8): C07K5/02C07K1/00A61K38/07A61P25/00A61P27/02A61P25/28A61P25/16A61P21/00A61P25/14A61P27/06
CPCC07K5/0207A61K38/00
Inventor 向家宁徐雪松万军波戚祖德
Owner XW LAB INC
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