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Tripeptide macrocyclic derivatives, preparation method and application thereof

A technology of macrocyclic derivatives and drugs, applied in the field of drugs, can solve problems such as cell cycle arrest, apoptosis, and protein level imbalance

Active Publication Date: 2021-05-04
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 derivatives, preparation method and application thereof
  • Tripeptide macrocyclic derivatives, preparation method and application thereof
  • Tripeptide macrocyclic derivatives, 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 macrocycle derivative and its optical isomer or a pharmaceutically acceptable salt or solvate thereof. By using the carboxyl-protected compound as the starting material, it is condensed with an acid, followed by olefin ring-closing metathesis and carboxyl removal, and at the same time, the Boc-protected amino acid is condensed with the epoxy ketone segment, and then the amino protecting group is removed. Condensation of the carboxyl intermediate gives the desired product. Experiments have proved that the novel skeleton of the present invention has better proteasome inhibitory activity, and has better proliferation inhibitory effect on multiple myeloma such as RPMI 8226 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 operation is simple and convenient, and the method is suitable for industrial production. It has formula (I) structure:

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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Patent Type & Authority Patents(China)
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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