Lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof

A compound and targeted technology, which can be used in medical preparations containing active ingredients, organic chemistry, drug combinations, etc., can solve the problems of limited inhibitory effect and drug resistance, and achieve good anti-tumor activity, good application prospects, and good EGFR. The effect of protein degradation levels

Inactive Publication Date: 2020-08-25
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the currently used EGFR inhibitors have limited inhibitory effects, and there are certain drug resistance problems. Therefore, the development of a compound that can degrade EGFR protein has extremely important clinical application value

Method used

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  • Lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof
  • Lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof
  • Lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Preparation of E3 Ligand Small Molecule Compound (Compound 6)

[0051] (1) Preparation of compound 2

[0052] Preparation of compound 2a:

[0053] Dissolve diethylene glycol (7.0g, 66.0mmol) in 10mL of dichloromethane solution, add triethylamine (13.3g, 132.2mmol), and add p-toluenesulfonyl chloride (15.1g, 79.1mmol) under ice-cooling. After the addition was complete, the reaction solution was stirred at room temperature for 12 h. Adjust the pH of the solution to 7 with 6 mol / L HCl, extract with dichloromethane (3×30 mL), combine the organic phases, and dry over anhydrous sodium sulfate. Column chromatography gave a yellow liquid product with a yield of 40%.

[0054] 1 H NMR (500MHz, Chloroform-d) δ7.75 (d, J = 8.4Hz, 2H), 7.31 (d, J = 8.0Hz, 2H), 4.19–4.09 (m, 2H), 3.62 (ddd, J = 12.1,5.4,4.1Hz,4H),3.48(dd,J=5.3,3.8Hz,2H),2.40(s,3H).

[0055] Preparation of compound 2b:

[0056] Dissolve triethylene glycol (5.0g, 33.3mmol) in 10mL of dichlorometha...

Embodiment 2

[0099] Embodiment 2: Preparation of PROTACs compound ALL-1

[0100]

[0101] Compound 6a (140mg, 0.26mmol) prepared in Example 1 was dissolved in 5mL N,N-dimethylformamide, compound 7 (141mg, 0.29mmol), N,N-diisopropylethylamine ( 101mg, 0.78mmol), heated at 90°C for 8h. Added 10 mL of water, extracted three times with 20 mL of dichloromethane, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and obtained a yellow solid by column chromatography with a yield of 53%. 1 H NMR (500MHz, CDCl 3 )δ9.74(s,1H),9.56(d,J=12.0Hz,1H),8.91(s,1H),8.78(d,J=11.5Hz,1H),8.37(dd,J=5.4,2.6 Hz,1H),8.15–7.99(m,1H),7.77(s,1H),7.70(dd,J=7.6,4.7Hz,1H),7.64(d,J=7.9Hz,1H),7.47–7.34 (m,3H),7.17(dd,J=5.3,3.3Hz,1H),6.72(s,1H),6.42(dd,J=16.9,1.8Hz,1H),5.69(dd,J=9.9,1.8 Hz,1H),5.13(dt,J=13.4,4.6Hz,1H),4.38(d,J=5.5Hz,2H),4.07(d,J=2.2Hz,2H),3.95(s,3H), 3.84(s,3H),3.75–3.51(m,8H),2.94(s,3H),2.83–2.65(m,5H),2.62(d,J=7.1Hz,4H),2.40–2.28(m, 4H),2.13–2.09(m,1H)p...

Embodiment 3

[0102] Embodiment 3: Preparation of PROTACs compound ALL-2

[0103]

[0104] Compound 6b (200mg, 0.35mmol) prepared in Example 1 was dissolved in 5mL N,N-diisopropylethylamine, and compound 7 (186mg, 0.38mmol), N,N-diisopropylethylamine (136mg, 1.05mmol), heated at 90°C for 8h. Add 10 mL of water, extract three times with 20 mL of dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and obtain a yellow solid by column chromatography with a yield of 62%. 1 H NMR (500MHz, CDCl 3 )δ9.79(s,1H),9.59(s,1H),8.98(d,J=17.9Hz,2H),8.38(d,J=5.3Hz,1H),8.12–8.01(m,1H), 7.79(s,1H),7.75–7.67(m,2H),7.44(t,J=7.8Hz,1H),7.41–7.35(m,1H),7.29–7.25(m,3H),7.18(d, J=5.3Hz, 1H), 6.76(s, 1H), 6.42(dd, J=16.6, 1.9Hz, 1H), 5.73–5.65(m, 1H), 5.16(dd, J=13.3, 5.2Hz, 1H ),4.39(s,2H),4.08(d,J=8.5Hz,2H),3.96(s,3H),3.85(s,3H),3.67(dt,J=5.3,2.6Hz,2H),3.61 –3.49(m,5H),3.42(dt,J=16.3,5.6Hz,5H),2.91(s,3H),2.83–2.71(m,2H),2.63(s,3H),2.52(s,2H ),2.29–2.26...

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Abstract

The invention relates to a lenalidomide-based small-molecular compound targeting to EGFR protein degradation, and preparation and application thereof, and provides a compound targeting to ubiquitination induced EGFR protein degradation and shown as a formula (I) which is described in the specification, and a preparation method and application thereof. Based on lenalidomide, chimeric small molecules capable of targeting to EGFR protein degradation are designed; in-vitro anti-tumor activity tests and in-vitro EGFR protein degradation activity show that the compound has good anti-tumor activity and EGFR protein degradation level, can be used for preventing or / and treating various cancers, and has good application prospects in the field of medicine.

Description

technical field [0001] The invention relates to a compound targeting and degrading EGFR protein, its preparation method and application. Background technique [0002] The ubiquitin-proteasome system (UPS) is the main pathway for intracellular protein degradation, and it is involved in the degradation of more than 80% of intracellular proteins. UPS is a multi-step reaction process involving many different proteins. Proteins are first Ubiquitin (polypeptide) tag is then recognized and degraded by the proteasome. [0003] The system consists of ubiquitin, ubiquitin activating enzyme E1, ubiquitin conjugating enzyme E2, ubiquitin ligase E3, proteasome and its substrate (protein). The process of UPS specific protein degradation is divided into two stages: (1) protein substrate ubiquitination: ubiquitin molecules are powered by APP, activated by E1 and transferred to E2, and then combined with specific protein substrates through E3; (2) ) Degradation of protein substrates: Ubiqu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/506A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/14
Inventor 张兴贤何凯伦王文冰
Owner ZHEJIANG UNIV OF TECH
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