Pyrrole and morpholine spirocyclic alkaloid compound and preparation method and application thereof

A technology of pyrrolomorpholine spiro and rolomorpholine spiro, which is applied in the field of pharmacy and can solve problems such as oxidative stress, disruption of oxygen free radical homeostasis, damage to antioxidant defense system, etc.

Inactive Publication Date: 2016-08-24
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that under normal circumstances, there is a dynamic balance between the generation and removal of free radicals, but under certain pathological conditions, the body's excessive generation of oxygen free radicals and (or) damage to the antioxidant defense system, the production of oxygen free radicals and The dynamic balance of scavenging is disrupted. When the rate of active oxygen generation is greater than the rate of clearance, it will cause the accumulation of active oxygen, leading to the appearance of oxidative stress

Method used

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  • Pyrrole and morpholine spirocyclic alkaloid compound and preparation method and application thereof
  • Pyrrole and morpholine spirocyclic alkaloid compound and preparation method and application thereof
  • Pyrrole and morpholine spirocyclic alkaloid compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1 extracts and isolates compounds 1, 2, and 3 by Wuling powder

[0049] 20kg of Wuling bacteria powder (Xylaria nigripes) was sequentially extracted 3 times with 20L of 75% ethanol for 36 hours each time, and the obtained extracts were combined and concentrated under reduced pressure at 65°C to obtain 1.3kg of extracts, which were dispersed with 1L of water, followed by Extract with petroleum ether (3×1L) and ethyl acetate (4×2L); after concentrating under reduced pressure, obtain 70.5g of petroleum ether part extract and 281.6g of ethyl acetate part extract respectively, use silica gel For column chromatography, the ethyl acetate part was eluted through a normal phase silica gel column, and PE: EA (20:1-2:1), CH 2 Cl 2 : MeOH (50:0–0:1) gradient elution to obtain 15 components (Fr.1-Fr.15). Fr.11f (300.0mg) was purified by silica gel column chromatography to CH 2 Cl 2 : MeOH (50:1)) after elution by Sephadex LH-20 (MeOH, CH 2 Cl 2 : MeOH, 2:1) was puri...

Embodiment 2

[0051] Step 1, synthesis of (S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol

[0052] Dissolve 5g (38.5mmol) of compound 7 in dry tetrahydrofuran (35ml), cool down to -78°C, slowly add 34ml (57.8mmol) of 1.7M allylmagnesium chloride dropwise, and keep the temperature below -70°C during the dropwise addition After the addition, continue to react at this temperature for 2 hours, slowly add 30ml of saturated ammonium chloride solution at low temperature to quench the reaction, dilute with water, extract the aqueous phase with ethyl acetate for 3 times, combine the organic phases and wash once with saturated sodium chloride , dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 5.7 g of colorless liquid (8), with a yield of 86.0%.

[0053] 1 H NMR (400MHz, CDCl 3 ):δ8a:5.85(m),5.18(m),5.13(m),4.03(m),3.94(m),3.78(m),2.34(m),2.23(m),1.44(s),1.37 (s); 8b: δ5.85(m), 5.15(m), 4.03(m),...

Embodiment 3

[0069] Step 1, the operation of synthesizing (S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol compound 8 and The operation of embodiment 1 is the same, and the reaction reagent allylmagnesium chloride is changed into allylmagnesium bromide, and the yield is 80%

[0070] Step 2, synthesis of tert-butyl (((S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-1-yl )Oxy)dimethylsilane

[0071] Take 1g (5.8mmol) of compound 8, dissolve it in dry dichloromethane (10ml), fill it with nitrogen protection, after cooling in an ice-water bath, add triethylamine (1.2g) and tert-butyldimethylsilyl chloride ( 1.1g), after the addition, slowly rise to room temperature and react for 16h, add water to quench the reaction, wash once with 1M potassium bisulfate, extract the aqueous phase twice with dichloromethane, wash the combined organic phase once with saturated sodium chloride, and wash with anhydrous sulfuric acid Dried over magnesium, filtered and concentrated, the crude product was...

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PUM

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Abstract

The invention belongs to the field of medicine, relates to a pyrrole and morpholine spirocyclic alkaloid compound and application thereof to preparing anti-oxidative stress medicine for treating cardiovascular diseases and further relates to an extraction and preparation method of the compound. The compound can be obtained by being extracted and separated from traditional Chinese medicine xylaria nigripes powder or obtained through chemical synthesis. Test results show that the compound has a protective function on cell injuries generated by oxidative stress and can be used for preparing the medicine for treating cardiovascular diseases. The compound can further be used for preparing antioxidant medicine and preparations including injections, oral medicine, external medicine and other preparation forms. Please see the molecular formula in the description, wherein configuration of the position 9 and the position 11 is R or S.

Description

technical field [0001] The invention belongs to the field of pharmacy, and specifically relates to pyrrolomorpholine spirocyclic alkaloid compounds, their preparation method and application. Background technique [0002] Studies have disclosed that oxidative stress (OS) refers to excessive accumulation of oxygen free radicals and their related metabolites due to excessive production of oxygen free radicals and / or damage to the intracellular antioxidant defense system, thereby causing various damage to cells. Pathological state of toxic effects. Studies in recent years have shown that oxidative stress is one of the important causes of abnormal structure and function of the cardiovascular system. Oxidative stress and the reactive oxygen species produced during oxidative stress are closely related to the occurrence and development of various cardiovascular diseases. [0003] Reactive oxygen radicals (reactive oxygen species, ROS) are the products of oxygen molecules metabolize...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/01C07H1/00C07H1/08C07D498/20A61P39/06
Inventor 胡金锋李明魏邦国刘新华熊娟黄亚杨国勋
Owner FUDAN UNIV
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