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Preparation method and use of 9-bit-substituted double functional group berberine derivatives

A derivative, the technology of berberine, which is applied in the field of food and pharmacy, can solve the problems of low fat solubility, low water solubility of berberine hydrochloride, and influence on systemic therapeutic effects.

Active Publication Date: 2016-12-07
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Berberine hydrochloride has little water solubility, even less fat solubility, and poor absorption in the gastrointestinal tract, resulting in low oral bioavailability, which affects its systemic therapeutic effect
Although sartans and berberine have many similar pharmacological activities, they all limit their clinical use to a certain extent due to their low bioavailability. It will be of great clinical significance to use the synergy between the two

Method used

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  • Preparation method and use of 9-bit-substituted double functional group berberine derivatives
  • Preparation method and use of 9-bit-substituted double functional group berberine derivatives
  • Preparation method and use of 9-bit-substituted double functional group berberine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] a) Synthesis of Berberine

[0021] Add 7.4g of berberine to a 250mL round flask, heat at 190-200°C for about 30min at a vacuum of 20-30mmHg, the yellow solid gradually turns dark red, cool to room temperature in a vacuum desiccator, and purify by silica gel column chromatography. Obtained 4.7 g of dark red powder with a yield of 75%.

[0022] b) Synthesis of 9-O-3-hydroxyl-ethyl berberine hydrobromide

[0023] Add 3.2g (10mmol) of berberine into a 25mL round bottom flask, add 30mL of DMF to dissolve, heat at 70°C, add 4.4g (20mmol) of 2-bromoethanol, follow the reaction by TLC, add 100mL of anhydrous ether after the reaction is complete, and precipitate The solid was filtered and purified by silica gel column chromatography to obtain 3.3 g of 9-O-3-hydroxy-ethyl berberine hydrobromide with a yield of 76%

[0024] c) Synthesis of eprosartan-9-O-acetate berberine

[0025] Add 425mg (1mmol) eprosartan, 20ml dichloromethane, 178mg (1.1mmol) CDI to a 25mL round bottom fla...

Embodiment 2

[0027] a) Synthesis of Berberine

[0028] Same as a) in Example 1

[0029] b) Synthesis of 9-O-3-hydroxyl-ethyl berberine hydrobromide

[0030] Same as b) in Example 1

[0031] c) Synthesis of valsartan-9-O-acetate berberine

[0032] Add 436mg (1mmol) valsartan, 20ml dichloromethane, 178mg (1.1mmol) CDI to a 25mL round bottom flask, stir for 10min, then add 446mg 9-O-3-hydroxy-ethylberberine hydrobromide (1mmol), stirred at room temperature, followed by TLC reaction, after the reaction was complete, 20ml of water was added, stirred, extracted, the organic phase was dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain valsartan-9-O-acetic acid Ester berberine 659mg, yield 86%. ESI-MS(M+H) + m / z calcd C 45 h 47 N 6 o 7 + for784.35found784.35.

Embodiment 3

[0034] a) Synthesis of Berberine

[0035] Same as a) in Example 1

[0036] b) Synthesis of 9-O-3-hydroxyl-ethyl berberine hydrobromide

[0037] Same as b) in Example 1

[0038] c) Synthesis of candesartan-9-O-acetate berberine

[0039] Add 440mg (1mmol) candesartan, 20ml dichloromethane, 178mg (1.1mmol) CDI to a 25mL round bottom flask, stir for 10min, then add 9-O-3-hydroxy-ethylberberine hydrobromide 446 mg (1 mmol), stirred at room temperature, TLC followed the reaction, after the reaction was complete, 20 ml of water was added, stirred, extracted, the organic phase was dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain candesartan-9-O- Acetate berberine 694mg, yield 88%. ESI-MS(M+H) + m / z calcd C 45 h 38 N 7 o 7 + for789.28found789.28.

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Abstract

The invention provides a preparation method of 9-bit-substituted double functional group berberine derivatives and belongs to the field of chemical synthesis. A pharmacological experiment proves that the derivatives have drug activity with a plurality of values and especially, the derivatives have the easy absorption performance which does not belong to a single function group drug. An animal experiment proves that the derivatives have excellent effects of adjusting hypertension rat blood pressure. The 9-bit-substituted double functional group berberine derivatives can prevent bonding of angiotensins II obtained through various approaches and their special acceptors so that blood pressure increasing effects are reduced or inhibited.

Description

technical field [0001] The invention relates to the technical field of food and pharmaceuticals, in particular to the application of 9-position substituted bifunctional berberine derivatives in the preparation of products for preventing or treating hypertension and related diseases or symptoms. Background technique [0002] Hypertension is the most common cardiovascular and cerebrovascular disease and the largest public health problem in the world. According to WHO analysis, by 2020, the death caused by hypertension will rank first among all non-infectious diseases. According to survey data, the prevalence of hypertension in adults over 18 years old in my country is 18.8%. It is estimated that there are about 200 million hypertensive patients in my country, and 2 out of every 10 adults suffer from high blood pressure, accounting for about the total number of hypertensive people in the world. 1 / 5 of. Among the hypertensive population in my country, the vast majority are mild ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61K31/4375A61P9/12
CPCC07D455/03
Inventor 高永好何勇吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH
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