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Quasi-peptide compound containing serine and preparation method and application thereof

A compound, serine technology, applied in the direction of active ingredients of heterocyclic compounds, organic chemistry, drug combinations, etc., can solve problems such as adverse reactions and drug resistance

Active Publication Date: 2019-04-19
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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  • Quasi-peptide compound containing serine and preparation method and application thereof
  • Quasi-peptide compound containing serine and preparation method and application thereof
  • Quasi-peptide compound containing serine and preparation method and application thereof

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preparation example Construction

[0036] see figure 1 , the preparation method of the serine-containing peptoid compound of above-mentioned structure, comprises the following steps:

[0037] 1) Acylation of 5-bromo-2-aminopyridine with the corresponding acid chloride compound to prepare acylated 5-bromo-2-aminopyridine;

[0038] The specific process of the described step 1) is: dissolving 5-bromo-2-aminopyridine in anhydrous dichloromethane, adding triethylamine, and slowly adding the corresponding acid chloride compound dropwise to the above solution under ice-bath conditions After the dropwise addition was completed, the ice bath was removed and the reaction was carried out at room temperature for 12 hours. After the reaction, add dichloromethane to dilute, wash with water, wash with saturated sodium bicarbonate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, distill under reduced pressure, and separate by column chromatography to obtain a white solid, which is the acylated 5- Brom...

Embodiment 1

[0054] A serine-containing peptoid compound, R is , the preparation method is as follows:

[0055] 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 reaction was raised to room temperature overnight (ie 12h). 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%. Mp78-81℃; EI-MS(m / z):214[M] + .

[0056] 2) Synthesis of 4-(6-(acetylamino)pyridin-3-yl)benzoic acid: N-(5-bromopyridin-2-yl)acetamide (4.30g, 20mmol), p-carboxyph...

Embodiment 2

[0064] A peptoid compound containing serine, R as The preparation method is as follows:

[0065] 1) in N 2 Under 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) in an ice bath. 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 phases, anhydrous Na 2 SO 4 dry. Column chromatography separation and purifica...

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Abstract

The invention discloses a quasi-peptide compound containing serine and a preparation method and application thereof. The target compound is synthesized using acylation, Suzuki coupling, condensation reactions and the like. The compound is a Bcr-Abl small molecular tyrosine kinase inhibitor with a novel molecular structure. According to the compound, a medicine designing strategy based on segmentsis adopted, piphenylpyridine is adopted as a hinge region combining segment, L-serine is introduced to be a flexible Linker to construct a quasi-peptide small molecular compound library with kinase inhibitory activity, and a tyrosine kinase inhibitor with Bcr-Abl kinase inhibitory activity is discovered through an ADP-Glo kinase activity sieve. Kinase screening experiments show that the compound has certain inhibitory activity on Abl kinase and T315I mutated Abl kinase, and the activity on the Abl kinase is the optimal when R is trimethylacetamide, and cell proliferation experiments show thatmost compounds have certain inhibitory activity on K562 cells.

Description

technical field [0001] The invention relates to a serine-containing peptoid compound 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 ...

Claims

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Application Information

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IPC IPC(8): C07D213/75C07D213/74C07D213/81C07D213/82A61K31/44A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D213/74C07D213/75C07D213/81C07D213/82Y02P20/55
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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