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Tripeptide macrocyclic derivative as well as preparation method and application thereof

A technology of macrocyclic derivatives and compounds, applied in the field of anti-tumor applications, can solve problems such as cell cycle arrest, cell apoptosis, and protein level imbalance

Active Publication Date: 2018-06-22
ZHEJIANG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thus, inhibition of proteasome function can lead to dysregulation of protein levels associated with multiple signaling pathways, leading to cell cycle arrest and apoptosis

Method used

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  • Tripeptide macrocyclic derivative as well as preparation method and application thereof
  • Tripeptide macrocyclic derivative as well as preparation method and application thereof
  • Tripeptide macrocyclic derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0072] Preparation Example 1, 2-(allyloxy) methyl benzoate (1a)

[0073] Methyl salicylate (4.2ml, 33mmol), potassium carbonate (13.8g, 99mmol) and 3-bromopropene (4.0ml, 46mmol) were placed in a 100mL three-necked flask, 50mL of acetone was added, and the reaction solution was refluxed The reaction was carried out for 18 hours. After the reaction was monitored by TLC, the reaction solution was cooled to room temperature, the solvent was removed under reduced pressure, 100ml of ethyl acetate was added, washed with water (2×100ml) and saturated brine (2×100ml) successively, dried over anhydrous sodium sulfate and then decompressed The solvent was removed and separated by column chromatography to obtain 5.9 g of a colorless oily liquid with a yield of 93%. 1 H NMR (500MHz, CDCl 3 )δ7.80(dd,J=8.0,2.0Hz,1H),7.44(ddd,J=8.0,7.5,2.0Hz,1H),7.01–6.94(m,2H),6.11–6.02(m,1H) ,5.54–5.48(m,1H),5.32–5.27(m,1H),4.63(dt,J=5.0,1.5Hz,2H),3.90(s,3H)ppm; ESI-MS: m / z=193 [M+H] + .

preparation Embodiment 2

[0074] Preparation Example 2, 2-(3-buten-1-yloxy)methyl benzoate (1b)

[0075] Using 4-bromo-1-butene as raw material, the synthesis and post-treatment were the same as in Preparation Example 1 to obtain 4.0 g of a colorless oily liquid with a yield of 88%. 1 H NMR (500MHz, CDCl 3)δ7.77(dd,J=7.5,1.5Hz,1H),7.47–7.38(m,1H),7.00–6.91(m,2H),6.00–5.88(m,1H),5.22–5.07(m, 2H), 4.08(t, J=6.5Hz, 2H), 3.88(s, 3H), 2.62–2.54(m, 2H)ppm; ESI-MS: m / z=207[M+H] + .

preparation Embodiment 3

[0076] Preparation Example 3, 2-(4-penten-1-yloxy)methyl benzoate (1c)

[0077] Using 5-bromo-1-pentene as raw material, the synthesis and post-treatment were the same as in Preparation Example 1 to obtain 5.8 g of a colorless oily liquid with a yield of 80%. 1 H NMR (500MHz, CDCl 3 )δ7.78(dd, J=7.5,1.5Hz,1H),7.44(ddd,J=8.0,7.5,1.5Hz,1H),6.99–6.94(m,2H),5.92–5.80(m,1H) ,5.09–5.04(m,1H),5.02–4.98(m,1H),4.05(t,J=6.5Hz,2H),3.89(s,3H),2.34–2.25(m,2H),1.98–1.88 (m,2H)ppm; ESI-MS: m / z=221[M+H] + .

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Abstract

The invention provides a tripeptide macrocyclic derivative as well as an optical isomer, a pharmaceutically acceptable salt or a solvent compound thereof. A preparation method comprises the followingsteps: by taking a carboxyl protected compound as an initial raw material, condensation with an acid, performing olefin ring closing metathesis, removing carboxyl, condensing Boc protected amino acidwith an epoxy ketone segment, removing an amino protection group, and further condensing with an intermediate of which the carboxyl is removed, so as to obtain a target product. Experiments show thatthe derivative which has a completely novel framework and relatively good proteasome inhibition activity has a very good propagation inhibition function on multiple myeloma such as RPMI 8226, and MM.1S. The compound provided by the invention is easy in raw material obtaining, reasonable in route design, gentle in reaction condition, simple and convenient to operate and applicable to industrial production. The derivative is of a structure of formula (I) as shown in the specification.

Description

technical field [0001] The present invention relates to the field of medicine, relates to a tripeptide macrocycle derivative and its preparation method and application, and relates to a tripeptide macrocycle derivative as a proteasome inhibitor, a salt containing it, and the compound or its salt as an active ingredient The application of the prepared medicine in anti-tumor. Background technique [0002] With the increasing population and the aging trend of the population, coupled with the widespread existence of various unhealthy lifestyles including smoking and environmental pollution, malignant tumors are seriously threatening human life, and malignant tumors have become the first in my country. A fatal disease, its prevention and treatment has become an important research topic in the medical circles of our country and even the world. Traditional cancer treatment methods mainly include surgery, radiation therapy and drug chemotherapy, among which drug chemotherapy is the ...

Claims

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Application Information

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IPC IPC(8): C07K5/097C07K1/06A61K38/06A61P35/00
CPCA61K38/00C07K5/0821Y02P20/55
Inventor 刘滔李佳胡永洲周宇波李大强高立信董晓武许磊洪对对张小团
Owner ZHEJIANG UNIV
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