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Berberrubine 12-site derivatives as well as preparation method and applications thereof

A technology of berberine and aminomethylberberine, which is applied in the field of medicinal chemistry and drug therapy, and achieves the effect of simple synthesis and abundant synthetic raw materials

Inactive Publication Date: 2013-01-02
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, there are no research reports on the 12-position derivatives of berberine and their pharmacological activities in antidiabetic aspects at home and abroad.

Method used

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  • Berberrubine 12-site derivatives as well as preparation method and applications thereof
  • Berberrubine 12-site derivatives as well as preparation method and applications thereof
  • Berberrubine 12-site derivatives as well as preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of Berberine

[0026]

[0027] Put 20g of dry berberine hydrochloride in a round bottom flask, vacuumize to a pressure of 10mmHg, and react at 180°C for 20min until the raw material completely changes from yellow to dark red. The obtained crude product was eluted with dichloromethane / methanol (V / V=10:1) column chromatography to obtain 22 g of red solid powder.

[0028] 1 H NMR (400 MHz, DMSO-d 6 ,): δ 9.22 (s, 1H), 8.06 (s, 1H), 7.56 (d, 1H, J = 8 Hz), 7.43 (s, 1H), 6.96 (s, 1H), 6.85 (d, 1H, J = 8 Hz), 6.10 (s, 2H), 4.70 (t, J = 6 Hz, 2H), 3.78 (s, 3H), 3.23 (t, J = 6 Hz, 2H). MS (ESI) m / z: 322 [M+H] + .

Embodiment 2

[0030] Preparation of 12-(N,N-dimethylamino-methyl)-berberine

[0031]

[0032]Add 322mg (1mmol) of berberine hydrochloride and 5ml of absolute ethanol to the reaction bottle, add 0.66ml of aqueous dimethylamine (33%) (5mmol) and 0.4ml of aqueous formaldehyde (37%) (5mmol) under stirring at room temperature, React at 80°C for 24 hours. At the end of the reaction, the solvent was concentrated under reduced pressure and subjected to flash column chromatography, eluting with dichloromethane: methanol (V / V = 20: 1), to obtain 286 mg of a dark red solid.

[0033] 1 H NMR (400 MHz, DMSO-d 6 ,): δ 9.07 (s, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 7.13 (s, 1H), 6.96 (s, 1H), 6.10 (s, 2H), 4.47 (t, J = 6 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H), 3.03 (t, J = 6 Hz, 2H), 2.16 (s, 6H). MS (ESI) m / z: 379 [M+H] + .

Embodiment 3

[0035] Preparation of 12-(pyrroline-1-methyl)-berberubine

[0036]

[0037] Add 322mg (1mmol) of berberine hydrochloride and 5ml of absolute ethanol to the reaction bottle, add 0.42ml of tetrahydropyrrole (5mmol) and 0.4ml of formaldehyde aqueous solution 0.4 (37%) (5mmol) under stirring at room temperature, and react at room temperature for 24 Hour. After the reaction, the solvent was concentrated and dried under reduced pressure, followed by flash column chromatography, eluting with dichloromethane: methanol (V / V = 20: 1), to obtain 312 mg of a dark red solid.

[0038] 1 H NMR (400 MHz, CDCl 3 ): δ 9.17 (s, 1H), 8.01 (s, 2H), 7.26 (s, 2H), 6.74 (s, 1H), 6.05 (s, 2H), 4.36 (t, J = 6 Hz, 2H), 3.93 (s, 3H), 3.78 (s, 2H), 3.05 (t, J = 6 Hz, 2H), 2.55 (s, 4H), 1.68 (s, 4H). MS (ESI) m / z: 406 [M+H].

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Abstract

The invention provides berberrubine 12-site derivatives with a structure shown in a formula (I) or physiologically-acceptable salt thereof, applications of the derivatives and a medicament combination comprising the derivatives. Invitro cell experiments show that the berberrubine 12-site derivatives play roles in promoting adipose cells and muscle cells to absorb glucose and improving the sugar tolerance and insulin resistance; and the compound can be used for treating diabetes, obesity, fatty liver and complications thereof caused by insulin resistance.

Description

technical field [0001] The invention relates to the fields of medicinal chemistry and medicinal therapy, in particular to berberine 12-position derivatives which can be used as insulin sensitizers, pharmaceutical compositions and medical applications thereof. Background technique [0002] Diabetes is a group of clinical metabolic diseases caused by the interaction of genetic and environmental factors. Due to the absolute or relative insufficiency of insulin secretion and the decreased sensitivity of target tissue cells to insulin, a series of metabolisms such as sugar, protein, fat, water and electrolytes are caused. disorder. Clinically, hyperglycemia is the main common sign, and prolonged illness can cause damage to multiple systems. Severe complications such as cardiovascular disease, kidney disease, blindness, and gangrene of the extremities were significantly higher in diabetics than in non-diabetics. Therefore, diabetes and its complications have become a worldwide p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61K31/4375A61K31/4545A61K31/5377A61K31/496A61P3/10A61P3/04A61P1/16A61P3/06
Inventor 吴勇海俐吴建波雷凡张勇李晓岑
Owner SICHUAN UNIV
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