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Compound to induce degradation of CDK4/6 (cyclin dependent kinase 4/6) based on CRBN (cereblon) ligand, preparation method of compound, pharmaceutical composition and application of compound

A compound and composition technology, applied in the field of compounds and their preparation based on CRBN ligand-induced degradation of CDK4/6, can solve problems such as side effects, and achieve the effects of reducing toxic side effects, good anti-tumor activity, and excellent anti-cancer effect

Pending Publication Date: 2019-10-08
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 CDK4 / 6 often requires the drug to be maintained at a high concentration for a long time, which may cause serious side effects

Method used

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  • Compound to induce degradation of CDK4/6 (cyclin dependent kinase 4/6) based on CRBN (cereblon) ligand, preparation method of compound, pharmaceutical composition and application of compound
  • Compound to induce degradation of CDK4/6 (cyclin dependent kinase 4/6) based on CRBN (cereblon) ligand, preparation method of compound, pharmaceutical composition and application of compound
  • Compound to induce degradation of CDK4/6 (cyclin dependent kinase 4/6) based on CRBN (cereblon) ligand, preparation method of compound, pharmaceutical composition and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] (1) Preparation of 2-(2-((2-(2,6-piperidinedione-3-yl)-1-oxoindoline-4-yl)amino)ethoxy)ethyl-4 -Toluenesulfonate (2-1):

[0033]

[0034] Add diethylene glycol bis-p-toluenesulfonate (414mg, 1mmol), lenalidomide (258mg, 1mmol), potassium carbonate (150mg, 1.2mmol) and DMF10mL in 25mL of three necks, and react at 100 degrees Celsius 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).

[0035] (2) Preparation of 3-(4-((2-(2-((4-((4-fluoro-3-chlorophenyl)amino)-7-methoxyquinazolin-6-yl)oxo )ethoxy)...

Embodiment 2

[0041] The specific preparation method is the same as in Example 1, preparing 3-(4-((2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7- Oxo-7,8-dihydropyridin[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethoxy)ethoxy)ethyl)amino )-1-oxoindoline-2-yl)piperidine-2,6-dione (1-2), its structure is as follows

[0042]

[0043] 1 H NMR(400MHz,DMSO)δ11.16(s,1H),10.42(s,1H),8.64(s,1H),7.23-7.30(m,3H),7.16(d,J=3.5Hz,1H) ,6.80(m,1H),6.76(m,1H),6.62(m,1H),4.53(t,J=9.1Hz,1H),4.21(s,2H),3.43-3.60(m,13H), 3.15(m,6H),2.53(t,2H),2.42(s,3H),2.37(s,3H),1.62-1.73(m,4H),1.84-1.91(m,8H).HRMS m / z :calcd.for C 43 h 53 N 10 o 7 [M+H]+821.0217,found821.0209.

Embodiment 3

[0045] The specific preparation method is the same as in Example 1, preparing 3-(4-((2-(2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl -7-oxo-7,8-dihydropyridin[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1 yl)ethoxy)ethoxy)ethoxy Base) ethyl) amino)-1-oxoindoline-2-yl)piperidine-2,6-dione (1-3), its structure is as follows:

[0046]

[0047] 1 H NMR (400MHz, DMSO)δ 1 H NMR(400MHz,DMSO)δ11.19(s,1H),10.32(s,1H),8.61(s,1H),7.24-7.31(m,3H),7.11(d,J=3.5Hz,1H) ,6.81(m,1H),6.75(m,1H),6.64(m,1H),4.50(t,J=9.1Hz,1H),4.22(s,2H),3.43-3.61(m,15H), 3.17(m,8H),2.52(t,2H),2.41(s,3H),2.38(s,3H),1.61-1.72(m,4H),1.85-1.90(m,8H).HRMS m / z :calcd.for C 45 h 57 N 10 o 8 [M+H]+865.0094, found 865.0099.

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Abstract

The invention discloses a compound to induce degradation of CDK4 / 6 (cyclin dependent kinase 4 / 6) based on CRBN (cereblon) ligand. A compound shown as formula I and a pharmaceutically acceptable salt and hydrate thereof are included herein. The invention also discloses a preparation method of the compound, a pharmaceutical composition of the compound, and application of the compound and the pharmaceutical composition in the preparation of drugs to prevent or / and treat cancers. Degradation of CDK4 / 6 can be induced just with a low quantity of the compound, and toxic and side effects upon the human body can be alleviated; excellent CDK4 / 6 degrading action and anticancer activity can be exhibited; the anticancer effect is better than that of a CDK4 / 6 inhibitor; the compound herein is suitable for preventing or / and treating various cancers and has a great application prospect in the field of medicine.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical compounds, in particular to a compound based on CRBN ligand-induced degradation of CDK4 / 6 and 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D471/04
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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