A class of ocotillol-type esterified derivatives and its preparation method and use for making anti-inflammatory drugs

A technology of derivatives and esterification, which is applied in the preparation and application of new compounds, can solve the problems of affecting the safety of drugs, shortening the half-life of compounds, and deteriorating stability, so as to achieve good cell non-toxicity, good anti-inflammatory activity, The effect of good security

Active Publication Date: 2022-05-13
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ocotillol-type sapogenin derivatives have tumor drug resistance reversing activity (patent application publication number CN109021058A), and a certain type of derivative has been found to have an inhibitory effect on pro-inflammatory factors (patent application publication number CN110642913A1), but the hydroxyl group in the synthesized compound is more easily oxidized Metabolism, which will lead to shortened half-life and poor stability of the compound
At the same time, there is currently no research on the toxic and side effects of this type of compound on normal cells and physiological tissues, and the toxicity of the active substance affects the safety of the drug.

Method used

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  • A class of ocotillol-type esterified derivatives and its preparation method and use for making anti-inflammatory drugs
  • A class of ocotillol-type esterified derivatives and its preparation method and use for making anti-inflammatory drugs
  • A class of ocotillol-type esterified derivatives and its preparation method and use for making anti-inflammatory drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: (20S,24R)-epoxy-25-hydroxy-3-ketone-dammarane-12-one

[0083] 20S-protopanaxadiol (1.000 g, 2.17 mmol) was dissolved in dichloromethane (21.7 mL), m-CPBA (549 mg, 3.18 mmol) was added, and stirred at room temperature for 3 h. Diluted with chloroform and washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography gave white solid compound 1 [(20S,24R)-epoxydammarin-3β,12β,25-triol] (530mg, 1.11mmol, yield 53%) and white solid compound 2 [(20S,24S)-epoxydammarin-3β,12β,25-triol] (419mg, 0.88mmol, yield 41%).

[0084] The above compound 1 (20S,24R)-epoxydammarane-3β,12β,25-triol (727mg, 1.52mmol), sodium bicarbonate (769mg, 9.15mmol) was dissolved in anhydrous dichloromethane (15mL) , add DMP (1617mg, 3.81mmol), add 2mL tert-butanol to accelerate the dissolution of DMP, react for 1 hour, remove the ice bath and react at room temperature. After reacting for 4 hours, add saturated sodium...

Embodiment 2

[0086] Example 2: (20S,24S)-epoxy-25-hydroxy-dammarane-3,12-dione

[0087]

[0088] The above compound 2(20S,24S)-epoxydama-3β,12β,25-triol (605mg, 1.27mmol), sodium bicarbonate (639mg, 7.61mmol) was dissolved in anhydrous dichloromethane (13mL) , DMP (1345 mg, 3.17 mmol) was added, and 2 mL of tert-butanol was added to accelerate the dissolution of DMP. After 1 hour of reaction, the ice bath was removed for reaction at room temperature. After reacting for 4 hours, add saturated sodium bicarbonate and sodium sulfite aqueous solution to the reaction system to adjust the pH and stir for half an hour, extract with ethyl acetate, and the organic phase is washed with saturated sodium bicarbonate aqueous solution and saturated brine respectively, and then merged into the Erlenmeyer flask , dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (petroleum ether: ethyl acetate = 3:1 → 1:1) was eluted to obtain compound 4 (20S, 24S)-epoxy-25-hydroxyl-...

Embodiment 3

[0089] Example 3: (20S,24R)-epoxy-25-hydroxy-3β-hydroxy-dammarane-12-one

[0090]

[0091] Compound 3 (214mg, 0.45mmol), sodium borohydride (34mg, 0.91mmol) was dissolved in isopropanol (6.5mL), stirred at room temperature for 24h. The reaction was quenched with water, extracted with dichloromethane, and the organic phase was washed with anhydrous sulfuric acid Sodium-dried, filtered, concentrated, and obtained compound 5 (20S, 24R)-epoxy-25-hydroxyl-3β-hydroxyl-dammarane-12-one (180mg, 0.38mmol, yield 83.7%) by column chromatography

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PUM

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Abstract

The present invention provides a class of Ocotillol-type esterified derivatives represented by formula (I-R) or formula (I-S) and Ocotillol-type esterified derivatives represented by formula (II-R) or formula (II-S) , the compound represented by formula (II-R) or formula (II-S) is obtained by deprotecting the compound represented by formula (I-R) or formula (I-S). The present invention also provides the compound represented by the formula (I-R), the formula (I-S), the formula (II-R) or the formula (II-S) and the preparation method of the pharmaceutically acceptable salt thereof and the same. Application in the preparation of anti-inflammatory drugs or anti-inflammatory drug compositions. The Ocotilol-type esterified derivative provided by the present invention is significantly better than the existing clinical drug hydrocortisone sodium succinate in inhibiting the production of the inflammatory signal molecule NO. Moreover, it has high bio-friendliness, good drug safety, and at the same time shows a longer half-life in the evaluation of in vitro metabolic stability, which can improve the safety and stability of the finished drug.

Description

technical field [0001] The invention relates to a class of Ocotillol-type esterified derivatives, a preparation method thereof and an application for preparing anti-inflammatory drugs, and belongs to the technical field of preparation and application of new compounds. Background technique: [0002] Inflammation is an important and common physiological effect, which is considered to be a tissue protective immune response against harmful stimuli (such as damaged cells, irritants and bacteria), which regulates the inflammatory process by initiating, maintaining and shutting down signals. However, unbalanced inflammation may induce cell and tissue damage in different diseases, such as atherosclerosis, hypertension, diabetes, cancer and neurodegenerative diseases, seriously threatening people's health. [0003] Nitric oxide (NO) is an important pro-inflammatory mediator. NO activates COX-2, stimulates the production of inflammatory prostaglandins, and promotes acute inflammatory ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J17/00A61K31/58A61P29/00A61P11/00
CPCC07J17/00A61P29/00A61P11/00
Inventor 杨刚强章琛高萌高洪艳邹宗吉原震
Owner YANTAI UNIV
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