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Preparation and application of deubiquitinating enzyme inhibitor

A technology of compounds and nitrogen oxides, applied in anti-inflammatory agents, digestive system, organic chemistry, etc., can solve problems such as tumor cell death, excessive degradation of target proteins, and hindrance to deubiquitination of target proteins

Inactive Publication Date: 2021-06-04
刘丽萍
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The USP28 protease inhibitor inhibits the deubiquitination activity of USP28 protease, prevents the deubiquitination of the ubiquitination-labeled target protein, causes excessive degradation of the target protein, and finally causes tumor cell death

Method used

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  • Preparation and application of deubiquitinating enzyme inhibitor
  • Preparation and application of deubiquitinating enzyme inhibitor
  • Preparation and application of deubiquitinating enzyme inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Synthesis of intermediate tert-butyl 2-acetylthioacetate

[0085] Potassium thioacetate (239.84g, 2.1mol) and anhydrous DMF (500mL) were added to the reaction flask (1L), cooled to 0–5°C, and tert-butyl bromoacetate (390.10g, 2.0mol ), the reaction was continued for 1 h after the dropwise addition at room temperature. The solvent was distilled off from the reaction solution under reduced pressure at 80°C. After cooling, water (500 mL) was added to separate the organic layer. The aqueous layer was extracted with chloroform (150 mL×2), and the combined organic layers were washed with saturated NaCl solution (200 mL×3). Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to obtain tert-butyl 2-acetylthioacetate (380.5 g of red liquid, yield 100%).

[0086]

[0087] R f = 0.53 (PE / EtOAc = 9:1); 1 H NMR (600MHz, CDCl 3 )δ3.61(s,2H),2.37(s,3H),1.45(s,9H).

Embodiment 2

[0089] Synthesis of intermediate A1-2 with X=Y=CH, R 1 = Me as an example.

[0090]

[0091] Add 2-chloro-3-cyano-6-picoline (50.35 g, 0.330 mol), tert-butyl 2-acetylthioacetate (69.06 g, 0.363 mol) and DMF (330 mL) into a reaction flask (500 mL) ), cooled to 0–5°C, added NaOMe (21.39g, 0.396mol) in batches, and reacted at room temperature for 1h. The reaction solution was poured into water (3L), and a large amount of yellow solids precipitated out. Suction filtration, washing with water until neutral, and drying gave tert-butyl 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylate ( Yellow solid 75.51g, yield 87%).

[0092]

[0093] R f = 0.36 (PE / Acetone = 17:3); ESI-MS: 265.0 [M+H] + ; 1 H NMR (600MHz, CDCl 3 )δ7.77(d, J=8.3Hz,

[0094] 1H), 7.13(d, J=8.3Hz, 1H), 5.79(s, 2H), 2.66(s, 3H), 1.59(s, 9H).

Embodiment 3

[0096] Synthesis of Carboxylic Acid A1 with X=Y=CH,R 1 = Me as an example.

[0097] Add 3-amino-6-methylthieno[2,3-b]pyridine-2-carboxylic acid tert-butyl ester (75.34g, 0.285mol), NaHCO 3 (47.89g, 0.570mol) and DCM (285mL), trifluoroacetic anhydride (71.83g, 0.342mol) was added dropwise under stirring at room temperature, and the reaction was continued for 0.5h at room temperature after the dropwise addition was completed. The reaction solution was added dropwise with water (200mL), stirred until no gas was produced, the DCM layer was separated, the aqueous phase was extracted with DCM (200mL×2), the organic phases were combined, washed with saturated NaCl solution (200mL×2), and washed with anhydrous NaCl 2 SO 4 Drying, concentration under reduced pressure, multiple recrystallizations from MeOH gave tert-butyl 3-trifluoroacetylamino-6-methylthieno[2,3-b]pyridine-2-carboxylate (light yellow solid 93.26g, yield 91%).

[0098]

[0099] R f = 0.57 (PE / EtOAc = 17:3); ESI-...

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Abstract

The invention aims to provide a compound with single / double inhibitory activity on USP25 and USP28 proteases. The invention provides a compound shown as a formula I and a racemate, a stereoisomer, an isotope label, nitrogen oxide, a solvate, a polymorphic substance, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound.

Description

technical field [0001] The invention relates to the field of medicine, in particular, the invention relates to a preparation method and application of a class of deubiquitinase inhibitors. Background technique [0002] Since the proteasome inhibitors bortezomib and carfilzomib were approved by the US FDA for the treatment of multiple myeloma in 2003 and 2012, respectively, the ubiquitin-protease system has become a popular anticancer drug target. Ubiquitin-proteasome pathway (ubiquitin proteasome pathway, UPP) mediates the selective degradation of cellular proteins. It marks ubiquitin on target proteins through ubiquitination, and the marked target proteins are recognized and degraded by 26S proteasomes. Ubiquitination is a reversible process through the joint regulation of ubiquitinases and deubiquitinases. Deubiquitination is the process of hydrolyzing the ubiquitin that has been marked on the target protein, and deubiquitination enzyme is the key molecule that catalyzes ...

Claims

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Application Information

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IPC IPC(8): C07D495/04C07D519/00A61P37/06A61P17/06A61P17/00A61P1/04A61P19/02A61P29/00A61P13/12A61P5/14A61P3/10A61P1/16A61P9/00A61P25/00A61P21/04A61P15/00A61P27/02A61P7/00A61P35/00A61P31/12A61P31/04A61K31/4995A61K31/4545A61K31/46A61K31/496A61K31/506A61K31/5386
CPCA61P1/04A61P1/16A61P3/10A61P5/14A61P7/00A61P9/00A61P13/12A61P15/00A61P17/00A61P17/06A61P19/02A61P21/04A61P25/00A61P27/02A61P29/00A61P31/04A61P31/12A61P35/00A61P37/06C07D495/04C07D519/00
Inventor 刘丽萍
Owner 刘丽萍
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