Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof

A compound, alpha protein technology, applied in the direction of drug combinations, peptide/protein components, medical preparations containing active ingredients, etc., can solve the problems of limited development, large molecular weight, and drug resistance.

Pending Publication Date: 2020-06-05
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many disadvantages of small molecule inhibitors: First, the long-term use of small molecule drugs will produce drug resistance; secondly, in order to achieve the desired effect, small molecule compounds need to maintain a high concentration in the cell, which will lead to off-target and adverse effects. Reaction; at the same time, many potential target proteins do not have pockets that can be directly bound by small molecule inhibitors, such as non-enzyme proteins such as transcription factors, it is difficult to develop small molecule inhibitors
The reported PROTACs are all polypeptide compounds, which have disadvantages such as large molecular weight, poor cell permeability, and poor activity, which limit the development of this technology

Method used

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  • Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof
  • Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof
  • Compound for targeted ubiquitination degradation of ERRalpha protein and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Example 1: (Z)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-fluoroacrylic acid

[0168]

[0169] Step 1: Synthesis of 4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxybenzaldehyde

[0170]

[0171] Dissolve compound 26 (3.07g, 10mmol) and vanillin (1.52g, 10mmol) in DMF (10ml), add K 2 CO 3 (2g, 14mmol), stirred at 80°C for 3 hours. After cooling to room temperature, the resulting mixture was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, washed with Na 2 SO 4 dry. After the solvent was spin-dried under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=7:1) to obtain the product 27 (3.21 g, 8.50 mmol, 85%) as a white solid: 1 H NMR (400MHz, CDCl 3 )δ9.87(s,1H),7.97(d,J=8.4Hz,2H),7.85(d,J=8.5Hz,1H),7.48(d,J=1.7Hz,1H),7.42(dd, J=8.2,1.8Hz,1H),6.93(d,J=8.2Hz,1H),5.47(s,2H),3.99(s,3H).MS(ESI)m / z 379[M+H] + .

[0172] Step 2: Synthesis of ...

Embodiment 2

[0178] Example 2: (Z)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)-3-methoxyphenyl)-2-(trifluoromethyl) acrylic acid

[0179]

[0180] The difference from the steps in Example 1 is that after compound 27 is synthesized, the following reaction is carried out directly to prepare (Z)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy)- 3-methoxyphenyl)-2-(trifluoromethyl)acrylic acid:

[0181] Compound 27 (3.78g, 10mmol), 3,3,3-trifluoropropionic acid (10mmol, 0.88ml) were dissolved in anhydrous THF (20ml) under argon protection. Titanium tetrachloride (16mmol, 1.8ml) was added dropwise at 0°C. Stirring was continued for 30 minutes and triethylamine (5.6ml, 40mmol) was added dropwise. After stirring overnight at room temperature, it was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, washed with Na 2 SO 4 dry. After the solvent was spin-dried under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ...

Embodiment 3

[0182] Example 3: (E)-3-(4-((2,4-bis(trifluoromethyl)benzyl)oxy-3-methoxyphenyl-2-cyanoacrylic acid

[0183]

[0184] The difference from the steps in Example 1 is that after compound 27 is synthesized, the following reaction is directly carried out:

[0185] Compound 27 (2.9g, 7.7mmol) and 2-cyanoacetic acid (977.9mg, 11.4mmol) were dissolved in acetonitrile (20ml), piperidine (1.5ml) was added, and stirred at 80°C for 3 hours. After cooling to room temperature, the resulting mixture was treated with water. Hydrochloric acid (2N) was then added to precipitate a solid. The mixture was extracted with ethyl acetate and water. The organic layer was separated, washed with brine, washed with Na 2 SO 4 dry. After the solvent was spin-dried under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to obtain the product 3 as a pale yellow solid (2.6 g, 5.8 mmol, 75.6%): 1 H NMR (400MHz, DMSO-d 6 )δ13.79(s,1H),8.2...

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PUM

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Abstract

The invention provides a compound with a structure shown as a formula (I), which has the effects of inhibiting ERRalpha protein activity and degrading ERRalpha protein activity, has relatively strongsubtype selectivity and can also effectively inhibit triple-negative breast cancer MDA-MB-231 cell migration. Therefore, the compound can be used for diseases related to abnormal expression of the ERRalpha protein, such as various cancers.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a compound targeting ubiquitination to degrade ERRα protein, a pharmaceutical composition and application thereof. Background technique [0002] Breast cancer is a type of tumor with strong heterogeneity. With the development and widespread application of technologies such as genomics, epigenomics, transcriptomics, and proteomics, researchers have gained insights into the molecular complexity of breast cancer. Clearer and systematic cognition. Although the mechanism is complex, most clinically based on estrogen receptor (oestrogen receptor, ER), progesterone receptor (progesterone receptor, PgR) and human epidermal growth factor receptor-2 (human epidermal growth factor receptor-2, HER2 / ErbB2) The level of expression in breast cancer is classified for treatment. Among them, clinically effective hormone therapy methods can be used for ER+, PgR+ or / and HER2+ breast cancer, incl...

Claims

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Application Information

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IPC IPC(8): C07C59/68C07C255/41C07C69/734C07C235/34C07C259/06A61P35/00A61P35/02A61K31/192A61K31/277A61K31/216A61K31/165C07K5/062A61K38/05
CPCC07C59/68C07C255/41C07C69/734C07C235/34C07C259/06C07K5/06034A61K38/00
Inventor 丁克彭丽洁张振声任小梅张章雷冲李姗
Owner JINAN UNIVERSITY
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