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Hydroxamic acid-containing substituted heterocyclic compound as well as preparation method and application thereof

A technology of hydroxamic acid and compound, applied in the field of medicinal chemistry, can solve the problems of poor selectivity, inability to apply, poor stability of phosphatase, etc.

Active Publication Date: 2019-02-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reported direct inhibitors of acid sphingomyelinase are only substrate analogs, diphosphates, 3,5-diphosphate inositols and a few natural products.
The reported inhibitors have defects such as poor selectivity, poor drug-likeness, poor phosphatase stability, and poor membrane penetration ability, and cannot be applied to drug development for related diseases (Cell Physiol. Biochem. 2010, 26: 01-08)

Method used

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  • Hydroxamic acid-containing substituted heterocyclic compound as well as preparation method and application thereof
  • Hydroxamic acid-containing substituted heterocyclic compound as well as preparation method and application thereof
  • Hydroxamic acid-containing substituted heterocyclic compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 Synthesis of some compounds of the present invention.

[0030] Preparation of 3-(decyloxy)-N-hydroxyisoxazole-5-carboxamide:

[0031]

[0032] Dissolve 1 g (6.99 mmol) of 3-hydroxyisoxazole-5-methyl carboxylate in 20 mL of acetone, add 1.93 g (13.98 mmol) of potassium carbonate, 50 mg of potassium iodide, and 1.85 g (8.39 mmol) of bromodecane, and heat up to The reaction was refluxed for 10h and cooled to room temperature. The reaction solution was filtered, the filter cake was washed three times with dichloromethane, the organic phases were combined, the solvent was spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain 1.88 g of a white solid, with a yield of 95%. Dissolve the obtained product in 10 mL of methanol, add 20 mL of 1.76M methanol solution of potassium hydroxylamine, stir at room temperature for 6 h under nitrogen protection, add 15% HCl aqueous solution to make it acidic, and precipitate the produc...

Embodiment 2

[0048] Example 2 Experiment of compounds inhibiting acid sphingomyelinase activity.

[0049] Acid sphingomyelinase can hydrolyze sphingomyelin in cells to generate ceramide. For a certain amount of fluorescently labeled reaction substrates, different enzyme activities catalyze and generate different amounts of products. By detecting the content of products, the level of enzyme activity can be investigated. The present invention carries out experimental design according to this principle. Extract the protein in the cultured cells, add buffer, fluorescently labeled reaction substrate, and then add different concentrations of compounds respectively, set up a blank control group, perform fluorescence analysis after the reaction, and finally calculate the IC of the compound 50 value.

[0050] The specific results are shown in the table:

[0051] Table 1: Acid sphingomyelinase inhibitory activity of some compounds of the present invention

[0052]

Embodiment 3

[0053] Example 3 Anti-atherosclerotic activity of compounds

[0054] Experimental method: 40 male ApoE knockout mice were selected and randomly divided into blank group, atorvastatin control group, I-1 high-dose administration group, and I-1 low-dose administration group. Atorvastatin is used at a dose of 12mg / Kg. The low dose of I-1 is 12mg / Kg, and the high dose is 24mg / kg. Ten mice in each group were fed with high-fat diet for 12 weeks. At the same time as high-fat feeding, intragastric administration was started. After 12 weeks of administration, the animals were sacrificed, and the aorta was cut for Oil Red O staining.

[0055] Table 2: Compound I.1 reduces aortic fatty plaque in atherosclerotic mice

[0056] group

[0057] The experimental results show that compound I-1 can effectively reduce the formation of atherosclerotic plaques in the aorta of mice fed a high-fat diet, and inhibit the occurrence of atherosclerosis.

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Abstract

The invention belongs to the field of medicinal chemistry and in particular relates to a hydroxamic acid-containing substituted heterocyclic compound as well as a preparation method and application thereof. The specific structure of the compounds provided by the invention is shown as a formula I, and the compounds have acid sphingomyelinase inhibitory activity. The invention further provides a synthetic method of compounds in the formula I and application of the compounds in atherosclerosis and depression. The compounds can be used for developing related drugs for treating atherosclerosis (AS), diabetes, pulmonary emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary arterial hypertension, non-alcoholic fatty liver disease, Alzheimer's disease (AD), multiple sclerosis (MS), cerebral apoplexy and depression. The structural formula is as shown in the specification.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a compound represented by formula I, its preparation method and its application in related diseases. [0002] Background technique [0003] Ceramide is an important lipid signaling molecule, which can play a role in the signal transduction process and participate in various cellular functions, such as regulating cell growth, proliferation, variation, causing apoptosis, regulating protein secretion, participating in immune processes and Inflammation and other effects (Progress in Lipid Research, 2016, 61:51-62). [0004] Hydrolysis of sphingomyelin by acid sphingomyelinase is the fastest and most direct way to generate ceramide in vivo. So far, a variety of endogenous and exogenous factors have been found, including tumor necrosis factor-α (TNF-α), interleukin-β (IL-β), interferon-γ, etc., as well as oxidative stress, ionizing radiation , ultraviolet radiation, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/18C07D413/12A61P9/10A61P3/10A61P11/00A61P9/12A61P1/16A61P25/28A61P25/00A61P25/24A61K31/4439A61K31/42
CPCA61P1/16A61P3/10A61P9/10A61P9/12A61P11/00A61P25/00A61P25/24A61P25/28C07D261/18C07D413/12
Inventor 王进欣杨侃农克意
Owner CHINA PHARM UNIV
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