Borate compound and pharmaceutically acceptable salt thereof, and preparation method and application of boric acid ester compound and pharmaceutically acceptable salt thereof

A technology of boric acid esters and compounds, applied in the field of drug synthesis, can solve problems such as toxic and side effects, and achieve good stability

Pending Publication Date: 2021-07-13
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the anticancer drugs currently on the market have certain curative

Method used

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  • Borate compound and pharmaceutically acceptable salt thereof, and preparation method and application of boric acid ester compound and pharmaceutically acceptable salt thereof
  • Borate compound and pharmaceutically acceptable salt thereof, and preparation method and application of boric acid ester compound and pharmaceutically acceptable salt thereof
  • Borate compound and pharmaceutically acceptable salt thereof, and preparation method and application of boric acid ester compound and pharmaceutically acceptable salt thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: The preparation of the compound of the present invention can be implemented according to the following process:

[0054] Preparation of compound (II)

[0055]

[0056] 1. Preparation of compound (II-3):

[0057] Dissolve compound (II-1), HOBt in anhydrous DCM (dichloromethane) and stir at -5°C for 10 min, then add EDCI·HCl at this temperature, stir for 15-20 min, then add compound (II-2) Stir for 15-20 minutes, then add DIPEA and stir for 20 minutes, then move to room temperature for reaction. After the reaction is complete, pour it into water, and use dilute HCl, NaHCO 3 The solution was washed, the combined organic phases were washed with saturated brine, extracted with DCM, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain compound (II-3).

[0058] 2. Preparation of compound (II-4):

[0059] Compound (II-3) was dissolved in anhydrous DCM, TFA was slowly added dropwise at -5°C, stirred for 0.5 hours, then raised to room temp...

Embodiment 2

[0118] Example 2: Determination of inhibition of proteasome activity

[0119] 1. Proteasome inhibitory activity

[0120] The present invention utilizes fluorescent polypeptide substrate Suc-Leu-Leu-Val-Tyr-AMC (abbreviation Suc-LLVY-AMC, Suc represents succinyl, AMC represents 7-amide-4-methylcoumarin) to measure proteasome Chymotrypsin-like enzyme activity.

[0121] The proteasome used in the present invention is human erythrocyte 20S proteasome, and the enzyme, fluorescent substrate and test buffer are all purchased from Enzo Company. The experimental system was 16 μL, including 8 μL of substrate, 4 μL (0.8 ng) of proteasome, the final concentration was 50 μM, and 4 μL of drug (inhibitor), the final concentration was 2×10 -6 M~4.88×10 -10 M, the last concentration is 0M, the actual configuration concentration is 8×10 -6 M~1.95×10 -9 M, the last concentration is 0M. The specific experimental process is as follows:

[0122] 1. Drug configuration: weigh the drug, add DMS...

Embodiment 3

[0135] Embodiment 3: compound stability test

[0136] 1. Stability of compounds in simulated gastric juice, intestinal juice and pH6.8 phosphate buffer

[0137] In the experiment, LC-MS was used to detect the peptide boronic acid fragments obtained by decomposition at different time points in different pH solutions, and the content of the fragments corresponded to the decomposition amount of the parent compound.

[0138] 1. Each pH buffer solution configuration: pH1.2: add 8-9ml (8.33ml) concentrated hydrochloric acid to dilute to 1000ml with water; pH4.5: take 7.7g of ammonium acetate, add 50ml of water to dissolve, add 6ml of glacial acetic acid, and then dilute to volume to 100ml; pH6.8: Take 250ml of 0.2mol / L potassium dihydrogen phosphate solution, add 118ml of 0.2mol / L sodium hydroxide solution, dilute to 1000ml with water, and shake well.

[0139] 2. Compound preparation: The compound was prepared with different pH buffer solutions to a concentration of 1 mg / ml, and pl...

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PUM

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Abstract

The invention relates to a borate compound as shown in a formula (1), a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The borate compound is novel in structure and has a proteasome inhibition function. The stability of the borate compound disclosed by the invention in a solution is far higher than that of Ixazomib. Especially when the pH is 1.2 and the pH is 6.8, the stability of the compound provided by the invention is more advantageous. Besides, microsome stability results show that the compound has good stability in five different liver microsomes, the half-life period of the microsomes of Ixazomib in cynomolgus monkeys is too long, the medicine is basically not metabolized, and serious toxicity can be caused. The compound can be used for preparing medicines for treating inflammation, immune-related diseases, cancers or hyperproliferative diseases and changing antigen peptides generated by proteasomes in organisms.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a boric acid ester compound and a pharmaceutically acceptable salt thereof, a preparation method and an application thereof. Background technique [0002] At present, malignant tumors are still one of the major diseases that threaten people's lives. Although the treatment of cancer has made great progress, it has not been able to treat cancer fundamentally. Although the currently marketed anticancer drugs have certain curative effects, most of them are cytotoxic drugs with serious toxic and side effects. Therefore, how to start from effective tumor targets to study targeted new anticancer drugs has become a top priority for medical workers. [0003] The Ubiquitin-Proteasome Pathway (UPP) can regulate the level of proteins involved in cell cycle control. This pathway has an important relationship with the pathogenesis of cancer, cardiovascular and cerebrovascular diseas...

Claims

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Application Information

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IPC IPC(8): C07F5/02A61K31/69A61P35/00
CPCC07F5/02A61P35/00Y02P20/55
Inventor 朱永强雷萌张文
Owner NANJING NORMAL UNIVERSITY
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