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Boric acid compounds, and preparation method and use thereof

A compound and boronic acid technology, applied in the field of medicinal chemistry and pharmacotherapeutics, can solve the problems of inconvenience, unclearness, and multiple side effects of 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

The successful development of bortezomib proved that proteasome inhibition is an effective therapeutic strategy; however, clinical data show that bortezomib has more toxic side effects, such as diarrhea, vomiting, painful peripheral neuropathy, and thrombocytopenia disease
To date, the mechanisms underlying these toxic side effects are unclear; moreover, clinical use of bortezomib requires a twice-weekly intravenous or subcutaneous dosing regimen, which poses significant inconvenience to patients

Method used

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  • Boric acid compounds, and preparation method and use thereof
  • Boric acid compounds, and preparation method and use thereof
  • Boric acid compounds, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1: Preparation of lithium dichloromethylene (compound III-2)

[0158] LiCHCl 2

[0159] (III-2)

[0160] Under nitrogen protection, add anhydrous dichloromethane (4.6mL, 72mmol) to 200mL of anhydrous tetrahydrofuran, the temperature is reduced to -110℃, dropwise add 1.6M n-butyl lithium n-hexane solution (38mL, 60mmol) ), after the addition is complete, continue to stir at -110°C for 1 hour; the reaction solution is directly used in the next step without purification.

Embodiment 2

[0161] Example 2: Preparation of dimethyl dichloromethylene borate (compound III-3)

[0162]

[0163] Under nitrogen protection, the temperature was continuously 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, then Add 12 mL of 5N HCl solution, the reaction slowly rises to room temperature, the reaction solution is transferred to a separatory funnel, the organic phase is separated, the aqueous phase is extracted with ether (3×10 mL), the organic phases are combined, and dried by adding anhydrous sodium sulfate. After drying, it was filtered, and the solvent was removed by a rotary evaporator to obtain 8.7 g of white solid, with a yield of 92%. The reaction product was directly used in the next step without purification.

Embodiment 3

[0164] Example 3: Preparation of (+)-α-Pinanediol (Compound III-4-a)

[0165]

[0166] Under nitrogen protection, add Me to 100mL tert-butanol 3 NO·2H 2 O (11g, 102mmol) aqueous solution, add (+)-α-pinene (15mL, 97mmol), pyridine (7mL) and osmium tetroxide (51mg, 0.2mmol) under stirring, then heat to reflux, after 24 hours TLC detection showed that the reaction was complete, the reaction was cooled to room temperature, and NaHSO was added 3 (1.2g, 12mmol) stirred for 1 hour, transfer the reaction solution to a separatory funnel, separate the organic phase, extract the aqueous phase with ether (3×20mL), combine the organic phases, add anhydrous sodium sulfate to dry, after drying is complete After filtration, the solvent was removed by a rotary evaporator, and the column chromatography was separated (petroleum ether: ethyl acetate = 30:1) to obtain 15 g of a white solid with a yield of 91%.

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PUM

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Abstract

The invention relates to the fields of pharmaceutical chemistry and medicine therapeutics, concretely relates to a new boric acid compounds, and a preparation method and a use thereof, and especially relates to new substituted five-membered heterocyclic boric acid and substituted benzo five-membered boric acid compounds, and a preparation method thereof. A result of bioactive screening test of the substituted five-membered heterocyclic boric acid and substituted benzo five-membered boric acid compounds having a structure represented by a formula shown in the description shows that the compounds have a proteasome inhibition effect, and can be further used for preparing medicines for treating proteasome correlated diseases.

Description

Technical field [0001] The invention relates to the fields of medicinal chemistry and pharmacotherapy. Specifically, it relates to new boronic acid compounds and their preparation methods and uses, in particular to new substituted five-membered heterocyclic boronic acids and substituted benzo five-membered heterocyclic boronic acids, preparation methods thereof, and preparation of drugs for treating diseases related to the proteasome In the application. Background technique [0002] The prior art discloses that the Ubiquitin-Proteasome Pathway (UPP) is the main pathway of 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; and experiments have shown that the pathogenesis of cancer, cardiovascular and cerebrovascular diseases, and neurodegene...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61P43/00
CPCC07F5/025C07B2200/07
Inventor 邵黎明许玉龙陈益宜李炜谢琼
Owner FUDAN UNIV
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