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Dipeptide compound constructed from piperidine or piperazine, its preparation method and application

A technology of peptide compounds and compounds, applied in the field of medicine, can solve the problems of high toxicity and side effects, and achieve the effects of simple operation, mild reaction conditions, and reasonable route design

Active Publication Date: 2021-09-03
杭州市西溪医院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is precisely because of this unique covalent binding effect that the side effects of such inhibitors are relatively large.

Method used

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  • Dipeptide compound constructed from piperidine or piperazine, its preparation method and application
  • Dipeptide compound constructed from piperidine or piperazine, its preparation method and application
  • Dipeptide compound constructed from piperidine or piperazine, its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1 Preparation of 1-(pyrazine-2-acyl)piperidine-4-carboxylic acid

[0097]

[0098] Pyrazine-2-carboxylic acid (1.5g, 12mmol) was dissolved in 40mL of anhydrous dichloromethane, HOBt (1.6g, 12mmol) and EDCI (3.5g, 18mmol) were added, and reacted at room temperature for half an hour. Immediately, compound 1 (1.4 g, 10 mmol) and diisopropylethylamine (3.6 mL, 20 mmol) were added to the reaction solution, and reacted at room temperature for 3 hours. Add 30 mL of saturated sodium bicarbonate for dilution, separate the organic layer, dry over anhydrous sodium sulfate, recover the solvent, and separate by column chromatography to obtain 2.3 g of white solid 5 with a yield of 92%. 1 H NMR (500MHz, CDCl 3 ):δ=8.88(d,1H,J=1.0Hz,pyrazine-H),8.61(d,1H,J=2.5Hz,pyrazine-H),8.52(s,1H,pyrazine-H),4.51(m ,1H,CH 2 ),3.91(m,1H,CH 2 ),3.70(s,3H,CH 3 ),3.20(m,1H,CH 2 ),3.09(m,1H,CH 2 ),2.62(m,1H,CH),2.04(m,1H,CH 2 ),1.91(m,1H,CH 2 ),1.81(m,2H,CH 2 ); ESI-MS: m / z=250[M+H...

Embodiment 2

[0100] Example 2 Preparation of 1-(4-fluorobenzoyl)piperidine-4-carboxylic acid

[0101]

[0102] Synthesis of Compound 6: Using 4-fluorobenzoic acid as the raw material, the synthesis and post-treatment were the same as in Example 1 to obtain 2.3 g of white solid with a yield of 87%. 1 H NMR (500MHz, CDCl 3 ): δ=7.41(dd, 2H, J=8.5, 5.5Hz, Ar-H), 7.10(t, 2H, J=8.5Hz, Ar-H), 4.48(m, 1H, CH 2 ),3.80(m,1H,CH 2 ),3.72(s,3H,CH 3 ),3.06(m,2H,CH 2 ),2.61(m,1H,CH),1.96(m,2H,CH 2 ),1.74(m,2H,CH 2 ); ESI-MS: m / z=266[M+H] + .

[0103] The synthesis and post-treatment of compound 16 were the same as in Example 1, and a white solid 16 was obtained, which was directly used in the next reaction.

Embodiment 3

[0104] Example 3 Preparation of 4-(pyrazine-2-carboxamido)piperidine

[0105]

[0106] Synthesis of Compound 7: Using 4-amino-1-Boc-piperidine as raw material, the synthesis and post-treatment were the same as in Example 1 to obtain 2.7 g of white solid with a yield of 88%. 1 H NMR (500MHz, CDCl 3 ):δ=9.40(s,1H,pyrazine-H),8.75(d,1H,J=2.0Hz,pyrazine-H),8.52(d,1H,J=1.5Hz,pyrazine-H),7.72(d ,1H,J=8.0Hz,NH),4.10(m,3H,CH+CH 2 ),2.95(t,2H,J=13.5Hz,CH 2 ),2.00(d,2H,J=12.5Hz,CH 2 ),1.46(m,11H,CH 2 +CH 3 ); ESI-MS: m / z=307[M+H] + .

[0107] Compound 7 (1.5 g, 5.0 mmol) was dissolved in 15 mL of dichloromethane, 8 mL of trifluoroacetic acid was added dropwise, and reacted at room temperature for 1 hour. The solvent was evaporated under reduced pressure, diethyl ether was added to precipitate a white solid, and the white solid 17 was obtained by suction filtration and drying, which was directly used in the next reaction.

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Abstract

The present invention designs and synthesizes a series of novel non-covalent small molecule short peptide proteasome inhibitors, which are dipeptide compounds constructed from six-membered heterocycles with the structure of general formula (I): Ⅰ The six-membered heterocycle of the present invention The short peptide non-covalent compound constructed by the ring has good proteasome inhibitory activity, and has a strong in vitro proliferation inhibitory effect on multiple myeloma cell lines such as RPMI8226, H929, and MM‑1S. The raw materials required for the synthesis of the compound of the invention are easily available, the route design is reasonable, the reaction conditions are mild, the yield of each step is high, the operation is simple and convenient, and the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicine, specifically, the present invention relates to a new class of dipeptide compounds containing a piperidine or piperazine ring in the peptide skeleton, its preparation method and application, and the use of the compound in the preparation of antitumor drugs application. Background technique [0002] Whether in developed countries or developing countries, cancer is one of the diseases with the highest mortality rate. However, due to different dietary habits and poor medical and health conditions in developing countries, whether it is the number of patients, the number of deaths or the number of deaths rate is higher than that of developed countries. In China, it is estimated that there will be 4.292 million new cancer cases and 2.814 million deaths in 2015. The morbidity and mortality of various tumors continue to rise, and the treatment of tumors is facing great challenges (CA-Cancer.J.Clin. 2016,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/065C07K5/062C07K5/075C07K5/072A61K38/05A61P35/00A61P35/02A61P37/00A61P25/28A61P25/16A61P25/00
CPCA61K38/00C07K5/06026C07K5/06043C07K5/06078C07K5/06104C07K5/06113C07K5/0613Y02P20/55
Inventor 张建康蔡兆斌刘寿荣庄让笑邵益丹赵艳梅席建军潘旭旺何若愚方红英黄玮玮孙晶晶潘金明柯云玲
Owner 杭州市西溪医院
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