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Withanolides useful for the treatment of neurodegenerative diseases

一种化合物、烯基的技术，应用在神经系统疾病、神经肌肉系统疾病、肌肉系统疾病等方向，能够解决半衰期短毒性等问题

Active Publication Date: 2016-09-14
YINGXING PHARM CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although WA is a promising therapeutic agent for the treatment of ALS and other neurodegenerative diseases, it has a short half-life and some toxicity when administered in vivo

Method used

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  • Withanolides useful for the treatment of neurodegenerative diseases
  • Withanolides useful for the treatment of neurodegenerative diseases
  • Withanolides useful for the treatment of neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0114] Preparation of compounds of formula (I)

[0115] The following reaction scheme shows a semi-synthetic method for the preparation of compounds of formula (Ia) using withaferin A as a starting material. More specifically, withaferin A (available from Sigma-Aldrich Canada) can be treated with one or more alkylating agents to alkylate the -OH group of withardin A.

[0116] Reaction formula

[0117]

[0118] This reaction can produce compounds that are monoalkylated at C-4 or C-27, as well as mixtures of dialkylated WAs at both C-4 and C-27. The alkylated compound can be isolated and isolated by methods known in the art. When R 1 and R 3 At the same time, a single alkylation step can be performed. When R 1 and R 3 At different times, two alkylation steps can be carried out. For example, the alkylating agent R can be used 1 -X and R 3 -X (X is a leaving group) undergoes a stepwise reaction to independently alkylate the hydroxyl group of withaferin A.

[0119] Se...

Embodiment 1

[0127] Preparation of WA methyl ether analogs from WA

[0128]

[0129] 1 Withaferin A:R 1 = R 2 =H

[0130] 2 27-O-Methyl withaferin A:R 1 =CH 3 , R 2 =H

[0131] 3 4-O-Methyl withaferin A:R 1 =H,R 2 =CH 3

[0132] 4 4,27-O-Dimethyl withafarain A:R 1 = R 2 =CH 3

[0133] preparation

[0134] 150 mg of withaferin A (available from Sigma-Aldrich Canada) was treated with sodium hydride dissolved in methyl iodide (WA 1). This reaction produces a mixture of monomethylated compound and dimethylated WA. The reaction mixture was filtered to remove excess sodium hydride and sodium iodide. The filtrate was dried and the residue was redissolved in dichloromethane. The resulting solution was chromatographed on a silica gel column. combined with a single methyl ether ( 2 and 3 ) and dimethyl ether ( 4 ) and the compound was isolated by reverse phase chromatography.

[0135] The pure fractions of each compound were combined, concentrated, extracted into dichlo...

Embodiment 2

[0139] Brain bioluminescence of GFAP-luciferase mice exposed to LPS.

[0140] Therapeutic activity of two novel withanolides was tested in vivo using a transgenic mouse model. The ability of withanolalide to inhibit inflammation-associated astrocyte glialization induced by exposure to lipopolysaccharide (LPS) was assessed using transgenic GFAP luciferase mice generated in the laboratory of Dr. J.P. Julienwere. In vivo bioluminescence imaging was performed to assess the inflammatory response in the cranium. The decrease in the bioluminescent signal in the assessed area compared to the control (saline) group indicated that withanolide crossed the blood-brain barrier and subsequently inhibited gliosis.

[0141] Dilute withabalide [4-O-methyl withafanaline A (4-O-methyl WA) and 27-O-methyl withafanaline A (27-O-methyl WA)] in 100% In dimethyl sulfoxide (DMSO), the final concentration was 2 mg / ml. The in vivo efficacy of these analogs was tested using GFAP-luc transgenic mice. ...

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Abstract

Provided herein are synthetic analogs of withanolide natural products of formula (I), wherein R1-R4 are as defined herein, and their pharmaceutical uses in treating neurodegenerative diseases.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 61 / 908,455, filed November 25, 2013 under 35 U.S.C. §119(e), the contents of which are incorporated herein by reference. technical field [0003] The present application relates to synthetic analogues of the natural product of withanalide and their pharmaceutical use. Background technique [0004] Neurodegenerative diseases are characterized by selective neurodegeneration of specific regions of the brain and spinal cord. Amyotrophic lateral sclerosis (ALS), commonly known as "George's disease", is a progressive neurodegenerative disease of unknown etiology. The disease progressively impairs an individual's ability to control voluntary muscle movements. The disease tends to progress rapidly, leading to paralysis and death within 2-5 years of diagnosis in most cases. Currently, patients with ALS have very few treatment options. The only FDA-app...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J71/00A61K31/58A61P25/28
CPCC07J71/001A61P21/00A61P25/02A61P25/16A61P25/28A61K31/58
Inventor 安东尼·A·肖琼-皮埃尔·朱利恩艾格尼丝·H·陈
Owner YINGXING PHARM CO
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