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D-amino acid derivative aminopeptidase N inhibitor as well as preparation method and application thereof

A technology of derivatives and amino acids, applied in anti-inflammatory agents, drug combinations, pharmaceutical formulations, etc., can solve problems such as poor drugability and single compound structure, and achieve rich structural diversity, simple operation, and environmental friendliness

Active Publication Date: 2022-03-15
SHANDONG UNIV OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this invention also has similar deficiencies with CN102382014A. In this invention, the compound structure is relatively single, and the amino acid side chain only has L-leucine. Whether other types of amino acid derivatives have inhibitory activity has not been reported; wherein the compound 11ff with the best activity has no effect on The inhibitory activity of aminopeptidase N was IC 50 = 32nM, which is a moderate inhibitory level; L-leucine side chain and aromatic ring are connected by ureido group, and the druggability of urea group is not good compared with amide bond

Method used

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  • D-amino acid derivative aminopeptidase N inhibitor as well as preparation method and application thereof
  • D-amino acid derivative aminopeptidase N inhibitor as well as preparation method and application thereof
  • D-amino acid derivative aminopeptidase N inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0088] Example 1. The preparation of compounds 3a-3i, taking 3h as an example.

[0089] The preparation method of (R)-N-hydroxyl-4-methyl-2-(2,2,2-triphenylacetamido)pentanamide (3h), the steps are as follows:

[0090] 1) Preparation of methyl (2,2,2-triphenylacetyl)-D-leucine (2h)

[0091] 2,2,2-Triphenylacetic acid (0.5g, 1.74mmol) was dissolved in anhydrous dichloromethane (10mL), at 0°C, 1-ethyl-(3-dimethylaminopropyl)carbon was added Imide hydrochloride (0.38g, 1.98mmol), 1-hydroxybenzotriazole (0.26g, 1.93mmol) and 4-dimethylaminopyridine (0.04g, 0.33mmol). After reacting at 0°C for 30 minutes, add D-leucine methyl ester hydrochloride (0.34g, 1.87mmol) and triethylamine (0.22g, 2.17mmol); react at 25°C for 12 hours; dichloromethane was concentrated and the residue Add ethyl acetate (20 mL), wash with 10% phosphoric acid (20 mL) three times, once with saturated aqueous sodium bicarbonate (20 mL), once with saturated aqueous sodium chloride (20 mL), and dry over anhydrou...

Embodiment 2

[0111] Example 2. The preparation of compounds 9a-9j, taking 9i as an example;

[0112] (R)-N-(2-(hydroxylamino)-1-(4-methoxyphenyl)-2-oxoethyl)-2,2,2-triphenylacetamide (9i) Preparation method, the steps are as follows:

[0113] 1) Preparation of methyl (R)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetate (5)

[0114] (R)-4-Hydroxyphenylglycine methyl ester hydrochloride (6.51g, 30mmol) was dissolved in dichloromethane (50mL), and triethylamine (7.58g, 75mmol) was added at 0°C. At 0℃, add dropwise (Boc) 2 O (7.84 g, 36 mmol) in dichloromethane (20 mL). After the dropwise addition was completed, the reaction was carried out at 25° C. for 24 hours. Dichloromethane was concentrated, and the residue was dissolved in ethyl acetate (100 mL), washed three times with 10% phosphoric acid (50 mL), once with saturated aqueous sodium bicarbonate (50 mL), and once with saturated aqueous sodium chloride (50 mL). Second-rate. Purification by column chromatography: volume rati...

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Abstract

The invention provides a D-amino acid derivative aminopeptidase N inhibitor as well as a preparation method and application thereof. The inhibitor has a structure as shown in a general formula I or II. The invention also provides application of the D-amino acid derivative aminopeptidase N inhibitor in preparation of drugs for preventing or treating diseases related to abnormal aminopeptidase activity. Compared with existing inhibitors such as L-configuration compounds with ureido as a linking group, the partial D-amino acid derivative aminopeptidase N inhibitors have more excellent activity on aminopeptidase N inhibition.

Description

technical field [0001] The invention relates to a D-amino acid derivative-like aminopeptidase N inhibitor and its preparation method and application, belonging to the technical field of organic compound synthesis and medical application. Background technique [0002] Aminopeptidase N (APN, CD13, EC 3.4.11.2) is a zinc ion-dependent membrane-bound metalloprotease anchored on the surface of the cell membrane in the form of a homodimer in a "hippocampus" shape. Its catalytic domain is located outside the cell and participates in the substrate degradation process by hydrolyzing the N-terminal amino acids of the substrate. Studies have shown that aminopeptidase N plays an important role in tumor occurrence, development, invasion and metastasis, apoptosis and tumor angiogenesis. [0003] Aminopeptidase N has the following effects: (1) Aminopeptidase N promotes tumor metastasis. The main components of the extracellular matrix that act as a barrier are collagen, fibronectin, lamin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/06A61P29/00A61P35/00A61P35/02A61P1/02A61P33/06A61K31/166A61K31/165
CPCC07C259/06A61P29/00A61P35/00A61P35/02A61P1/02A61P33/06C07C2601/08
Inventor 曹江营周洪雷蔡晓青马艳张晨
Owner SHANDONG UNIV OF TRADITIONAL CHINESE MEDICINE
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