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N-hydroxyl-5-substituted-1H-pyrazol-3-formamide compound as well as preparation method and use thereof

A technology of compounds and substituents, applied in the field of medicinal chemistry, can solve problems such as inapplicability, poor membrane permeability, and poor selectivity

Active Publication Date: 2019-01-18
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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  • N-hydroxyl-5-substituted-1H-pyrazol-3-formamide compound as well as preparation method and use thereof
  • N-hydroxyl-5-substituted-1H-pyrazol-3-formamide compound as well as preparation method and use thereof
  • N-hydroxyl-5-substituted-1H-pyrazol-3-formamide compound as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Synthesis of some compounds of the present invention.

[0025] Preparation of ethyl 5-phenyl-1H-pyrazole-3-carboxylate:

[0026]

[0027] Add 383mg (16.7mmol) sodium metal in batches to 15mL absolute ethanol, stir at room temperature until dissolved, then add diethyl oxalate (1.28g, 8.75mmol). Dissolve 1g (8.33mmol) of acetophenone in 15mL of absolute ethanol, and add it dropwise to the freshly prepared sodium ethoxide solution under ice-cooling, return to room temperature after the dropwise addition, stir for 6 hours, add 15mL of 15% dilute hydrochloric acid to acidify, Subsequently, most of the ethanol was removed by rotary evaporation, diluted with 10 mL of water, extracted three times with 100 mL of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The ethyl acetate in which the product was dissolved was directly spin-dried to obtain the crude product of the intermediate, which was re-dissolved by adding 15 mL...

Embodiment 2

[0052] Example 2 Experiment of compounds inhibiting acid sphingomyelinase activity.

[0053] 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.

[0054] The specific results are shown in the table:

[0055] Table 1: Acid sphingomyelinase inhibitory activity of some compounds of the present invention

[0056]

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PUM

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Abstract

The invention belongs to the field of medicine chemistry, and particularly relates to an N-hydroxyl-5-substituted-1H-pyrazol-3-formamide compound as well as a preparation method and use thereof. The specific structure of the compound is as shown in a formula I. The invention also provides a synthesis method of the compound in the formula I and inhibition activity thereof for acidic sphingomyelinase. The compound can be used for developing drugs for treating atherosclerosis (AS), diabetes, emphysema, pulmonary edema, pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, pulmonary arterial hypertension, non-alcoholic fatty liver disease, Alzheimers (AD), multiple sclerosis (MS), cerebral stroke and depression diseases. (the formula I is shown in the description).

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 second messenger that plays an important role in the signal transduction process and participates in various cellular functions, such as regulating cell growth, proliferation, mutation, causing apoptosis, regulating protein secretion, participating in immune processes and inflammation Reaction 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 radia...

Claims

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Application Information

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IPC IPC(8): C07D231/14A61P9/10A61P3/10A61P11/00A61P9/12A61P1/16A61P25/28A61P25/24
CPCA61P1/16A61P3/10A61P9/10A61P9/12A61P11/00A61P25/24A61P25/28C07D231/14
Inventor 王进欣杨侃支卓尔农克意
Owner CHINA PHARM UNIV
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