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Preparation method and application of 9-position substituted bifunctional berberine derivatives

A technology of berberine and derivatives, applied in the field of food and pharmaceuticals, can solve the problems of malabsorption, affecting systemic therapeutic effect, and low oral bioavailability

Active Publication Date: 2019-02-05
HEFEI HUAFANG PHARMA SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, due to the poor water solubility of statins, the oral bioavailability is low, which limits the full play of their efficacy.
However, berberine hydrochloride has very 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 statins and berberine have many similar pharmacological activities, their clinical use is limited to a certain extent due to their low bioavailability. And the method of exerting the synergistic effect of the two will have very important clinical significance

Method used

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  • Preparation method and application of 9-position substituted bifunctional berberine derivatives
  • Preparation method and application of 9-position substituted bifunctional berberine derivatives
  • Preparation method and application of 9-position substituted bifunctional berberine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] a) Synthesis of Berberine

[0022] 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%.

[0023] b) Synthesis of 9-O-3-bromo-ethyl berberine hydrobromide

[0024] Add 3.2g (10mmol) of berberine into a 25mL round bottom flask, add 30mL of DMF to dissolve, heat at 70°C, add 3.5g (20mmol) of 1,2-bromoethane, follow the reaction by TLC, add 100mL of anhydrous Diethyl ether, precipitated solid, filtered, and purified by silica gel column chromatography to obtain 3.9 g of 9-O-3-bromo-ethyl berberine hydrobromide, yield 76%

[0025] c) Synthesis of fluvastatin-9-O-acetate berberine hydrobromide

[0026] Add 411 mg (1 mmol) fluvastatin to a 25 mL round bottom flask, add 5 mL DMF to dissolve, stir at room temperature, add 44 g (1.1 ...

Embodiment 2

[0028] a) Synthesis of Berberine

[0029] Same as a) in Example 1

[0030] b) Synthesis of 9-O-3-hydroxyl-ethyl berberine hydrobromide

[0031] Same as b) in Example 1

[0032] c) Synthesis of simvastatin-9-O-acetate berberine hydrobromide

[0033] Add 437 mg (1 mmol) of simvastatin to a 25 mL round bottom flask, add 5 mL of DMF to dissolve, stir at room temperature, add 44 g (1.1 mmol) of sodium hydroxide, stir for 10 min, then add 9-O-3-bromo-ethyl berberine 509 mg (1 mmol) of hydrobromide, heated to 70°C, stirred for reaction, followed by TLC, after the reaction was complete, 20 ml of anhydrous ether was added, and solid was precipitated, filtered to obtain simvastatin-9-O-acetate berberine Hydrobromide 746mg, yield 86%. ESI-MS(M+H) + m / z calcd C 45 h 56 NO 10 + for 771.39 found 771.40.

Embodiment 3

[0035] a) Synthesis of Berberine

[0036] Same as a) in Example 1

[0037] b) Synthesis of 9-O-3-hydroxyl-ethyl berberine hydrobromide

[0038] Same as b) in Example 1

[0039] c) Synthesis of pitavastatin-9-O-acetate berberine hydrobromide

[0040] Add 420 mg (1 mmol) of pitavastatin to a 25 mL round bottom flask, add 5 mL of DMF to dissolve, stir at room temperature, add 44 g (1.1 mmol) of sodium hydroxide, stir for 10 min, then add 9-O-3-bromo-ethyl berberine 509 mg (1 mmol) of hydrobromide, heated to 70°C, stirred and reacted, TLC followed the reaction, after the reaction was complete, 20 ml of anhydrous ether was added to precipitate a solid, filtered to obtain pitavastatin-9-O-acetate berberine Hydrobromide 709mg, yield 84%. ESI-MS(M+H) + m / z calcd C 46 h 41 FNO 8 + for755.28found755.28.

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Abstract

The invention provides a preparation method of a 9-substituted double-functional-group berberine derivative and belongs to the field of chemical synthesis. Pharmacological experiments find that the derivative has medicinal activity with various values, and especially has easy-to-absorb performance that single-functional-group medicine does not have. Particularly, the derivative presents excellent effect on regulating blood lipid of high-cholesterol rats in animal experiments. The derivative mainly functions in remarkably lowering blood lipid, especially low-density lipoprotein cholesterol (LDL-C).

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 hyperlipidemia and related diseases or symptoms. Background technique [0002] About 12 million people die of cardiovascular disease and cerebral apoplexy every year in the world, and atherosclerosis caused by hyperlipidemia is the main cause of coronary heart disease, hypertension and cerebrovascular disease. In 2002, the global annual sales of only atorvastatin (a blood lipid-lowering drug) was nearly 8 billion US dollars, becoming the world's best-selling drug that year. It can be seen that the research and development of blood lipid-lowering drugs has significant social benefits and market prospects. Statins are hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which block the endogenous cholesterol synthesis r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/03A61K31/4375A61P3/06
CPCC07D455/03
Inventor 高永好何勇吴宗好
Owner HEFEI HUAFANG PHARMA SCI & TECH