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Novel securinine dimer as well as preparation method and application thereof

A technology of hagiline dimer and dimer, which is applied in the field of medicine, can solve the problems affecting the treatment effect, achieve the effect of improving cognitive function, optimizing the activity of inducing neural differentiation and promoting protein synthesis, and good stability

Active Publication Date: 2022-03-25
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some simple types of trichopine dimer compounds (such as SN3-L6) can significantly up-regulate the synthesis level of neuronal proteins, and at the same time have the effect of promoting neuronal differentiation and enhancing synaptic function (Tang G, et al, ACS Chem Neurosci, 2016, 7:1442–1451; Liao Y, et al, Front Pharmacol, 2018, 9:290), but these compounds are rapidly eliminated in animals, which affects their good therapeutic effect in vivo

Method used

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  • Novel securinine dimer as well as preparation method and application thereof
  • Novel securinine dimer as well as preparation method and application thereof
  • Novel securinine dimer as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] The general preparation method of embodiment 1 compound N1~N6

[0058]

[0059] At room temperature, dissolve chinensis (217mg, 1mmol) in a stirred mixed solvent of dichloromethane (5mL) and methanol (0.5mL), and add potassium phosphate (K 3 PO 4 , 64mg, 0.3mmol) and the corresponding primary amine (R-NH 2 ,5mmol). After heating up to 35°C, the reaction was carried out for 8 hours. The organic solvent was concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography to obtain the corresponding compounds N1-N6.

Embodiment 2

[0060] The preparation of embodiment 2 compound 1

[0061]

[0062] At room temperature, dissolve trimethylsilyl azide (6.58mL, 50mmol) and acetic acid (2.86mL, 50mmol) in a stirred dichloromethane (50mL) solvent at room temperature. and DBU (75L, 0.5mol). After the temperature was raised to 35°C, the reaction was carried out for 8 hours, and the organic solvent was concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography to obtain a pair of diastereomer azides N10a and N10b. Subsequently, the azide compound N10a was dissolved in a stirred DMSO (2 mL) solvent, and copper (127 mg, 2 mmol), copper sulfate pentahydrate (13 mg, 0.05 mmol) and 1,5-hexadiyne (26 μL, 0.27 mmol) were successively added ). After reacting in the dark for 5 hours, ethyl acetate (10 mL) was added, and the filtrate was obtained by filtration. The filtrate was washed 3 times with water (3×10 mL), washed wi...

Embodiment 3

[0064] The preparation of embodiment 3 compound 2

[0065]

[0066] Referring to the synthesis method of Example 2, using the azide compound N10b as the starting material, a white solid compound 2 was obtained (47% yield).

[0067] 1H NMR (300MHz, CDCl3) δ7.30(d, J=10.2Hz, 2H), 5.78(d, J=22.4Hz, 2H), 4.81(s, 2H), 3.58(s, 2H), 3.38(s ,4H),3.03(s,9H),2.43(dd,J=11.1,5.7Hz,2H),1.86(s,2H),1.70–1.13(m,13H); 13CNMR(75MHz,CDCl3)δ172.3,171.1 , 146.9, 120.4, 111.5, 90.4, 64.1, 60.1, 48.7, 32.3, 28.1, 25.9, 25.0, 23.9, 21.7; HR-ESI-MS m / z 599.3088 [M+H]+.

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Abstract

The invention relates to the field of medicines, in particular to application of a novel securinine dimer or pharmaceutically acceptable salt thereof in preparation of a medicine for treating Alzheimer's disease. The novel securinine dimer has a structural formula as shown in a general formula I or a pharmaceutically acceptable salt or a stereoisomer or a prodrug molecule of the novel securinine dimer, wherein a linking group Linker is selected from a group consisting of R1 and R2; x is selected from or n is 1, 2, 3 or 4.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a medicine for treating Alzheimer's disease. In particular, it relates to the application of the novel monophyllin dimer in the preparation of drugs for treating Alzheimer's disease. Background technique [0002] Alzheimer's disease (AD), commonly known as Alzheimer's disease, is a degenerative disease of the central nervous system characterized by progressive cognitive dysfunction and memory impairment. The common clinical symptoms are progressive memory impairment, Cognitive impairment, personality disorder, etc., the pathological features of the brain are mainly loss of a large number of neurons, senile plaques composed of β-amyloid (Aβ), and neurotangles composed of Tau protein. AD is the most common type of senile dementia, accounting for 60% to 80% of all dementia patients, and has become the third leading cause of death in the elderly after cardiovascular disease and cancer. Epid...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/439A61P25/28
CPCC07D519/00A61P25/28
Inventor 叶文才师蕾陈卫民王英胡利军李刘任马暄越廖玉梅庄晓吉黄志星黄小杰
Owner JINAN UNIVERSITY