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A Substituted Acethydrazide Derivative, Preparation Method and Use Thereof

a technology of acethydrazide and derivative, applied in the field of substituted acethydrazide derivative, preparation method, etc., can solve the problem of hindering degradation of acethydrazid

Inactive Publication Date: 2017-07-06
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a new compound, called a substituted acethydrazide derivative, which can inhibit proline hydroxylase and stabilize HIF-α, a protein that plays a crucial role in regulating the expression of genes involved in various physiological phenomena such as carcinogenesis, vasculogenesis, cell survival, glucose metabolism, etc. This compound can be used to manufacture a medicament for the treatment and prevention of diseases such as anemia, acute ischemic reperfusion injury, etc. The invention is based on the discovery of the effectiveness of this compound in inhibiting proline hydroxylase and stabilizing HIF-α.

Problems solved by technology

Under anoxic conditions, deactivation of PHD results in that proline residues cannot be hydroxylated, HIF-1α, cannot bind to pVHL, so that its degradation is hindered.

Method used

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  • A Substituted Acethydrazide Derivative, Preparation Method and Use Thereof
  • A Substituted Acethydrazide Derivative, Preparation Method and Use Thereof
  • A Substituted Acethydrazide Derivative, Preparation Method and Use Thereof

Examples

Experimental program
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Effect test

preparation example 1

[0072]

[0073]9.6 mL (0.36 mol) of N,N′-dimethylethanediamine and 100 mL of tetrahydrofuran were added to a three-necked bottle equipped with constant pressure funnel, reflux condensing tube and thermometer, mixed evenly and then heated. When the reaction solution was slightly boiled (about 56° C.), 10 g (0.06 mol) of 1-chloromethylnaphthalene was slowly added in dropwise to the reaction solution, white precipitate was gradually generated, and thin-layer chromatography (TLC) was used to monitor the end of reaction. When the spot of 1-chloromethylnaphthalene in the reaction solution disappeared on thin-layer chromatography, heating was stopped, cooling was carried out, solvent was dried out by rotary evaporation, 3 mol / L of sodium hydroxide solution was used for washing, dichloromethane was used for extracting the washing liquid in which pH≧12 was maintained during extraction, all organic phases were combined, separated by silica column (eluent: dichloromethane / methanol=20 / 1) to Obtain...

preparation example 3

[0076]

[0077]2.1 g (0.06 mol) of 85% hydrazine hydrate and 50 ml of anhydrous ethanol were added to 250 mL three-necked bottle equipped with constant pressure funnel, reflux condensing tube and thermometer, mixed evenly and then heated to reflux, 5.0 g (0.02 mol) of methyl 2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acetate was slowly added to the reaction solution, and reacted for 2 h, then heating was stopped, cooling was carried out, solvent was dried out by rotary evaporation, silica column separation was carried out (eluent: dichloromethane / methanol=10 / 1) to obtain 2-{N-{2-[N-(naphthalen-1-yl-methylene)-N-methylamino]ethyl}N-methylamino}acethydrazide, white solid, yield 86%. 1H-NMR (400 MHz, CDCl3) δ: 8.18 (7H, m), 4.10 (2H, s), 3.29 (2H, s), 2.37 (4H, m), 2.26 (6H, s); EI-MS (m / z): 301.2 [M+H]+.

preparation example 4

[0078]

[0079]Pare- and meta-trifluoromethylbenzyl chloride was used as raw material, and operations were the same for Intermediate 1. Light yellow liquid product was obtained. MS[M]+=246.1 m / e.

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Abstract

The present invention pertains to the field of pharmaceutical chemicals, and relates to a substituted acethydrazide derivative, preparation method and use thereof; preferably, relates to a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof can effectively inhibit proline hydroxylase, stabilize HIF-α, particularly HIF-1α, and has potency in the manufacture of a medicament for treatment and / or prophylaxis and / or adjuvant therapy of anemia, acute ischemic reperfusion injury.

Description

TECHNICAL FIELD[0001]The present invention pertains to the field of pharmaceutical chemicals, and relates to a substituted acethydrazide derivative, preparation method and use thereof.BACKGROUND ART[0002]In 1992, Semenza et al. found a protein capable of specifically binding to hypoxia responsible element of erythropoietin gene, and this protein is named as Hypoxia inducible factor-1 (HIF-1). HIF-1 widely exists in mammalian cells, and mainly regulates angiogenesis, cellular survival and death, as well as pH. HIF-1 is a heterodimer consisting of two subunits (HIF-α and HIF-β) and both of these two subunits are members of alkaline helix-loop-helix transcription factor superfamily, and have PER-AHR / ARNT-SIM (PAS) domain. HIF-α has 3 subunits, which are separately HIF-1α, HIF-2α and HIF-3α, in which HIF-1α and HIF-2α have a high sequence identity, recognize the same DNA binding domain, but have different biological effects.[0003]Under normoxia condition, proline residues at sites 402 a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C251/86
CPCC07C251/86C07C255/58A61K31/165A61K31/277C07C249/16C07C253/30
Inventor LI, SONGXIAO, JUNHAIWANG, LILILONG, LONGLI, WEILUO, HAOMINGLI, FEIFEIZHONG, WUZHENG, ZHIBINGXIE, YUNDELI, XINGZHOUZHOU, XINBOWANG, XIAOKUICAO, RUIYUAN
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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