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Compound containing hydroxyproline and preparation method and application of compound

A technology for hydroxyproline and compounds, which is applied to the field of compounds containing hydroxyproline, can solve problems such as drug resistance and adverse reactions, and achieve the effects of improving affinity, good spatial matching, and improving inhibitory activity.

Active Publication Date: 2019-05-17
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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  • Compound containing hydroxyproline and preparation method and application of compound
  • Compound containing hydroxyproline and preparation method and application of compound
  • Compound containing hydroxyproline and preparation method and application of compound

Examples

Experimental program
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preparation example Construction

[0033] see figure 1 , the preparation method of the compound containing hydroxyproline as above-mentioned structure, comprises the following steps:

[0034] 1) 5-bromo-2-aminopyridine is acylated with the corresponding acid chloride compound to prepare acylated 5-bromo-2-aminopyridine;

[0035] 2)N 2 Under protection, 5-bromo-nicotinic acid reacts with thionyl chloride and corresponding amine compounds to prepare ammoniated 5-bromo-nicotinic acid;

[0036] 3) Under the catalysis of tetrakistriphenylphosphine palladium, acylated 5-bromo-2-aminopyridine or ammoniated 5-bromonicotinic acid undergoes Suzuki coupling reaction with p-carboxyphenylboronic acid to obtain a biphenyl compound;

[0037]4) Condensation of Boc-protected hydroxyproline with 3-trifluoromethyl-4-chloroaniline to generate tert-butyl-(2R,4S)-2-((4-chloro-3-(trifluoromethyl)benzene Base) carbamoyl)-4-hydroxypyrrolidinyl-1-carboxylate;

[0038] 5) tert-butyl-(2R,4S)-2-((4-chloro-3-(trifluoromethyl)phenyl)carb...

Embodiment 1

[0053] A compound containing hydroxyproline, characterized in that R is , the preparation method is as follows:

[0054] 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] + .

[0055] 2) Synthesis of 4-(6-(acetylamino)pyridin-3-yl)benzoic acid: N-(5-bromopyridin-2-yl)acetamide (4.30g...

Embodiment 2

[0062] A compound containing hydroxyproline, characterized in that R is , the preparation method is as follows:

[0063] 1) Synthesis of 5-bromo-N-cyclopropyl nicotinamide: 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, ...

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Abstract

The invention discloses a compound containing hydroxyproline and a preparation method and application of the compound. Biphenyl pyridine serves as a hinge area bonded group, a design strategy of fragment drugs is adopted, L-hydroxyproline is introduced as a flexible Linker to construct a peptoid type small molecule compound library with kinase inhibitory activity, and a tyrosine kinase inhibitor with Bcr-Abl kinase inhibitory activity is found through screening by tests such as ADP-Glo. The compound can be used for preparing the anti-tumor (chronic granulocytic leukemia) drugs, has activity ofinhibiting kinase of Bcr-Abl and Bcr-AblT315I, and has cell proliferation inhibitory activity for K562 cells; and meanwhile, the activity result shows that a certain effect on the inhibitory activityof the compound is achieved by introducing an L-hydroxyproline structure, and the L-hydroxyproline structure can serve as a novel Linker efficacy fragment of the Bcr-Abl tyrosine kinase inhibitor.

Description

technical field [0001] The invention relates to a compound containing hydroxyproline 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): C07D401/12A61P35/00
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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