Unlock instant, AI-driven research and patent intelligence for your innovation.

Preparation of coumarin derivative metabolite and application of metabolite in prevention and treatment of cerebral ischemia and Alzheimer disease

A technology of coumarin derivatives and metabolites, which is applied in the field of medicine, can solve the problems of IMM-H004-7-O-β-glucuronic acid and other problems that have never been seen, and can improve the area of ​​cerebral infarction, behavioral damage and structure. Novel, high-conversion effects

Active Publication Date: 2018-11-02
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no research reports on IMM-H004 metabolites, no research reports on IMM-H004-7-O-β-glucuronic acid for the treatment of cerebral ischemia and Alzheimer's disease, and no IMM-H004-7-O-β-glucuronic acid preparation method patent literature

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation of coumarin derivative metabolite and application of metabolite in prevention and treatment of cerebral ischemia and Alzheimer disease
  • Preparation of coumarin derivative metabolite and application of metabolite in prevention and treatment of cerebral ischemia and Alzheimer disease
  • Preparation of coumarin derivative metabolite and application of metabolite in prevention and treatment of cerebral ischemia and Alzheimer disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Glycosyltransferase UGT88D4 catalyzes glucuronidation of IMM-H004

[0049] The reaction system was 304mg (1.0mM) of IMM-H004, 930mg (1.5mM) of glycosyl donor UDP-glucuronic acid, 80mg of glycosyltransferase (UGT88D4), and the pH 7.4 Tris-HCl buffer was adjusted to 80ml. The reaction conditions were 30°C water bath, shaking (60rpm) for 24h. Through HPLC-UV detection, the conversion rate of glycosylation reaction can reach more than 85%.

Embodiment 2

[0051] Isolation, purification and identification of IMM-H004 glucuronide

[0052] The enzymatic reaction solution was repeatedly extracted 5 times with 160ml of ethyl acetate to remove the unreacted substrate IMM-H004. Subsequently, the raffinate was evaporated to dryness under reduced pressure and resuspended with 2 ml of methanol. Centrifuge at 15,000 g for 30 min, take the supernatant, and use reverse semi-preparative HPLC to separate and prepare glycosylated products. The initial HPLC mobile phase (methanol / water) ratio is 15 / 85, and the mobile phase ratio gradient increases to 100 / 0 within 30min; the flow rate is 3ml / min; the semi-preparative column is Shiseido capcell pak C18column (250mm×10mm I.D., Shiseido Co ., Ltd., Tokyo, Japan); glycosylation product t R It is 7.1min. After UV, MS, 1 H NMR, 13 It was identified as IMM-H004-7-O-β-glucuronic acid by means of spectroscopy such as C NMR, HSQC, and HMBC, and its structure was as in formula I. The compound has a n...

experiment example 1

[0058] Metabolism of IMM-H004 citrate in rat and human liver microsomes

[0059] IMM-H004 citrate (100μM) and rat and human liver microsomes (1mg / mL protein) were incubated for 30min after adding UDPGA (3mM) and alamethicin (50μg / mL) and all decreased by 99.8%, and could A glucuronide-conjugated product was detected. The glucuronic acid conjugation product was collected for NMR analysis, and the product was IMM-H004-7-O-β-glucuronic acid (IMM-H004G).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a coumarin derivative metabolite IMM-H004-7-O-beta-glucuronic acid (IMM-H004G) of a novel structure, a preparation method of the metabolite and application of compounds in prevention and treatment of cerebral ischemia and Alzheimer disease. Pharmacokinetic study discovers that intracerebral half life of IMM-H004 is less than 20 minutes, half life of the metabolite IMM-H004G can reach 24 hours, and intracerebral exposure is 2.3 times that of a drug prototype. The preparation method of the compound comprises the following steps: performing enzymatic glucuronization on IMM-H004 by utilizing glycosyl transferase, separating and purifying, thereby obtaining the novel compound IMM-H004G. Pharmacological experiments prove that the compound can achieve effects of effectively inhibiting nerve cell damage induced by oxygen glucose deprivation, A beta and okadaic acid, obviously improving behavioral disorder caused by artery occlusion reperfusion in rat brains and reducing the brain infarction area, and has an anti-cerebral ischemia effect similar to that of the IMM-H004. The IMM-H004G is possibly a main active metabolite of the in-vivo anti-cerebral ischemia effect of IMM-H004, and can be prepared into medicines for preventing and treating the cerebral ischemia and Alzheimer disease.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to the preparation of a new compound IMM-H004-7-O-β-glucuronic acid, a metabolite of a coumarin derivative IMM-H004, and its role in the prevention and treatment of cerebral ischemia and Alzheimer's disease. Applications in Alzheimer's disease. Background technique [0002] Cerebral ischemia and Alzheimer's disease are two important diseases of the elderly. With the acceleration of the aging process in our country, these two diseases will further endanger the life and health of the elderly in our country. [0003] At present, anti-ischemic drugs clinically at home and abroad mainly include: (1) improving cerebral blood circulation: A, thrombolytic drugs, such as recombinant tissue plasminogen activator (rt-PA), urokinase (UK); B, Anticoagulant drugs, such as heparin, heparin; C, antiplatelet drugs, such as clopidogrel, aspirin; D, defibrotic drugs, such as defibrase. (2) Neuropr...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/075C12P19/60A61K31/706A61P9/10A61P25/28
CPCA61P9/10A61P25/28C07H17/075C12P19/605
Inventor 陈乃宏李燕戴均贵宋修云盛莉乐田楚世峰张梓倩解可波谭圳
Owner INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI