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Compound based on CRBN ligand inducing EGFR degradation and preparation method thereof, pharmaceutical composition and application

A compound and composition technology, applied in the field of pharmaceutical compound synthesis, can solve the problems of side effects, reduce the anti-tumor effect of EGFR inhibitors, drug resistance, etc., and achieve the effects of reducing toxic side effects, excellent EGFR protein degradation, and good anti-tumor activity.

Active Publication Date: 2019-10-25
ZHEJIANG ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, the inhibition of EGFR often needs to maintain the drug at a high concentration for a long time, which may cause serious side effects, and long-term use will lead to drug resistance and reduce the anti-tumor effect of EGFR inhibitors

Method used

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  • Compound based on CRBN ligand inducing EGFR degradation and preparation method thereof, pharmaceutical composition and application
  • Compound based on CRBN ligand inducing EGFR degradation and preparation method thereof, pharmaceutical composition and application
  • Compound based on CRBN ligand inducing EGFR degradation and preparation method thereof, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Preparation of 2-(2-((2-(2,6-piperidinedione-3-yl)-1-oxoindoline-4-yl)amino)ethoxy)ethyl-4 -Toluenesulfonate (2-1):

[0032]

[0033] Add diethylene glycol bis-p-toluenesulfonate (414mg, 1mmol), II-a (258mg, 1mmol), potassium carbonate (150mg, 1.2mmol) and DMF10mL in a 25mL three-necked flask, and react at 100°C under nitrogen protection After 2 hours, the reaction solution was poured into water, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and separated by medium chromatography to obtain 296 mg of a light yellow solid with a yield of 60%. 1 H NMR (400MHz, CDCl 3 )δ7.81(d, J=8.3Hz, 2H), 7.33(m, 4H), 6.92(d, J=7.2Hz, 1H), 5.17(m, 1H), 4.24(m, 2H), 4.16– 4.11(m,2H),4.03(t,J=5.7Hz,2H),3.69–3.64(m,2H),3.65(m,2H),3.03–2.75(m,2H),2.44(s,3H) ,2.23(m,2H).

[0034] (2) Add 2-1 (500mg, 1mmol), II-a (320mg, 1mmol), potassium carbonate (150mg, 1.2mmol) and DMF10mL to 25mL of three necks, ...

Embodiment 2

[0039] The specific preparation method is the same as in Example 1, and 3-(4-((2-(2-(2-((4-((4-fluoro-3-chlorophenyl) amino)-7-methoxyquin Azolin-6-yl)oxo)ethoxy)ethoxy)ethyl)amino)-1-oxoindolin-2-yl)piperidine-2,6-dione(1-2) , whose structure is as follows:

[0040]

[0041] 1 H NMR (400MHz, DMSO) δ9.62(s, 1H), 8.54(s, 1H), 8.13(dd, J=6.8, 2.6Hz, 1H), 7.81–7.73(m, 2H), 7.44(t, J=9.1Hz, 1H), 7.27–7.10(m, 2H), 6.97(d, J=7.1Hz, 1H), 6.74(d, J=7.4Hz, 1H), 5.15(m, 1H), 4.33– 4.17(m,3H),4.06(m,1H),3.94(s,3H),3.82(t,J=4.1Hz,2H),3.62(t,J=5.7,3.4Hz,2H),3.52-3.46 (m,8H),3.09–2.97(m,1H),2.84–2.75(m,1H),2.36–2.19(m,1H),2.03(m,1H).HRMS m / z: calcd for C 34 h 35 ClFN 6 o 7 [M+H] + 693.0414, found 693.0398.

Embodiment 3

[0043] The specific preparation method is the same as in Example 1, and 3-(4-((2-(2-(2-(2-((4-((4-fluoro-3-chlorophenyl) amino) amino)-7-methyl Oxyquinazolin-6-yl)oxo)ethoxy)ethoxy)ethoxy)ethyl)amino)-1-oxoindolin-2-yl)piperidine-2,6- Diketone (1-3), its structure is as follows:

[0044]

[0045] 1 H NMR (400MHz, DMSO) δ9.60(s, 1H), 8.52(s, 1H), 8.10(dd, J=6.8, 2.6Hz, 1H), 7.79–7.72(m, 2H), 7.41(t, J=9.1Hz, 1H), 7.24–7.06(m, 2H), 6.90(d, J=7.1Hz, 1H), 6.74(d, J=7.4Hz, 1H), 5.14(m, 1H), 4.30– 4.12(m,3H),4.01(m,1H),3.93(s,3H),3.79–3.70(m,4H),3.61(dd,J=5.7,3.4Hz,2H),3.50–3.42(m, 10H),3.07–2.93(m,1H),2.80–2.69(m,1H),2.34–2.17(m,1H),2.01(m,1H).HRMS m / z: calcd for C 36 h 39 ClFN 6 o 8 [M+H] + 737.0519, found 737.0522.

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Abstract

The invention discloses a compound based on CRBN ligand inducing EGFR degradation as shown in the following formula I or a pharmacologically acceptable salt and hydrate. The invention further discloses a preparation method of the compound and a pharmaceutical composition of the compound, and application of the compound and the pharmaceutical composition to preparation of drugs for prevention or / and treatment of a cancer. The compound can carry out ubiquitination labeling on the EGFR, protein degradation can be induced with only less dosage, the process is similar to a catalytic reaction, drugswith same molar weight do not need, and the toxic and side effect on a human body can be reduced; and the excellent EGFR protein degradation effect and anticancer activity can be further shown, the anticancer effect of the compound is better than that of an EGFR inhibitor, the compound can be used for preventing or / and treating a variety of cancers, and has a great application prospect in the field of healing drugs.

Description

technical field [0001] The present invention relates to the field of pharmaceutical compound synthesis, in particular to a compound based on CRBN ligand-induced EGFR degradation, its preparation method, pharmaceutical composition and application. Background technique [0002] Cereblon is a protein encoded by the human CRBN gene, and the CRBN homologs are highly conserved, suggesting its importance in physiology. Cereblon forms the E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDBl), Cullin-4A (CUL4A) and Cullin-1 regulator (ROCI), which can ubiquitinate a series of proteins, but the specific mechanism is not yet clear. clear. Cereblon ubiquitination of target proteins resulted in an increase in fibroblast growth factor 8 (FGFB) and fibroblast growth factor 10 (FGF10), indicating that the ubiquitinase complex is important for embryonic limb growth. [0003] Studies have shown that lenalidomide has multiple effects such as anti-tumor, immune regulation and ...

Claims

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Application Information

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IPC IPC(8): C07D401/14A61K31/517A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D401/14
Inventor 张智敏黄文海沈正荣郑晓亮王尊元梁美好马臻章迟啸曾申昕
Owner ZHEJIANG ACAD OF MEDICAL SCI
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