Cereblon ligand-induced BET degradation-based bifunctional molecule and preparation and application thereof

A small molecule ligand and reaction technology, applied in organic chemistry, drug combination, anti-tumor drugs, etc., can solve problems such as thrombocytopenia, toxic side effects, and unsatisfactory anti-tumor effects of drugs

Inactive Publication Date: 2017-08-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Phase I clinical results of OTX-015 show that when the dose is higher than 80mg per day, patients will experience severe side effects: thrombocytopenia, and when the dose is lower, the anti-tumor effect of the drug is not satisfactory

Method used

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  • Cereblon ligand-induced BET degradation-based bifunctional molecule and preparation and application thereof
  • Cereblon ligand-induced BET degradation-based bifunctional molecule and preparation and application thereof
  • Cereblon ligand-induced BET degradation-based bifunctional molecule and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Example 1: Preparation of 2-(2-(4-((6-(3,5-dimethylisoxazol-4-yl)-1-methyl-2-oxo-4-phenyl-1 , 4-dihydroquinazolin-3(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)-N-(2-(2,6 -Dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (I-1), its structural formula is as follows:

[0068]

[0069] Step 1) 2-Hydroxyethyl-4-methylbenzenesulfonate (1a)

[0070]

[0071] Dissolve ethylene glycol (3.91g, 62.95mmol) in 5mL of pyridine, add p-toluenesulfonyl chloride (6g, 31.47mmol) in batches, stir at room temperature for 4 hours, add 6mol / L hydrochloric acid (40mL), wash with ethyl acetate Extract, wash with saturated brine, collect the organic layer, dry over anhydrous sodium sulfate, evaporate the organic solvent under reduced pressure, and purify the residue by silica gel column chromatography using petroleum ether / ethyl acetate (V / V=20 / 1-10 / 1) was eluted to obtain a colorless liquid weighing 2 g with a yield of 29.39%.

[0072] 1 H NMR (300MHz, CDCl 3 )δ7.81(d, J=8....

Embodiment 2

[0094] Example 2: Preparation of 2-(2-(2-(4-((6-(3,5-dimethylisoxazol-4-yl)-1-methyl-2-oxo-4-benzene Base-1,4-dihydroquinazolin-3(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)-N- (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (I-2), its structural formula is as follows:

[0095]

[0096] Synthetic steps are with embodiment 1

[0097] MS (ESI, m / z): 838.05 [M+Na] +

[0098] 1 H NMR (300MHz, CDCl 3 )δ10.44(d, J=5.9Hz, 1H), 9.20(s, 1H), 8.85(d, J=8.2Hz, 1H), 7.77-7.66(m, 2H), 7.57(d, J=7.3 Hz, 1H), 7.39-7.27(m, 5H), 7.07(d, J=8.4Hz, 1H), 6.90(d, J=8.7Hz, 2H), 5.79(d, J=11.5Hz, 1H), 5.10(s, 1H), 4.98(s, 1H), 4.50(s, 2H), 4.19-3.84(m, 6H), 3.75(s, 4H), 3.41(s, 3H), 2.86(d, J= 13.4Hz, 4H), 2.20 (d, J = 41.5Hz, 9H).

Embodiment 3

[0099] Example 3: Preparation of 2-(2-(2-(2-(4-((6-(3,5-dimethylisoxazol-4-yl)-1-methyl-2-oxo- 4-phenyl-dihydroquinazolin-3(2H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethoxy) -N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide (I-3), its structural formula is as follows:

[0100]

[0101] Synthetic steps are with embodiment 1

[0102] MS (ESI, m / z): 782.30 [M+Na] +

[0103] 1 H NMR (300MHz, CDCl 3 )δ10.47(s, 1H), 9.08(s, 1H), 8.86(d, J=8.3Hz, 1H), 8.08-7.53(m, 3H), 7.31(d, J=16.6Hz, 5H), 7.09(d, J=7.7Hz, 1H), 6.93(d, J=8.4Hz, 2H), 5.84(s, 1H), 4.98(s, 1H), 4.51(s, 2H), 4.20(s, 2H ), 3.84-3.34 (m, 14H), 2.82 (s, 4H), 2.29 (s, 3H), 2.15 (s, 4H).

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Abstract

The invention relates to a novel preparation method of a bifunctional molecule and a pharmaceutically acceptable salt, hydrate or prodrug thereof and application of these compounds and a medicinal composition thereof in treatment of diseases such as tumors, inflammation and immunity. The bifunctional molecule is a protein degradation-targeted complex (PROTACs), and is capable of selectively inducing BET protein degradation. A BET protein small-molecule inhibitor is connected with a cereblon protein ligand in an E3 ubiquitin ligase complex to obtain the bifunctional molecule.

Description

technical field [0001] The present invention relates to the preparation method of new bifunctional small molecules and their pharmaceutically acceptable salts, hydrates or prodrugs and the application of these compounds and their pharmaceutical compositions in treating diseases such as tumors, inflammation and immunity. The bifunctional small molecules involved in the present invention are protein degradation targeting complexes (PROTACs), which can selectively induce BET protein degradation. The invention obtains the bifunctional small molecule by connecting the BET protein small molecule inhibitor with the cereblon protein ligand in the E3 ubiquitin ligase complex by using a connecting arm. 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 an E3 ubiquitin ligase complex with damage DNA binding protein 1 (DDB1), Cullin-4A (CUL4A) and Cullin-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/517A61P35/00A61P35/02
CPCC07D413/14
Inventor 张惠斌周金培赵雷磊武振威杨一飞张剑李向阳
Owner CHINA PHARM UNIV
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