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A class of 3'-aminoalkoxy-luteolin derivatives and its preparation method and application

A technology of luteolin and aminoalkoxy, which is applied in the field of 3′-aminoalkoxy-luteolin derivatives and their preparation, and can solve the problems of poor water solubility, poor drugability and limited efficacy of luteolin. problem, to achieve the effect of high protection of vasoactivity, good solubility and bioavailability

Active Publication Date: 2020-12-08
SHURELI BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the poor water solubility of luteolin leads to poor druggability, low bioavailability and limited efficacy.

Method used

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  • A class of 3'-aminoalkoxy-luteolin derivatives and its preparation method and application
  • A class of 3'-aminoalkoxy-luteolin derivatives and its preparation method and application
  • A class of 3'-aminoalkoxy-luteolin derivatives and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: Preparation of 3'-(dimethylamino)ethoxy-luteolin hydrochloride (1:1) (LTD2)

[0069] Under the protection of an inert gas, add 5.0g luteolin, 6.8g DIPEA and 30mL DMF into a 50mL three-necked flask, stir for 10min, and drop 4.15mL benzyl chloride in an ice-water bath. Stirring at 15-20° C. for 24-48 hours, TLC detection showed that the reaction of the raw materials was basically complete. After the reaction mixture was concentrated under vacuum, 100 mL of ethyl acetate and 200 mL of H 2 O, stirred for 30min, filtered, and the filter cake was detected as a dibenzyl substitute. The filtrate was separated into layers, the aqueous phase was discarded, and the organic phase was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: EA / PE=1 / 5-1 / 3), and the collected fractions were spin-dried to obtain 2.0 g of khaki solid LTD-Bn2 with a yield of 24.5%. Under the protection of inert gas, 1.0g LTD-Bn2, 0....

Embodiment 2

[0074] Example 2: Preparation of 3'-(monomethylamino)ethoxy-luteolin hydrochloride (1:1) (LTD7)

[0075] Under the protection of inert gas, 9.0g LTD-Bn2, 2.64g N-tert-butoxycarbonyl-N-methylaminoethanol and 4.87g PPh3 were added to a 250mL three-necked flask, stirred for 10min, and 2.92mL DEAD was added dropwise in an ice-water bath. After the dropwise addition was completed, the reaction solution was returned to room temperature, and stirring was continued for 16 h. LCMS detected that the reaction was complete. The reaction was concentrated under vacuum to give 20.0 g of crude brown product. Without further purification, it was directly used as the raw material LTD7a01 for the next reaction. Under the protection of an inert gas, 20.0 g of crude LTD7a01 was dissolved in 50 mL of dichloromethane, and 10 mL of TFA was slowly added dropwise at room temperature. After the dropwise addition, the stirring was continued for 16 h, and the reaction was monitored by LCMS to complete. ...

Embodiment 3

[0080] Example 3: Preparation of 3'-aminoethoxy-luteolin hydrochloride (1:1) (LTD8)

[0081] Under the protection of inert gas, 6.0g LTD-Bn2, 1.6mL N-(tert-butoxycarbonyl)ethanolamine and 3.38g PPh3 were added to a 250mL three-neck flask, stirred for 10min, and 1.91mL DEAD was added dropwise in an ice-water bath. After the dropwise addition was completed, the reaction solution was returned to room temperature, and stirring was continued for 16 h. LCMS detected that the reaction was complete. The reactant was concentrated under vacuum, and purified by column chromatography (DCM / MeOH=20 / 1-10 / 1) to obtain 3.3 g of light yellow crude product. Under the protection of an inert gas, 3.3 g of crude LTD8a01 was dissolved in 30 mL of dichloromethane, and 6.0 mL of TFA was slowly added dropwise at room temperature. Continue to stir for 16h after the dropwise addition. Completion of the reaction was monitored by HPLC. The reaction solution was concentrated, 30.0 mL of saturated NaHCO3...

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Abstract

The invention relates to preparation and applications of a class of 3'-aminoalkoxy-luteolin derivatives. The preparation method comprises: carrying out a reaction under an alkaline condition in the protection of an inert gas by using luteolin and a benzyl-containing active group substance as raw materials to obtain a dibenzyl substitute, carrying out a reaction with an amino-containing active group under an alkaline condition, and removing the benzyl from the reaction product in the presence of a metal catalyst to convert into the 3'-aminoalkoxy-luteolin derivative. According to the present invention, the compound can further form a salt; and the compound can antagonize the vascular injury, the myocardial ischemia injury and the cerebral ischemia injury of diabetic rats, has multiple target effects, can provide related pharmacological and pharmacodynamic effects by protecting blood vessels, and can be used for preparing drugs or health-care products and the like for preventing and treating diabetic vascular complications and cardiovascular and cerebrovascular diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of 3'-aminoalkoxy-luteolin derivatives and a preparation method and application thereof. Background technique [0002] Diabetes (Diabetes Mellitus, DM) is a metabolic disease characterized by hyperglycemia. The number of diabetic patients in the world is increasing year by year, and there are currently 415 million people. Yellow people are susceptible to high incidence. my country has become the country with the largest number of diabetic patients in the world ( The prevalence rate is as high as 11.6%), and 90% of diabetic patients are type 2 diabetes. Long-term high blood sugar damages the large blood vessels and microvessels, and seriously endangers the heart, brain, kidney, peripheral nerves, eyes, feet, etc., leading to diabetes as the disease with the most complications (up to more than 100). According to statistics from the American Diabetes Association...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/30C07D405/12A61P9/10A61P3/10A61P9/00A61P13/12A61P27/02A61P25/00
CPCA61P3/10A61P9/00A61P9/10A61P13/12A61P25/00A61P27/02C07D311/30C07D405/12
Inventor 杨为民李鲜翁稚颖刘伟军张秀娟陈晨肖创白春昀郑昌博
Owner SHURELI BIOPHARMA CO LTD
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