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Ocotillol type esterified derivatives, preparation method thereof and application of Ocotillol type esterified derivatives in preparation of anti-inflammatory drugs

A derivative and esterification technology, which is applied in the preparation and application of new compounds, can solve the problems of shortened half-life of compounds, poor stability, and impact on drug safety.

Active Publication Date: 2020-09-11
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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  • Ocotillol type esterified derivatives, preparation method thereof and application of Ocotillol type esterified derivatives in preparation of anti-inflammatory drugs
  • Ocotillol type esterified derivatives, preparation method thereof and application of Ocotillol type esterified derivatives in preparation of anti-inflammatory drugs
  • Ocotillol type esterified derivatives, preparation method thereof and application of Ocotillol type esterified derivatives in preparation of 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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Abstract

The invention provides Ocotillol type esterification 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 compounds represented by the formula (II-R) or the formula (II-S) are prepared from the compounds represented by the formula (I-R) or the formula (I-S) through deprotection. The invention further provides a preparation method of the compounds represented by the formula (I-R), the formula (I-S), the formula (II-R) or the formula (II-S) and pharmaceutically acceptable salts of the compounds, and application of the compounds in preparation of anti-inflammatory drugs or anti-inflammatory drug compositions. The Ocotillol type esterified derivatives provided by the invention are obviously superior to the existing clinical drug hydrocortisone sodium succinate in the aspect of inhibiting the generation of an inflammatory signal molecule NO. Moreover, the Ocotillol type esterification derivatives are high in biological friendliness and good in drug safety, show a longer half-life period in in-vitro metabolic stability evaluation, and can improve the safety and stability of the patent 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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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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