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Preparation of a coumarin derivative metabolite and its application in the prevention and treatment of cerebral ischemia and Alzheimer's disease

A technology of coumarin derivatives and metabolites, applied in the field of medicine, can solve the problems of IMM-H004-7-O-β-glucuronic acid and other problems that have not been seen before, and achieves improvement of cerebral infarction area and behavioral damage, good health Pharmacokinetic advantages, structurally novel effects

Active Publication Date: 2021-01-12
INST OF MATERIA MEDICA CHINESE ACAD OF MEDICAL SCI
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  • 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

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  • Preparation of a coumarin derivative metabolite and its application in the prevention and treatment of cerebral ischemia and Alzheimer's disease
  • Preparation of a coumarin derivative metabolite and its application in the prevention and treatment of cerebral ischemia and Alzheimer's disease
  • Preparation of a coumarin derivative metabolite and its application in the prevention and treatment of cerebral ischemia and Alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Glycosyltransferase UGT88D4 catalyzes glucuronidation of IMM-H004

[0049] The reaction system is IMM-H004 304mg (1.0mM), glycosyl donor UDP-glucuronic acid 930mg (1.5mM), glycosyltransferase (UGT88D4) 80mg, pH 7.4 Tris-HCl buffer solution 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 C18 column (250mm×10mm I.D., Shiseido Co., Ltd., Tokyo, Japan); glycosylation product t R It is 7.1min. After UV, MS, 1 HNMR, 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 nov...

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).

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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

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Application Information

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Patent Type & Authority Patents(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