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Danshensu derivativeS as well as preparation method and medical application thereof

A Danshensu derivative, Danshensu technology, applied in the direction of pharmaceutical formulations, drug combinations, bulk chemical production, etc., can solve the problems of limited application, strong hydrophilicity, unstable danshensu phenolic hydroxyl structure, etc., and achieve an improved balance Coordination ability, increasing drug stability, and reducing the effect of cerebral infarction volume

Active Publication Date: 2021-09-03
SHANGHAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the structure of Danshensu contains carboxylic acid and phenolic hydroxyl groups, which lead to its strong hydrophilicity and poor fat solubility, making it difficult to penetrate the blood-brain barrier; the structure of Danshensu's phenolic hydroxyl groups is unstable and easy to oxidize, which makes its half-life in vivo short and bioavailable. Low, these factors greatly limit its application in ischemic stroke

Method used

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  • Danshensu derivativeS as well as preparation method and medical application thereof
  • Danshensu derivativeS as well as preparation method and medical application thereof
  • Danshensu derivativeS as well as preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] The synthesis of embodiment 1 compound DE001-DE005

[0078] The synthetic route is as follows:

[0079]

[0080] The specific synthetic method comprises the following 14 steps of reaction:

[0081] [1] Take a 250ml reaction bottle, dissolve danshensu sodium (10g, 45mmol) in DMF (200ml), magnetically stir to dissolve, add sodium bicarbonate (7.6g, 90mmol) to react at room temperature, monitor the reaction by TLC, after 6h the product point The concentration does not change anymore, and the reaction ends. Pour the reaction liquid into 300mL ice water, extract 2-3 times with ethyl acetate, combine the organic phases and wash with saturated brine 2-3 times, dry over anhydrous sodium sulfate, and rotary evaporate to obtain a yellow oily crude product, which is directly used in the next step without purification. .

[0082]

[0083] [2] Weigh compound (R)-3-(3,4-dihydroxyphenyl)-2-hydroxypropionate benzyl ester (2) (1 equivalent) and dissolve it in DMF (200ml), under...

Embodiment 2

[0120] The synthesis of embodiment 2 compound DE009

[0121] The synthetic route is as follows:

[0122]

[0123] Concrete synthetic method, comprises following 5 steps reaction:

[0124] [1] Weigh compound 9 (1eq) into a reaction flask and add anhydrous methanol to dissolve it, add ethyl trifluoroacetoacetate (0.8eq), heat to 110-120°C for 4 hours, and evaporate the reaction system Dry and purify on a silica gel column (petroleum ether: ethyl acetate = 4:1-1:1) to obtain product 18 (45-63%).

[0125]

[0126] [2] Dissolve compound 1-(4-(benzyloxy)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-ol (18) (1 equivalent) in dichloromethane, Under magnetic stirring, Boc anhydride (1-1.5 equivalents), triethylamine (1.5-2 equivalents), and DMAP (0.1-0.3 equivalents) were sequentially added, reacted at room temperature, monitored by TLC, and the reaction was completed. The system was rotary evaporated to remove most of the solvents, the remaining reaction liquid was extracted 2-3 ...

Embodiment 3

[0138] The synthesis of embodiment 3 compound DE021

[0139] The synthetic route is as follows:

[0140]

[0141] Concrete synthetic method, comprises following 6 steps reaction:

[0142][1] Weigh benzyl alcohol (1eq) and dissolve it in 50ml THF, under magnetic stirring, cool to 0°C, dissolve the weighed NaH (1.2-1.5eq) in 20ml THF, and slowly drop it into the reaction flask , the reaction was continued for 30 min in an ice bath. The reaction system was cooled to 0° C. again, and ethyl 4-chloroacetoacetate (0.7-0.75 eq) was slowly added dropwise into the reaction system with an addition funnel. After reacting for 5 h, the end of the reaction was monitored by TLC. Rotate the system to remove the solvent, add a small amount of dilute hydrochloric acid and petroleum ether to extract 2-3 times, wash the organic phase with saturated brine 1-2 times, dry over anhydrous sodium sulfate, and rotate to evaporate. Purification by silica gel column chromatography (petroleum ether: ...

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Abstract

The invention discloses Danshensu derivatives as well as a preparation method and medical application thereof. The derivatives have a general structure as shown in a general formula (I) shown in the specification, wherein R1 represents OH or OCH3; R2 represents H or Ac; and R3 represents a first structure, a second structure or a third structure shown in the specification. Compared with a raw material medicine, the derivatives synthesized by the invention have the advantages that the fat solubility is increased, so that the derivatives can penetrate through the blood-brain barrier (BBB), the medicine stability is greatly improved, and the curative effect is further improved. Therefore, the derivatives disclosed by the invention can be applied to preparation of drugs for preventing, treating, treating and / or reducing the cerebral infarction volume of a patient, improving the balance coordination ability of the patient and other diseases, and a new therapeutic drug is provided for preventing and treating cerebrovascular or cranial nerve diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry related to danshensu, and in particular relates to a danshensu derivative, a preparation method and a medical application thereof. Background technique [0002] Cerebral stroke, also known as "stroke", is an acute cerebrovascular disease caused by sudden rupture of blood vessels in the brain or occlusion of blood vessels. It is a disease of the central nervous system that seriously affects people's quality of life and has a high incidence It is also the second leading cause of death in the world, second only to coronary artery disease. According to WHO statistics, there are more than 15 million people in the world every year, which is equivalent to one stroke patient in every 400 people. The most vulnerable people to stroke are those over the age of 65, but strokes can occur in all age groups, including children and infants. Stroke is the main cause of death from cerebrovascular dise...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/22A61K31/415A61P9/00A61P25/00A61P9/10
CPCC07D231/22A61P9/00A61P25/00A61P9/10Y02P20/55
Inventor 熊礼燕栗意王庭芳石浩罗云春朱晨晨杨诗雨高艺峻孟沙张川
Owner SHANGHAI UNIV
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