Cereblon ligand mediated novel BET protein degradation bifunctional molecules, preparation and application thereof

A dual-function, protein technology, applied in the direction of medical preparations containing active ingredients, pharmaceutical formulations, organic active ingredients, etc.

Inactive Publication Date: 2018-02-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although no BET inhibitor has been successfully marketed yet, a total of 16 candidate drugs are in phase I / II clinical research, and the main indication is malignant tumors

Method used

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  • Cereblon ligand mediated novel BET protein degradation bifunctional molecules, preparation and application thereof
  • Cereblon ligand mediated novel BET protein degradation bifunctional molecules, preparation and application thereof
  • Cereblon ligand mediated novel BET protein degradation bifunctional molecules, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095]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-oxoisoindoline-4-yl)acetamide; (I-1), its structural formula is as follows:

[0096]

[0097] Step 1) 2-Hydroxyethyl-4-methylbenzenesulfonate (1a)

[0098]

[0099] Dissolve ethylene glycol (4.00g, 64.05mmol) in 5mL of pyridine, add p-toluenesulfonyl chloride (6.14g, 32.22mmol) in batches, stir at room temperature for 4 hours, add 6mol / L hydrochloric acid (40mL), and wash with ethyl acetate Esters were extracted, washed with saturated brine, the organic layer was collected, dried over anhydrous sodium sulfate, the organic solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, using petroleum ether / ethyl acetate (V / V=20 / 1- 10 / 1) was eluted to obtain a colorless liquid weighing 2.34 g with a yield of 33.58%.

[0100...

Embodiment 2

[0122] 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-oxoisoindoline-4-yl)acetamide (I-2), its structural formula is as follows:

[0123]

[0124] Synthetic steps are with embodiment 1

[0125] MS (ESI, m / z): 800.00 [M-H]-

[0126] 1 H NMR (300MHz, CDCl3) δ9.18(d, J=78.9Hz, 1H), 8.63(d, J=14.2Hz, 1H), 7.81(dd, J=13.0, 7.8Hz, 2H), 7.69(d , J=7.5Hz, 1H), 7.45(dd, J=13.2, 7.5Hz, 1H), 7.30(dd, J=13.1, 5.4Hz, 5H), 7.06(d, J=8.5Hz, 1H), 6.88 (dd, J=8.2, 4.1Hz, 2H), 5.75(d, J=10.6Hz, 1H), 5.22(d, J=9.3Hz, 1H), 5.13-4.99(m, 1H), 4.51-4.30( m, 4H), 4.07(dt, J=15.2, 8.7Hz, 3H), 3.87(s, 2H), 3.76-3.56(m, 4H), 3.38(d, J=2.0Hz, 3H), 2.82(dd , J=11.9, 4.6Hz, 2H), 2.30(t, J=17.4Hz, 4H), 2.15(t, J=12.0Hz, 4H), 1.96(s, 1H).

Embodiment 3

[0127] 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-oxoisoindoline-4-yl)acetamide (I-3), its structural formula is as follows:

[0128]

[0129] Synthetic steps are with embodiment 1

[0130] MS (ESI, m / z): 844.05 [M-H]-

[0131] 1 H NMR (300MHz, CDCl3) δ9.17(d, J=49.8Hz, 2H), 7.75(d, J=7.0Hz, 1H), 7.63(s, 1H), 7.39(dd, J=55.8, 14.0Hz , 6H), 7.08(d, J=7.9Hz, 1H), 6.90(s, 2H), 5.82(s, 1H), 5.23(s, 1H), 4.51-4.12(m, 6H), 3.60(dd, J=62.3, 41.9Hz, 14H), 2.87(s, 2H), 2.25(t, J=34.5Hz, 9H), 1.81(s, 2H).

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Abstract

The invention relates to a preparation method of new bifunctional small molecules and pharmaceutically acceptable salts, hydrates or prodrugs thereof, and application of the compounds and pharmaceutical compositions thereof in treatment of tumors, inflammation, immunity and other diseases. The bifunctional small molecules involved in the invention are protein degradation targeting chimeras (PROTACs), and can selectively induce BET protein degradation. According to the invention, a connecting arm is employed to connect a BET protein small molecule inhibitor and a cereblon protein ligand in theE3 ubiquitin ligase complex so as to obtain the bifunctional small molecules.

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] The ubiquitination of the target protein generally requires the joint action of three enzymes, first the E1 activating enzyme to activate the ubiquitin molecule, then the E2 conjugating enzyme to "hold" the activated ubiquitin molecule, and finally the E3 b...

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 张惠斌王丽蕊武振威高颖生李向阳杨一飞张剑
Owner CHINA PHARM UNIV
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