Preparation and applications of 4-hydroxycoumarin compound

A kind of technology of hydroxycoumarin and compound, applied in the field of medicine

Inactive Publication Date: 2019-11-12
WUYI UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The drugs currently used in the clinical treatment of AD are mainly acetylcholinesterase (AChE) inhibitors, including donepezil, rivastigmine, galantamine and huperzine A, and there is no drug for brain neuroinflammation available

Method used

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  • Preparation and applications of 4-hydroxycoumarin compound
  • Preparation and applications of 4-hydroxycoumarin compound
  • Preparation and applications of 4-hydroxycoumarin compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Preparation of the 4-hydroxycoumarin compounds: under nitrogen protection, 2.0 mmol 4-hydroxycoumarin, 2.0 mmol fenamic acid non-steroidal anti-inflammatory drugs (mefenamic acid, flufenamic acid and trofenamic acid) and 2.4 mmol 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl), slowly dropwise add 0.2 mmol dimethylaminopyridine solution as a catalyst, react at room temperature for 2 h, concentrate After purification with a silica gel column, the 4-hydroxycoumarin compounds were obtained with yields of 88%, 91% and 85%, respectively. refer to figure 1 , figure 2 with image 3 , compound (I): 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (s, 1H), 8.19 (dd, J =8.5, 1.5 Hz, 1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H), 7.65-7.58 (m, 1H), 7.44-7.36 (m, 2H), 7.35-7.29 (m, 1H), 7.15 (dd, J = 7.2, 4.9 Hz, 2H), 7.11-7.04(m, 1H), 6.79 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 2.34 (s, 3H), 2.17 (s, 3H); HRMS (ESI) calcd for C 24 h 19 NO 4 [M + H] + : 385.4188, found ...

Embodiment 2

[0024] Evaluation of the inhibitory effect of 4-hydroxycoumarin compounds (I), (II) and (III) on lipopolysaccharide (LPS)-induced activation of microglial BV-2 by the determination of NO release (expressed as a percentage) , thus reflecting the in vitro anti-neuroinflammatory activity of the compound. The tested objects were all dissolved in DMSO to 10 mmol·L -1 , and then diluted with culture medium to the working concentration (20 μmol L -1 ),spare. BV-2 microglial cells in the logarithmic growth phase were taken to make cell suspension (primary isolation culture or BV-2 cell line), and 5×10 4 Cells were seeded in 96-well plates, 100 μL per well, and cultured overnight. Added LPS (100mg·L -1 ) and 20 μmol L -1 100 μL culture solution was added to the test target compound, the control group and the blank control group. 24 h after the addition, the release of NO in the cell solution of each well was detected by Griess reagent. The results show that the 4-hydroxycoumarin...

experiment example 3

[0032] Thirty healthy BALB / C female mice, weighing (30±4) g and aged (4±2) weeks, were randomly divided into 3 groups. Model group, drug group, and control group. The control group and the model group were intragastrically administered with distilled water (the volume was equivalent to that of the drug group, 0.3-0.5 mL / time), and the drug group was given 10 mg / (kg·d) for a total of 55 days. In addition to the control group, the model group and the drug group were established from the 8th day of intragastric administration, and the animals in each group were intraperitoneally injected with LPS 250 μg / (kg d), once every other day, for 7 consecutive days to establish LPS induction. Alzheimer's model. The blank group was injected intraperitoneally with normal saline (the volume is equivalent to that of other groups, 0.2 mL / time), once every other day, for 7 consecutive days.

[0033] 1 Detection of NO content

[0034] Decapitation was performed, and the brain was quickly removed...

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Abstract

The invention discloses preparation and applications of a 4-hydroxycoumarin compound. The 4-hydroxycoumarin compound is prepared through following steps: under nitrogen gas protection, 2.0mmol of 4-hydroxycoumarin, 2.0mmol of a fenamic acid non-steroidal anti-inflammatory drug (mefenamic acid, flufenamic acid, and tolfenamic acid), and 2.4mmol of 1-ethyl-(3-dimethyllaminopropyl)carbodiie hydrochlide (EDCI.HCl) are mixed, 0.2mmol of a dimethylaminopyridine solution is added slowly dropwise as a catalyst, and room temperature reaction is carried out for 2h, after condensation, a silica gel column is adopted for purifying so as to obtain a finished product. The 4-hydroxycoumarin compound can be used in preparation of neuroinflammation inhibitors and drugs used for treating senile dementia.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of a 4-hydroxycoumarin compound and its application in medicine. [0002] technical background [0003] Alzheimer's disease (Alzheimer's disease, AD), also known as senile dementia, is a progressive degenerative disease of the central nervous system, which mainly occurs in the elderly and pre-senile, manifested as memory impairment, aphasia, apraxia, and agnosia , Impairment of visuospatial ability, impairment of abstract thinking and calculation ability, personality and behavior changes, etc. At present, the etiology of Alzheimer's disease is still unclear so far, and it may be multi-factorial, such as genetics, environment, aging, metabolism, history of head trauma, estrogen deficiency, etc. It is a chronic and complex disease caused by various pathways. pathological process. Regarding its pathogenesis, the current academic circles have different opinions on it. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/52A61P25/28A61P25/00
CPCC07D311/52A61P25/28A61P25/00
Inventor 刘文锋黎妍文李冬利张焜
Owner WUYI UNIV
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