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Bifunctional molecule based on VHL ligand induced BET degradation as well as preparation and application thereof

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

Inactive Publication Date: 2017-05-31
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 molecule based on VHL ligand induced BET degradation as well as preparation and application thereof
  • Bifunctional molecule based on VHL ligand induced BET degradation as well as preparation and application thereof
  • Bifunctional molecule based on VHL ligand induced BET degradation as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Preparation of (2S, 4R)-(1-((2S)-2-(2-(2-(4-((6-(3,5-dimethylisoxazol-4-yl) -1-methyl-2-oxo-4-phenyl-1,4-dihydroquinazol-3(2H)-yl)methyl)-1H-1,2,3-triazole-1- Base) ethoxy) acetylamino) -3,3-dimethylbutyryl) -4-hydroxy-N-(4-(4-methylthiazol-5-yl) benzyl) -2-pyrrolidinyl Amide (I-1), its structural formula is as follows:

[0064]

[0065] Step 1) 2-Hydroxyethyl-4-methylbenzenesulfonate (1a)

[0066]

[0067] 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 o...

Embodiment 2

[0086] 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)methyl)-1H-1,2,3-triazole -1-yl)ethoxy)ethoxy)acetylamino)-3,3-dimethylbutyryl)-4-hydroxyl-N-(4-(4-methylthiazol-5-yl)benzyl )-2-pyrrolidinecarboxamide (I-2), its structural formula is as follows:

[0087]

[0088] Synthetic steps are with embodiment 1

[0089] MS (ESI, m / z): 995.15 [M+Na] +

Embodiment 3

[0090] 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)methyl)-1H-1,2,3- Triazol-1-yl)ethoxy)ethoxy)ethoxy)acetylamino)-3,3-dimethylbutyryl)-4-hydroxyl-N-(4-(4-methylthiazole -5-base) benzyl)-2-pyrrolidinecarboxamide (1-3), its structural formula is as follows:

[0091]

[0092] Synthetic steps are with embodiment 1

[0093] MS (ESI, m / z): 1039.15 [M+Na] +

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Abstract

The invention relates to a new bifunctional small molecule, a preparation method of pharmaceutically acceptable salt thereof, hydrate or prodrug and application of the compounds and medicinal compositions in treating diseases such as tumor, inflammation and immune diseases. The bifunctional small molecule provided by the invention is a protein degradation targeted combo (PROTACs) which can selectively induce BET protein degradation. According to the invention, a BET protein small molecular inhibitor is connected with a von Rippel-Lindau (VHL) protein ligand in E3 ubiquitin ligase complex by a connecting arm to obtain the bifunctional small 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. In the present invention, the bifunctional small molecule is obtained by connecting the BET protein small molecule inhibitor with the von Rippel-Lindau (VHL) protein ligand in the E3 ubiquitin ligase complex by using a connecting arm. Background technique [0002] E3 ubiquitin ligase promotes protein ubiquitination through substrate specificity, so E3 ubiquitin ligase has better therapeutic potential than proteasome inhibitors. However, the development of ligands for E3 ligases remains...

Claims

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Application Information

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IPC IPC(8): C07K5/062A61K38/05A61P35/00
CPCA61K38/00C07K5/06034
Inventor 张惠斌周金培赵雷磊李向阳杨一飞张剑武振威
Owner CHINA PHARM UNIV
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