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A substituted heterocyclic compound containing hydroxamic acid and its preparation method and application

A hydroxamic acid and compound technology, applied in the field of medicinal chemistry, can solve problems such as poor selectivity, inapplicability, and poor stability of phosphatase

Active Publication Date: 2022-06-17
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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  • A substituted heterocyclic compound containing hydroxamic acid and its preparation method and application
  • A substituted heterocyclic compound containing hydroxamic acid and its preparation method and application
  • A substituted heterocyclic compound containing hydroxamic acid and its preparation method and application

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 methyl 3-hydroxyisoxazole-5-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. 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%. The obtained product was dissolved in 10 mL of methanol, 20 mL of 1.76 M methanol solution of potassium hydroxylamine was added, stirred at room temperature for 6 h under nitrogen protection, and 15% HCl aqueous solution was added to adjust to acidity, and the product 3...

Embodiment 2

[0048] Example 2 Compounds inhibit acid sphingomyelinase activity assay.

[0049] Acid sphingomyelinase can hydrolyze sphingomyelin in cells to generate ceramide. For a certain amount of fluorescently labeled reaction substrate, different enzyme activities catalyze different amounts of products, and the level of enzyme activity can be examined by detecting the content of the products. The present invention conducts experimental design based on this principle. Extract the protein from the cultured cells, add buffer, fluorescently labeled reaction substrate, then add compounds of different concentrations, 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 Compound anti-atherosclerotic activity

[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 was used at a dose of 12 mg / Kg. The low dose of I-1 is 12mg / Kg and the high dose is 24mg / kg. 10 mice in each group were fed with high-fat diet for 12 weeks. Gavage was started at the same time as high-fat feeding. After 12 weeks of administration, the animals were sacrificed, and the aortas were excised for Oil Red O staining.

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

[0056] grouping blank Atorvastatin I-1(12mg / Kg) I-1(24mg / Kg) Arterial fatty plaque percentage (%) 25±1.2 11±0.4 16±1.0 10±0.3

[0057] The experimental results show that compound I-1 can effectively reduce the formation of atherosclerotic plaques in the large ...

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Abstract

The invention belongs to the field of medicinal chemistry, and specifically relates to a substituted heterocyclic compound containing hydroxamic acid, a preparation method and application thereof. The specific structure of the compound provided by the present invention is shown in formula I, and has acid sphingomyelinase inhibitory activity. The present invention also provides a synthesis method of the compound in formula I and its effect on atherosclerosis and depression. This kind of compound can be used to develop and treat atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary arterial hypertension, non-alcoholic fatty liver, Alzheimer's Drugs related to AD, multiple sclerosis (MS), stroke, and depression.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a compound represented by formula I, a preparation method thereof and its application in related diseases. [0002] Background technique [0003] Ceramide is an important lipid signaling molecule that can play a role in the process of signal transduction and participate in a variety of cellular functions, such as regulating cell growth, proliferation, mutation, 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 , UV radiation...

Claims

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Application Information

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Patent Type & Authority Patents(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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