Optical-activity neoclausenamidone derivative and application thereof

An optically active technology of xanthamidone, applied in the field of biomedicine, can solve the problems of further research and development, untargeted research results of compound structure or type, and the like, and achieves low cost, efficient synthesis method, The effect of shortening the reaction steps

Active Publication Date: 2019-04-16
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, there is still a large research gap in the research and application of pampidamide compounds in anti-AD, Parkinson's disease, cerebral apoplexy, traumatic brain injury and other diseases, and there are no targeted research results on the structure or type of symptomatic compounds. Subject to further research and development

Method used

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  • Optical-activity neoclausenamidone derivative and application thereof
  • Optical-activity neoclausenamidone derivative and application thereof
  • Optical-activity neoclausenamidone derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] The preparation of embodiment 1 (-)-bantamide ketone or (+)-bantamide ketone

[0078] The preparation process of (-)-bantamide ketone or (+)-bantamide ketone is as follows:

[0079] 1. Synthesis and resolution of racemic epoxy cinnamic acid ((±)-β-phenylglycidyl acid):

[0080]

[0081] ①Synthesis of racemic epoxy cinnamic acid ((±)-β-phenylglycidyl acid)

[0082]Weigh 148.20g of trans-cinnamic acid, dissolve it in 650mL of acetone, add 380.0g of sodium bicarbonate under stirring, cool to 0-20°C in an ice bath, add 650mL of water, then add 620.0g of potassium persulfate in 1250mL of aqueous solution, keep The temperature is lower than 20°C. After reacting for 3 hours, filter out insoluble salts, add 1.0L ethyl acetate to the filtrate and stir, adjust the pH to 5-6 with concentrated hydrochloric acid, separate the organic layer, and extract the aqueous layer with 3×500mL ethyl acetate , the organic layers were combined, washed with 1L of distilled water and 1L of sa...

Embodiment 2

[0097] The preparation of embodiment 2 compound (+)-58 and (-)-58

[0098] 1. Preparation of (-)-58:

[0099]

[0100] Weigh 0.590g (2mmol) (-)-Panthamide ketone, 1.150g (6mmol) DCC (dicyclohexylcarbodiimide) and 0.049g (0.4mmol) DMAP (4-dimethylaminopyridine) dissolved in 50mL Dichloromethane, add 6mmol p-trifluoromethylbenzoic acid under stirring at room temperature, TLC monitoring (EA:PE=2:1), after the reaction is complete, successively add 30mL 1M HCl, 30mL saturated sodium bicarbonate and 30mL saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was spinned off to obtain a crude product, which was subjected to column chromatography and recrystallized from methanol to obtain compound (-)-58, white crystal; yield: 0.748g (80.1%); m.p.131.5 -132.0°C; (c 0.2, CH 3 OH); 1 H NMR (500MHz, Chloroform-d) δ8.18–8.13(m,2H),7.70–7.64(m,2H),7.59–7.53(m,2H),7.48–7.41(m,1H),7.32–7.23 (m,2H),7.21...

Embodiment 3

[0105] The preparation of embodiment 3 compound (+)-58-1 and (-)-58-1

[0106] (-)-58-1:

[0107]

[0108] White needle-like crystals; yield: 0.508g (75.4%); m.p.176.3-177.1℃; (c 0.2, CH 3 OH); 1 H NMR (500MHz, Chloroform-d) δ7.55–7.49(m,2H),7.42(ddt,J=8.7,7.1,1.2Hz,1H),7.31–7.22(m,2H),7.15–7.10(m ,2H),7.10–6.98(m,3H),6.18–6.12(m,1H),5.44(d,J=8.8Hz,1H),4.03(dd,J=9.8,8.9Hz,1H),2.90( d,J=0.6Hz,3H),2.09(s,3H); 13 C NMR (126MHz, Chloroform-d) δ197.17, 171.03, 169.99, 136.46, 133.75, 133.38, 128.78, 128.76, 128.55, 128.26, 72.21, 64.88, 49.16, 29.95, 21.02; HRMS ([ESI): m / z 1] + Calculated 338.1387Found 338.1389; The enantiomeric excess was determined to be 99.9% by HPLC with a Daicel Chiralcel AD-H column (4.6mm×25cm) (n-hexane / i-PrOH=80 / 20, λ=254nm, 1mL / min) ,t=9.4min.

[0109] (+)-58-1:

[0110]

[0111] White needle-like crystals; yield: 0.494g (73.4%); m.p.178.1-179.3°C; (c 0.2, CH 3 OH); 1 H NMR (500MHz, Chloroform-d) δ7.55–7.49(m,2H),7.46–7.39(m,1H),7.29–...

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Abstract

The invention discloses an optical-activity neoclausenamidone derivative and application thereof. The structural formula of a compound is shown in the description (I), wherein R is C1-C4 paraffin, C2-C4 alkylene and C2-C4 alkyne or -COR1; R1 is selected from C1-C4 substituted or non-substituted paraffin, C1-C4 substituted or non-substituted alkylene and substituted or non-substituted phenyl or heterocyclic-ring aromatic rings; the substituent groups in R1 comprise phenyl, halogenated phenyl, C1-C4 alkyl-substituted phenyl, C1-C4 alkyl-halide-group-substituted phenyl, naphthoxy and pyridine orthiophene. The compound is novel in structure, has a great protection function on epencephalon particle nerve cell injuries induced by glutamic acid and nerve cell or tissue injuries caused by brain ischemia and can be used as a nerve cell protective agent, the injury of glutamic acid or oxygen and glucose deprivation to nerve cells is reduced, and accordingly neurodegenerative diseases, such as cerebral apoplexy, traumatic brain damage and senile dementia, caused by the injury are prevented and / or treated. The compound is shown in the description.

Description

technical field [0001] The invention relates to the technical field of biomedicine, and more specifically, to an optically active xanthinone derivative and its application. Background technique [0002] Glutamate is the main excitatory neurotransmitter in the central nervous system, involved in a variety of physiological functions, such as fast synaptic transmission, neuronal plasticity, learning and memory, etc. Excess glutamate activates the N-methyl-D-aspartate receptor (NMDAR), resulting in excess Ca 2+ Influx, resulting in damage to mitochondrial function, rapid increase in reactive oxygen species (reactive oxygen species, ROS), neurotoxicity, and eventually lead to neuronal cell death. The mechanism of nerve cell damage caused by excessive glutamate plays an important role in the occurrence and development of various brain diseases, such as neurodegenerative diseases, especially stroke, traumatic brain injury, Alzheimer's disease and other diseases. [0003] Ischemic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/273A61P25/28A61P25/00A61P9/10
CPCA61P9/10A61P25/00A61P25/16A61P25/28C07D207/273
Inventor 林汉森庞涛米俊儒徐亚洲许敬梓罗旭娜方成乔张陆勇
Owner GUANGDONG PHARMA UNIV
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