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Boric acid compound used as 20S proteasome inhibitor, and preparation method thereof

A proteasome inhibitor and proteasome technology, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve problems such as unclearness and inconvenience to patients

Inactive Publication Date: 2017-09-12
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical data show that bortezomib still has many side effects, such as diarrhea, vomiting, painful peripheral neuropathy and thrombocytopenia, etc.
To date, the mechanism of these toxic side effects is unclear, and in addition, clinical use of bortezomib requires a twice-weekly intravenous or subcutaneous dosing regimen, which brings great inconvenience to patients

Method used

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  • Boric acid compound used as 20S proteasome inhibitor, and preparation method thereof
  • Boric acid compound used as 20S proteasome inhibitor, and preparation method thereof
  • Boric acid compound used as 20S proteasome inhibitor, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 1: Preparation of dichloromethylenelithium (compound III-2)

[0090] LiCHCl 2

[0091] (III-2)

[0092] Under the condition of nitrogen protection, add anhydrous dichloromethane (4.6mL, 72mmol) to 200mL of anhydrous tetrahydrofuran, the temperature dropped to -110 ℃, dropwise added 1.6M n-butyllithium n-hexane solution (38mL, 60mmol ), after the dropwise addition, continued to stir at -110°C for 1 hour; the reaction solution was directly used in the next reaction without purification.

Embodiment 2

[0093] Embodiment 2: Preparation of dimethyl dichloromethylene borate (compound III-3)

[0094]

[0095] Under the condition of nitrogen protection, the temperature was continued to be controlled at -110°C, trimethyl borate (8mL, 72mmol) was added to the compound III-2 solution prepared in Example 1, and stirring was continued at -110°C for 1 hour, and then Add 12mL of 5N HCl solution, the reaction is slowly raised to room temperature, transfer the reaction solution into a separatory funnel, separate the organic phase, extract the aqueous phase with ether (3×10mL), combine the organic phases, add anhydrous sodium sulfate to dry, dry After the completion of the filtration, the solvent was removed by a rotary evaporator to obtain 8.7 g of a white solid with a yield of 92%. The reaction product was directly used in the next reaction without purification.

Embodiment 3

[0096] Embodiment 3: Preparation (+)-α-pinanediol (compound III-4-a)

[0097]

[0098] Under nitrogen protection, add Me to 100 mL tert-butanol 3 NO·2H 2 O (11g, 102mmol) in aqueous solution was added (+)-α-pinene (15mL, 97mmol), pyridine (7mL) and osmium tetroxide (51mg, 0.2mmol) successively under stirring, and then heated to reflux, and after 24 hours TLC detection shows that the reaction is complete, the reaction is down to room temperature, and NaHSO is added 3 (1.2g, 12mmol) was stirred for 1 hour, the reaction solution was transferred to a separatory funnel, the organic phase was separated, the aqueous phase was extracted with ether (3×20mL), the organic phases were combined, dried by adding anhydrous sodium sulfate, and after drying Filtrate, remove the solvent with a rotary evaporator, and separate by column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain 15 g of a white solid with a yield of 91%.

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Abstract

The invention relates to the fields of pharmaceutical chemistry and medicine therapeutics, concretely relates to new boric acid compounds, and a preparation method and a use thereof, and especially relates to a boric acid compound used as a 20S proteasome inhibitor, and a preparation method thereof. The invention also discloses a boric acid compound represented by formula I, and a preparation method thereof. A result of bioactive screening test shows that the compound prepared in the invention has a proteasome inhibition function, and can be further used for preparing medicines for treating proteasome correlated diseases.

Description

technical field [0001] The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics. It specifically relates to a new boric acid compound and its preparation method and application, especially a boric acid compound as a 20S proteasome inhibitor and its preparation method. Background technique [0002] Studies have reported that the Ubiquitin-Proteasome Pathway (UPP) is the main pathway for protein degradation in eukaryotic cells, which can regulate the level of proteins involved in cell cycle control and maintain the biological homeostasis of different cellular processes. Studies have shown that in most mammalian cells, this pathway can recognize and degrade misfolded proteins; a large number of experiments have proved that the pathogenesis of cancer, cardiovascular and cerebrovascular diseases, and neurodegenerative diseases are all related to the ubiquitin-proteasome pathway. connect. [0003] Studies have disclosed that in the ubiquitin-pr...

Claims

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Application Information

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IPC IPC(8): C07F5/02A61K31/69A61P35/00A61P25/28A61P9/00
CPCC07F5/025
Inventor 邵黎明许玉龙陈益宜李炜谢琼
Owner FUDAN UNIV
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