Soluble honokiol derivatives

a technology of honokiol and derivatives, applied in the field of compounds, compositions and methods of treatment or prevention, can solve the problems of brain cell ischemia or death or injury, unsuitable for clinical use in the treatment of ischemic stroke, etc., and achieve the effect of reducing edema and diminishing brain damag

Inactive Publication Date: 2019-04-25
TAIPEI MEDICAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]The present disclosure also provides a method of providing antioxidant and neuroprotective effects in a subject, comprising administering a therapeutically effective amount of a compound of the present disclosure to the subject. Certain embodiments of the method include that the method reduces edema and does not cause hemorrhage. In the methods described herein, the compound has a prolonged half-life compared to honokiol and / or converts to honokiol in plasma.
[0008]In one embodiment, the neuroprotective effect diminishes brain damage in the subject. In a further embodiment, the brain damage is ischemic stroke.

Problems solved by technology

Stroke is a medical condition in which the brain's blood vessels are clogged or broken, leading to brain cell ischemia or death or injury.
However, due to poor solubility in water or oil for honokiol, it is not suitable for clinical use in the treatment of ischemic stroke.

Method used

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  • Soluble honokiol derivatives
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Examples

Experimental program
Comparison scheme
Effect test

example

Example 1 Preparation of Tetrabenzyl (3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl) bis(phosphate) (2) (HP-TMU)

[0051]

[0052]A solution of N-chlorosuccinimide (5.0 equiv) in CH3CN was heated at 40° C. for 5 min. A solution of dibenzyl phosphite (5.0 equiv) in CH3CN was added to this prepared solution and stirred at room temperature for 4 hours. Meanwhile, a solution of honokiol (1, 1 equiv), N,N-diisopropylethylamine (DIPEA, 5.0 equiv), and 4-dimethylaminopyridine (DMAP, 0.2 equiv) in CH3CN was prepared and added to the stirring mixture at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched by H2O and extracted with toluene. The organic layer was collected and dried to afford tetrabenzyl (3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl) bis(phosphate) (referred as compound 2).

example 2

Preparation of Sodium 3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate) (3)

[0053]

[0054]Bromotrimethylsilane was added to a solution of compound 2 (1 equiv) in CH2Cl2 was added bromotrimethylsilane under ice bath and stirred at room temperature for 3 hours. The reaction mixture was quenched by H2O and extracted with ethyl acetate. The aqueous layer was collected and dried to afford a crude product. The resulting residue was dissolved in EtOH and then sodium methoxide (4.4 equiv) was added. After stirring at room temperature for 18 hours, the organic solvent was removed in vacuum. The resulting residue was dissolved in H2O and extracted with ethyl acetate. The aqueous layer was collected and dried to afford sodium 3′,5-diallyl-[1,1′-biphenyl]-2,4′-diyl bis(phosphate) (referred to as compound 3).

example 3

HP-TMU Exerts (1) Superior Neuroprotective Effects Against Embolic Stroke as Compared to Honokiol (2) without Causing the Risk of Hemorrhagic Incidence in Mice

[0055]Coronal sections of 2,3,5-triphenyltetrazolium chloride (TTC)-stained brains were taken after middle cerebral artery occlusion (MCAO) in the vehicle group treated with an isovolumetric solvent (normal saline, intravenous [i.v.]), and groups treated with HP-TMU (0.25, 0.5 and 1 mg / kg, i.v.) or honokiol (0.129, 0.258 and 0.516 mg / kg, i.v.; the doses of honokiol were adjusted by the ratio of the molecular weight of honokiol to HP-TMU (266.33 / 514.22)) after 30 min-embolic occlusion. The densitometric analyses for the measurement of infarct volume and brain edema were performed after treatment with HP-TMU or honokiol against embolic stroke in mice. Bleeding time was measured 10 min after the i.v. administration of normal saline (isovolumetric control) or HP-TMU (0.5 and 1 mg / kg, i.v.) for 30 min.

[0056]As shown in FIG. 1A, the...

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Abstract

The invention provides a soluble honokiol detivative (such as a water soluble honokiol derivative) and its application in antagonizing glycoprotein VI receptor and providing antioxidant and neuroprotective effects.

Description

FIELD OF THE INVENTION[0001]The present invention is related to the field of compounds, compositions and methods for treatment or prevention. Particularly, the invention provides a soluble honokiol derivative (such as a water soluble honokiol derivative) and its application in antagonizing glycoprotein VI receptor and providing antioxidant and neuroprotective effects.BACKGROUND OF THE INVENTION[0002]Stroke is a medical condition in which the brain's blood vessels are clogged or broken, leading to brain cell ischemia or death or injury. World Health Organization data shows that stroke is the second most frequent cause of death and each year about 6.0 million deaths resulted from stroke. Stroke can be divided into two types, namely, hemorrhagic stroke and ischemic stroke (about 80% of all stroke cases) which causes cerebral vascular thrombosis.[0003]Honokiol obtained from the stem of Magnolia officinalis was reported to have effects in improving brain damage caused by ischemic stroke ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/05A61K9/00A61P25/00
CPCA61K31/05A61K9/0019A61P25/00H03M13/1165H03M13/152H03M13/255H03M13/2707H03M13/2778H03M13/3761H03M13/3769H03M13/6356H03M13/6362H04L1/0041H04L1/0045H04L1/0057H04L1/0065H04L1/0067H04L1/0071H04L27/20
Inventor SHEU, JOEN-RONGLEE, FA-KUNGCHIEN, CHIH-CHENGHO, CHIH-MINGCHANG, CHAO-CHIENHSIEH, CHENG-YINGLIOU, JING-PING
Owner TAIPEI MEDICAL UNIV
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