Tripeptide epoxy ketone compound constructed by heterocycle as well as preparation method and application thereof

A technology of tripeptide epoxy ketone and compound, which is applied to tripeptide epoxy ketone compound, the application field in the preparation of antitumor drugs, can solve the problems of large toxic and side effects, easy to produce drug resistance and the like

Active Publication Date: 2015-09-30
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Traditional chemotherapeutic drugs such as alkylating agents and anti-metabolites generally have the disadvantages of high toxicity and side effects, and are prone to drug resistance. However, anti-tumor drugs designed for key proteins or kinases in signaling pathways are playing an important role in the field of tumor treatment. is playing an increasingly important role, and the development of new, low-toxicity, and high-efficiency anti-tumor drugs is of great significance to people's livelihood

Method used

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  • Tripeptide epoxy ketone compound constructed by heterocycle as well as preparation method and application thereof
  • Tripeptide epoxy ketone compound constructed by heterocycle as well as preparation method and application thereof
  • Tripeptide epoxy ketone compound constructed by heterocycle as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0067] Preparation Example 1, tert-butyl 4-(pyrazin-2-ylcarbamoyl)piperidine-1-carboxylate (1a, 1b)

[0068] 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.75g, 12mmol) was placed in a 50mL three-necked bottle, N 2 Add 25 mL of anhydrous CH under protection 2 Cl 2 , and then slowly drop into pyridine (2.5mL, 30mmol) and thionyl chloride (1.1mL, 14mmol), and the reaction solution was left at room temperature for half an hour. Subsequently, 2-aminopyrazine (0.95 g, 10 mmol) and triethylamine (5.7 mL, 40 mmol) were dissolved in 15 mL of CH 2 Cl 2 Afterwards, the above reaction solution was slowly added dropwise, and reacted at room temperature for 6 hours. The reaction solution was diluted with 30 mL of saturated saline, the organic layer was separated, and the aqueous layer was CH 2 Cl 2 Extract (15mL×3), combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, and separate by column chromatography to obtain 2.3g of...

preparation Embodiment 2、4

[0069] Preparation Example 2, tert-butyl 4-(pyrazine-2-yl)piperazine-1-carboxylate (1c, 1d)

[0070] Pyrazine-2-carboxylic acid (1.5 g, 12 mmol) was placed in a 50 ml reaction flask, and 35 mL of anhydrous CH was added 2 Cl 2 Dissolve, then add 1-hydroxybenzotriazole (1.6g, 12mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (3.5g, 18mmol), React at room temperature for half an hour. Subsequently, tert-butyl piperazine-1-carboxylate (1.9 g, 10 mmol) was added to the reaction liquid, and the reaction was carried out at room temperature for 3 hours. The reaction solution was diluted by adding 30mL saturated aqueous sodium bicarbonate solution, the organic layer was separated, washed with saturated brine (20mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, separated by column chromatography to obtain 2.4g of white solid with a yield of 83%. . m.p.: 146-148℃; 1 H NMR (500MHz, CDCl 3 ): δ = 8.97 (d, 1H,J =1....

preparation Embodiment 3

[0071] Preparation Example 3, tert-butyl 4-(4-fluorophenylcarbamoyl)piperidine-1-carboxylate (1e)

[0072] Using 4-fluoroaniline as raw material, the synthesis and post-treatment are the same as in Preparation Example 1. 2.4 g of white solid was obtained, yield 75%. m.p.: 147-149℃; 1 H NMR (500MHz, CDCl 3 ): δ = 7.47 (m, 2H, Ar-H), 7.20 (s, 1H, NH), 7.01 (t, 2H, J =8.0Hz, Ar-H), 4.18 (d, 2H, J =12.0Hz,CH 2 ), 2.80 (t, 2H, J =12.5Hz,CH 2 ), 2.37 (m, 1H, CH), 1.90 (d, 2H, J =12.5Hz,CH 2 ), 1.75 (m, 2H, CH 2 ), 1.47 (s, 9H, CH 3 ) ppm; ESI-MS: m / z = 323[M+H] + .

[0073]

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Abstract

The invention provides a tripeptide epoxy ketone compound constructed by heterocycles. Carfilzomib is taken a pilot compound, a Boc protecting group is removed under condensation and acid conditions, reaction is carried out under alkaline condition to obtain amino acid methyl ester isocyanate, and hydrolysis is carried out under the action of a condensation agent, so that the tripeptide epoxy ketone compound is obtained. The tripeptide epoxy ketone compound is a micromolecule short-peptide proteasome inhibitor; the tripeptide epoxy ketone compound has extremely strong proteasome inhibitory activity and cell prolifation inhibitory activity and has a prospect, and a new way is provided for study of a cancer treatment medicine; raw materials for synthesizing the tripeptide epoxy ketone compound are available, route design is reasonable, reaction conditions are mild, yield of each step is high, operation is easy, and the tripeptide epoxy ketone compound is applicable to industrial production; and the tripeptide epoxy ketone compound has a general structural formula shown in a formula I (described in the specification).

Description

technical field [0001] The present invention relates to the field of drug production, specifically, the present invention relates to a new class of tripeptide epoxy ketone compounds containing a heterocycle in the peptide skeleton, its preparation method and application, and the use of the compound in the preparation of antitumor drugs Applications. Background technique [0002] With the continuous increase of the global population and the deepening of the aging trend of the population, and because of the widespread existence of various unhealthy lifestyles including smoking and environmental pollution, tumors have become the number one killer and threat to human health in developed countries. The No. 2 killer threatening human health in developing countries (CA-Cancer. J. Clin. 2011, 61, 69-90). In our country, cancer has become the first cause of death. On February 3, 2014, the World Health Organization (WHO) published the "Global Cancer Report 2014", stating that China'...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/087C07K5/083C07K1/16C07K1/06A61K38/06A61P35/00A61P35/02A61P25/28A61P37/02
CPCA61K38/00C07K5/0808Y02P20/55C07K5/06043C07K5/06121C07K5/0812A61P1/04A61P13/08A61P15/00A61P25/28A61P35/00A61P35/02A61P37/02
Inventor 胡永洲李佳刘滔张建康周宇波杨波何俏军许磊胡小蓓
Owner ZHEJIANG UNIV
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