Preparation method and application of 9-bit substituent double-functional group berberine derivatives

A derivative, berberine technology, is applied in the field of preparation of 9-position substituted bifunctional berberine derivatives, can solve the problems of high liver toxicity, low bioavailability in vivo, etc., achieves less toxic side effects, inhibits Aβ Amyloid deposition, high therapeutic index effect

Inactive Publication Date: 2011-04-27
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, the above-mentioned inhibitors still have certain defects, mainly due to high toxicity to the liver, side effects of nausea and vomiting, and low bioavailability in the body. AD, vascular dementia and other diseases are very urgent and necessary

Method used

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  • Preparation method and application of 9-bit substituent double-functional group berberine derivatives
  • Preparation method and application of 9-bit substituent double-functional group berberine derivatives
  • Preparation method and application of 9-bit substituent double-functional group berberine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Embodiment 1: Preparation 9-(3-(N-phenylamino) propoxy) berberine hydrobromide (Ia-1)

[0062] a step reaction:

[0063] Put 20mmol, 7.5g of dried berberine hydrochloride in a vacuum drying oven, control the pressure below 15mmHg, raise the temperature to 190°C, and react for 20min to obtain a dark red powder. The crude product is chromatographed with chloroform-methanol (10:1) After elution, compound 2 was obtained as bright red powder with metallic luster. Yield: 75%. 1 H NMR (400MHz, DMSO-d6) δ: 9.07(s, 1H), 8.94(s, 1H), 7.98(s, 1H), 7.61(s, 1H), 7.19(d, J=8.4, 1H), 6.96(s, 1H), 6.34(d, J 8.4, 1H), 6.10(s, 2H), 4.48(t, J 6.3.2H), 3.73(s, 3H), 3.04(t, J=6.4, 2H ); LC / MS (ESI) m / z: [M-Br]+321+.

[0064] Step b reaction:

[0065] Add aniline (10mmol, 0.933g), triethylamine (15mmol, 1.524g), 1,3-dibromopropane (12mmol, 2.423g) and 25ml of acetonitrile into a 50ml round bottom flask, and heat to reflux for 24h. After filtration and concentration, 1.75 g of the produ...

Embodiment 2

[0068] Embodiment 2: Preparation of 9-O-(3-N-phenylamino)-4-oxopropyl) berberine hydrobromide (Ib-1)

[0069] a step reaction:

[0070] With embodiment 1.

[0071] c-step reaction:

[0072] Add aniline (5mmol, 0.461g) and 25ml of anhydrous chloroform into a 50ml round bottom flask, add 3-bromopropionyl chloride (6mmol, 1.042g) and pyridine (6mmol, 0.480g) dropwise at 0°C, after the addition is complete , Stir the reaction at room temperature for 3h. The reaction solution was washed once with 30 ml of saturated sodium carbonate aqueous solution, 3 times with 30 ml of water, and once with saturated aqueous sodium chloride solution, and the organic phase was dried with anhydrous magnesium sulfate and filtered, and the filtrate was concentrated to obtain 3-bromo-N-phenylpropane The crude amide can be directly used in the next reaction.

[0073] f-step reaction:

[0074] Compound 2 (1mmol, 0.322g), potassium carbonate (5mmol, 0.700g), potassium iodide (0.1mmol, 0.016g) and cru...

Embodiment 3

[0075] Embodiment 3: Preparation 9-O-(2-(O-phenyl) ethyl) berberine hydrobromide (Ic-1)

[0076] a step reaction:

[0077] With embodiment 1.

[0078] d-step reaction:

[0079] Phenol (10mmol, 0.950g), potassium hydroxide (15mmol, 0.845g), 1,2-dibromoethane (12mmol, 2.221g) and butanone 25ml were added to a 50ml round bottom flask, and stirred at room temperature for 3h. After filtration and concentration, the product (2-bromoethoxy)phenyl was obtained by silica gel column chromatography 1.76g, yield: 88%. 1 H NMR (400MHz, CDCl 3 )δ: 7.17-7.23(m, 2H), 6.83-6.90(m, 3H), 4.39(t, J=6.0Hz, 2H), 3.81(t, J=6.4Hz, 2H).

[0080] f step reaction:

[0081] Compound 2 (1mmol, 0.322g), potassium carbonate (5mmol, 0.694g), potassium iodide (0.1mmol, 0.016g) and (2 bromoethoxy)phenyl (1.2mmol, 0.244g) were placed in a 50ml round bottom flask 30ml of anhydrous acetonitrile was added, and the reaction was heated under reflux for 12h. After filtration and concentration, 0.398 g of produ...

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Abstract

The invention relates to a preparation method and application of 9-bit substituent double-functional group berberine derivatives. In-vitro biological activity assay research shows that the 9-bit substituent double-functional group berberine derivatives provided by the invention has acetylcholinesterase inhibition activity higher than that of berberine serving as a leading compound, and also has higher inhibition activity on butyrylcholine esterase. After being further optimized and screened, the derivatives have favorable foreground of being developed into medicaments for treating diseases such as AD disease, vascular dementia, cognitive dysfunction and the like. The general formula of the derivatives is shown as the following formula, wherein X, Y and Z are defined in specifications.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and specifically relates to a preparation method of a 9-position substituted bifunctional group berberine derivative and its use as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase in the treatment of Alzheimer's disease vascular dementia, memory loss, cognitive dysfunction and other related diseases. Background technique [0002] Alzheimer's disease (AD), also known as Alzheimer's disease, was first reported by Alois Alzheimer in 1907. It is a neurodegenerative disease, and its clinical symptoms mainly manifest as the gradual loss of memory and cognitive ability. According to statistics, the incidence of Alzheimer's disease is 5% over the age of 65, 10% over the age of 70, 30% over the age of 80, and as high as 40% over the age of 85, and it is still increasing. More than 27 million people suffer from the disease. [0003] Since the disease was disc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/03A61K31/4375A61P25/28
Inventor 黎星术黄玲石谙丁罗宗化
Owner SUN YAT SEN UNIV
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