A kind of alanine derivative and its preparation method and application

A derivative, alanine technology, applied in the field of alanine derivatives and its preparation, can solve problems such as adverse reactions and drug resistance, and achieve the effect of improving affinity and good space matching

Active Publication Date: 2020-06-19
XI AN JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but there are problems such as drug resistance and other clinical adverse reactions.

Method used

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  • A kind of alanine derivative and its preparation method and application
  • A kind of alanine derivative and its preparation method and application
  • A kind of alanine derivative and its preparation method and application

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Experimental program
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preparation example Construction

[0030] see figure 1 , as the preparation method of the alanine derivative of above-mentioned structure, comprises the following steps:

[0031] 1) 5-bromo-2-aminopyridine is acylated with an acid chloride compound to prepare acylated 5-bromo-2-aminopyridine;

[0032] 2)N 2 Under protection, 5-bromonicotinic acid, thionyl chloride and amine compounds react to prepare ammoniated 5-bromonicotinic acid;

[0033] 3) Under the catalysis of tetrakistriphenylphosphine palladium, acylated 5-bromo-2-aminopyridine or ammoniated 5-bromonicotinic acid and m-carboxyphenylboronic acid undergo Suzuki coupling reaction to obtain pyridine-benzene compound;

[0034] 4) Boc-L-alanine is condensed with 3-trifluoromethyl-4-chloroaniline to generate tert-butyl-(R)-(1-((4-chloro-3-(trifluoromethyl)phenyl )amino)-1-oxypropan-2-yl)carbamate;

[0035] 5) tert-butyl-(R)-(1-((4-chloro-3-(trifluoromethyl)phenyl)amino)-1-oxypropan-2-yl)carbamate removes Boc protection The base generates (R)-2-amino-N-(...

Embodiment 1

[0046] A kind of alanine derivative, is characterized in that, R is , the preparation method is as follows:

[0047] 1) Synthesis of N-(5-bromopyridin-2-yl)acetamide: 5-bromo-2-aminopyridine (5.19 g, 30 mmol) was dissolved in 100 ml of anhydrous dichloromethane, and 20 ml of triethylamine was added. Under the condition of ice bath, acetyl chloride (2.54ml) was slowly added dropwise to the above solution. After the dropwise addition was completed, the ice bath was removed, and the mixture was raised to room temperature to react overnight. After the reaction was finished, dichloromethane was added for dilution, washed with water (30ml×3), saturated NaHCO 3 Solution washing (30ml×3), saturated NaCl washing (30ml), organic phase anhydrous NaCl 2 SO 4 dry. Column chromatography separated 5.65 g of white solid with a yield of 88%. Mp 78-81℃; EI-MS(m / z):214[M] + .

[0048] 2) Synthesis of 3-(6-(acetylamino)pyridin-3-yl)benzoic acid: N-(5-bromopyridin-2-yl)acetamide (4.30g, 20...

Embodiment 2

[0054] A kind of alanine derivative, is characterized in that, R is , the preparation method is as follows:

[0055] 1) Synthesis of 5-bromo-N-cyclopropyl nicotinamide: in N 2Under protection, add thionyl chloride (36ml, 494mmol) dropwise to 5-bromonicotinic acid (5.00g, 24.7mmol). After the dropwise addition, heat to reflux for 2-3h until the solution is clear, and spin off the chloride under reduced pressure. Sulfoxide, a light yellow solid was obtained. The solid was dissolved in 30ml of anhydrous dichloromethane, and the reactive intermediate solution was slowly added dropwise to a solution of cyclopropylamine (3.77ml) in dichloromethane (30ml) under ice-bath conditions. After the dropwise addition, it was raised to room temperature and reacted overnight. After the reaction, add 2mol / L K to the reaction system 2 CO 3 Solution 20ml. Separate the liquid to take the dichloromethane phase, extract the aqueous phase with dichloromethane (15ml × 3), combine the organic ph...

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Abstract

The invention discloses an alanine derivative and a preparation method and application thereof. The preparation comprises the following steps: taking biphenylpyridine as a hinge region binding fragment, introducing L-alanine as a flexible linker by adopting a fragment drug design strategy to construct a compound library with kinase inhibitory activity, and discovering a tyrosine kinase inhibitor with Bcr-Abl kinase inhibitory activity through ADP-Glo kinase activity screening. The compound can be used for preparing anti-tumor (chronic myelogenous leukemia) drugs, inhibits kinase activity of Bcr-Abl and Bcr-AblT315I, and has the activity of inhibiting cell proliferation of K562 cells. The introduction of an alanine structure has an important effect on the inhibitory activity of the compound, the structural diversity of the kinase inhibitor can be expanded, and the activity result shows that the structure can be used as a Linker pharmacodynamic fragment of the Bcr-Abl tyrosine kinase inhibitor.

Description

technical field [0001] The present invention relates to a kind of alanine derivative and its preparation method and application Background technique [0002] Chronic myeloid leukemia (CML) is a malignant clonal proliferative disease that occurs in bone marrow hematopoietic stem cells, accounting for 15% to 20% of adult leukemia patients. It is characterized by the detection of Ph chromosomes in CML patients. The Ph chromosome is a breakpoint aggregation cluster-Alberson (BCR-ABL) fusion gene formed by the reciprocal translocation of normal chromosome 22 and chromosome 9 in the human body. This fusion gene encodes Bcr that produces continuous activation of tyrosine kinase activity -Abl fusion protein. Small molecule tyrosine kinase inhibitors targeting Bcr-Abl are currently on the market, but they all have problems such as drug resistance and other clinical adverse reactions. Subsequently, the research and development of novel Bcr-Abl tyrosine kinase inhibitors has become o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/75C07D213/76C07D213/73C07D213/81A61P35/00A61P35/02
CPCY02P20/55
Inventor 张杰潘晓艳梁丽媛卢闻王嗣岑贺浪冲司茹王瑾
Owner XI AN JIAOTONG UNIV
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