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Bifunctional molecules for induction of BET degradation based on VHL ligand and BET inhibitor, preparation and application thereof

A technology of -CH3 and CHF2, applied in the field of bifunctional molecules based on VHL ligand and BET inhibitors to induce BET degradation and its preparation and application, can solve the problems of thrombocytopenia, unsatisfactory anti-tumor effect of drugs, and toxic and side effects

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

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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  • Bifunctional molecules for induction of BET degradation based on VHL ligand and BET inhibitor, preparation and application thereof
  • Bifunctional molecules for induction of BET degradation based on VHL ligand and BET inhibitor, preparation and application thereof
  • Bifunctional molecules for induction of BET degradation based on VHL ligand and BET inhibitor, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0081] Example 1: (2S, 4R)-1-((2S)2-(2-(2-(2-(6-(3,5-lutidine-4-yl)-1-methyl- 2-oxo-4-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetamido)ethoxy)acetamido)-3,3-dimethylbutyryl)-4 -Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Ia-1), its structural formula is as follows:

[0082]

[0083] Step 1) 2-Hydroxyethyl-4-methylbenzenesulfonate (1a)

[0084]

[0085] 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%.

[0086] 1 H NMR (300MHz, CDCl 3 )δ7.8...

Embodiment 2

[0108] Example 2: Preparation of (2S, 4R)-(1-((2S)-2-(2-(2-(2-(4-((6-(3,5-dimethylisoxazole-4 -yl)-1-methyl-2-oxo-4-phenyl-1,4-dihydroquinazol-3(2H)-yl)acetamido)ethoxy)ethoxy)acetamido)- 3,3-dimethylbutyryl)-4-hydroxyl-N-(4-(4-methylthiazol-5-yl)benzyl)-2-pyrrolidinecarboxamide (Ia-2), its structural formula is as follows :

[0109]

[0110] Synthetic steps are with embodiment 1

[0111] MS (ESI, m / z): 947.10 [M-H] -

Embodiment 3

[0112] Example 3: Preparation of (2S, 4R)-(1-((2S)-2-(2-(2-(2-(2-(4-((6-(3,5-dimethylisoxan Azol-4-yl)-1-methyl-2-oxo-4-phenyl-1,4-dihydroquinazol-3(2H)-yl)acetamido)ethoxy)ethoxy)ethyl Oxy)acetylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-2-pyrrolidinecarboxamide (Ia -3), its structural formula is as follows:

[0113]

[0114] Synthetic steps are with embodiment 1

[0115] MS (ESI, m / z): 991.10 [M-H] -

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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 pharmaceutically 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 (Bromo-and Extra-terminal) protein degradation. According to the invention, a carbon chain or polyethylene glycol chain truss arm is utilized to connect the 3, 5-dimethyl isoxazole BET protein small molecule inhibitor with the von Hippel-Lindau (VHL) protein ligand in an E3 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 present invention coordinates 3,5-dimethylisoxazole BET protein small molecule inhibitors with von Rippel-Lindau (VHL) protein in E3 ubiquitin ligase complex by using carbon chain or polyethylene glycol chain linking arm body linking to obtain bifunctional small molecules. Background technique [0002] The present invention relates to a bifunctional compound (PROTAC), which has functions of ubiquitination and degradation for corresponding target protein (such as BRD protein) and po...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K38/05A61P35/00A61P35/02
CPCC07K5/06034A61K38/00
Inventor 周金培王丽蕊李向阳高颖生武振威杨一飞张剑
Owner CHINA PHARM UNIV
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