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Alpha-mangostin derivative and application thereof

A technology of drugs, compounds, applied in the field of medicine

Active Publication Date: 2020-06-09
GUANGZHOU UNIVERSITY OF CHINESE MEDICINE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no approved drugs for the treatment of VaD

Method used

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  • Alpha-mangostin derivative and application thereof
  • Alpha-mangostin derivative and application thereof
  • Alpha-mangostin derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1. Preparation of compounds 2b-2c, 3a-3g.

[0062] Synthesis of Intermediate 1: α-Mangostin (5.0 g, 12.18 mmol) was dissolved in dry benzene (80 mL), followed by the addition of dichlorodicyanobenzoquinone (DDQ) (3.0, 13.39 mmol). The reaction solution was heated to 80°C and refluxed for 3 h. After the reaction, filter while hot and evaporate the solvent in the filtrate. The resulting crude product was subjected to silica gel column chromatography (V 乙酸乙酯 :V 石油醚 =3:20) to obtain a yellow solid 1 (4.1 g, 10.04 mmol, yield 82%).

[0063] Compound: 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,-6H-pyrano[ 3,2-B]xanthen-6-one 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-2H,6H-pyrano[ 3,2-B] xanthen-6-one(1). Yield: 82 %. 1 H NMR (400 MHz, CDCl 3 ) δ 13.69 (s, 1H), 6.82 (s, 1H), 6.72 (d, J = 10.2 Hz, 1H), 6.35 (s, 1H), 6.24 (s, 1H), 5.56 (d, J = 10.0 Hz, 1H), 5.31-5.21 (m, 1H), 4.08 (d, J = 6.3 Hz, 2H), 3.80 (s, 3...

Embodiment 2

[0085] Example 2. Preparation of Compounds 4a-4g.

[0086] Synthesis of compound 4a: Hydroxylamine hydrochloride (31 mg, 0.44 mmol) and sodium hydroxide (44 mg, 1.10 mmol) were dissolved in anhydrous acetone (3 mL). After the reaction solution was stirred at room temperature for 10 minutes, 3a (110 mg, 0.22 mmol) was added, heated to 50°C, and refluxed for 6h. After the reaction, 10 ml of 5% dilute sulfuric acid was added and extracted three times with an equal volume of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness, and the crude product obtained was subjected to silica gel column chromatography (V 甲醇 :V 二氯甲烷 =1:99 ) to obtain yellow solid 4a (60.5 mg, 0.13 mmol, yield 59%).

[0087] Synthesis of compound 4b: Hydroxylamine hydrochloride (32 mg, 0.46 mmol) and sodium hydroxide (46 mg, 1.15 mmol) were dissolved in anhydrous acetone (5 mL). After the reaction solution was stirred at room...

Embodiment 3

[0101] Example 3. Preparation of Compound 5.

[0102] Synthesis of compound 5: 2b (56.4 mg, 0.10 mmol) and potassium carbonate (166 mg, 1.20 mmol) were dissolved in anhydrous acetone (5 mL), and then pyrrolidine (0.1 ml, 1.21 mmol) was added. The reaction solution was heated to 50°C and refluxed overnight. After the reaction, 10 ml of water was added and extracted three times with an equal volume of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness, and the crude product obtained was subjected to silica gel column chromatography (V 甲醇 :V 二氯甲烷 = 3:97) to obtain yellow solid 5 (40 mg, 0.07 mmol, yield 71%).

[0103] Compound: 5-Hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut-2-en-1-yl)-9-((6-(pyrrolidin-1- base)hexyl)oxy)-2H,-6H-pyrano[3,2-b]xanthen-6-one (5-hydroxy-8-methoxy-2,2-dimethyl-7-(3-methylbut -2-en-1-yl)-9-((6-(pyrrolidin-1-yl)hexyl)oxy)-2H,6H-pyrano[3,2-b]xanthen-6-one)(5). Yield:...

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Abstract

The invention discloses an alpha-mangostin derivative and an application thereof; the derivative is a compound represented by a general formula (I), a deuterated compound, a pharmaceutically acceptable salt or a solvate thereof, wherein n is 1-18, and R1 is selected from carboxyl and pyrrolidine groups. The invention also discloses an application of the compound represented by the formula I in preparation of medicines for treating diseases mediated by phosphodiesterase 4, improving cognitive functions or treating vascular dementia. It is proved that the compounds can obviously inhibit PDE4 andhave higher selectivity, and in-vivo experiments prove that the compounds can improve the cognitive function and treat vascular dementia.

Description

technical field [0001] The invention relates to the field of medicine, in particular to alpha-mangostin derivatives and applications thereof. Background technique [0002] Phosphodiesterases (PDEs), an 11-member enzyme superfamily responsible for degrading the second messengers cGMP and cAMP, have received extensive attention as drug targets for central nervous system (CNS) diseases. PDE4 (specifically hydrolyzed cAMP) is found throughout the central nervous system and is thought to play an important role in learning and memory by regulating the cAMP / PKA / CREB pathway. There are more than 20 different variants of PDE4, encoded by four isoforms (PDE4A, PDE4B, PDE4C, and PDE4D). These four PDE subtypes have distinct targets and regulatory properties in the CNS, which is also partly reflected in their different distribution patterns in brain regions. PDE4 inhibitors (e.g., rolipram, roflumilast, apremilast, and α-mangostin) show anti-inflammatory, cognitive improvement, and ne...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/352A61K31/4025A61P29/00A61P17/06A61P11/00A61P1/00A61P11/06A61P25/28A61P21/00A61P25/18A61P25/16A61P25/14A61P25/24A61P9/10
CPCC07D493/04A61P29/00A61P17/06A61P11/00A61P1/00A61P11/06A61P25/28A61P21/00A61P25/18A61P25/16A61P25/14A61P25/24A61P9/10
Inventor 何细新罗海彬梁津豪黄仪有于思
Owner GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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