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Piperidine or piperazine based dipeptide compounds as well as preparation method and application thereof

A compound, piperidine technology, applied in the application field of preparing antitumor drugs, can solve problems such as large toxic and side effects

Active Publication Date: 2017-12-01
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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  • Piperidine or piperazine based dipeptide compounds as well as preparation method and application thereof
  • Piperidine or piperazine based dipeptide compounds as well as preparation method and application thereof
  • Piperidine or piperazine based dipeptide compounds as well as preparation method and application thereof

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 invention designs and synthesizes a series of non-covalent small-molecule short peptide type proteasome inhibitors with a brand-new structure. The proteasome inhibitors are six-membered heterocyclic dipeptide compounds with the structure shown as general formula (I) in the description. The six-membered heterocyclic non-covalent short-peptide compounds have good proteasome inhibition activity and have quite strong in-vitro proliferation inhibition effect on multiple myeloma cell lines such as RPMI8226, H929, MM-1S and the like. For synthesis of the compounds, required raw materials are easily available, the route design is reasonable, reaction conditions are mild, yield in each step is high, the operation is simple and convenient, and the synthesis is applicable to 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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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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