Indole alkaloids possessing 1,2,4-oxadiazole fragment, and preparation method and application thereof

A technology of alkaloids and indoles, applied in the field of medicine, can solve the problems of accelerating the onset of AD and achieve the effect of novel structure, high yield and easy operation

Inactive Publication Date: 2016-01-27
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the other hand, oxidative stress further leads to the accumulation of Aβ, which eventually accelerates the pathogenesis of AD.

Method used

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  • Indole alkaloids possessing 1,2,4-oxadiazole fragment, and preparation method and application thereof
  • Indole alkaloids possessing 1,2,4-oxadiazole fragment, and preparation method and application thereof
  • Indole alkaloids possessing 1,2,4-oxadiazole fragment, and preparation method and application thereof

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preparation example Construction

[0089] The preparation method of formula I compound of the present invention comprises the following steps:

[0090] (a) the compound of formula 1 is condensed with the compound of formula 2 to obtain the compound of formula 3;

[0091]

[0092] (b) the compound of formula 3 and the compound of formula 4 obtain the compound of formula I through coupling reaction,

[0093]

[0094] Among them, R in each formula 1 is bromine or iodine;

[0095] The definition of A, R and n is as described in claim 1;

[0096] R 3 It is a boric acid group or a borate ester group.

[0097] In another preferred example, the R 3 for -B(OH) 2 or

[0098] The condensing agent used in the step (a) is N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl- (3-Dimethylaminopropyl)carbodiimide hydrochloride (EDCI), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1-hydroxy-7 -Azobenzotriazole (HOAT), 1-hydroxybenzotriazole (HOBT), O-(7-azoben...

Embodiment 1

[0127] The preparation of embodiment 1 formula 3 compound

[0128]

[0129] Dissolve 0.50g of the compound of formula 1 in 50mL of methanol, then add 1.20g of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 0.8mLN , N-Diisopropylethylamine. After the mixture was stirred at room temperature for 0.5 hour, 0.59 g of the compound of formula 2 was added, and stirring was continued at room temperature for 1 hour. Afterwards, the reaction solution was concentrated, and the organic phase was extracted with ethyl acetate / water. The organic phase was washed successively with water and saturated brine, and concentrated. The residue was dissolved in 50 mL of ethanol and heated to reflux for 6 hours. After concentration, the residue was purified by column chromatography to obtain compound Formula 3 as a white solid with a yield of 75%.

[0130] 1 HNMR (300MHz, acetone-d6): δ7.62(d, J=9.0Hz, 1H), 7.43(m, 2H), 7.17(d, J=6.0Hz, 1H), 7.14(dd, J=8.0, 8.0Hz, ...

Embodiment 2

[0131] The preparation of embodiment 2 formula I compound

[0132]

[0133] Under the protection of Ar, 20 mg of the compound of formula 3 was dissolved in 3 mL of 1,4-dioxane, and then 4 mg of tetrakis(triphenylphosphine) palladium, 0.5 mL of water, 20 mg of potassium carbonate and the compound of formula 4 were added. The above mixture was heated at 90° C. for 12 hours, then concentrated, and the residue was purified by column chromatography to obtain the compound of formula I. The compound numbers, specific structural formulas and raw materials used are shown in Table 1 below.

[0134] Table 1 Compound number, specific structural formula and raw materials used

[0135]

[0136]

[0137]

[0138]

[0139] The yield of compound I-1 was 87%. 1 HNMR (300MHz, acetone-d6): δ7.84(d, J=90Hz, 2H), 7.65(d, J=6.0Hz, 1H), 7.50-7.35(m, 5H), 7.25(d, J=6.0 Hz,1H),7.14(dd,J=6.0,6.0Hz,1H),7.08(d,J=6.0Hz,1H),7.05(m,dd,J=6.0,6.0Hz,1H),4.53(s ,2H).ESI-MS: 342.2[M+H + ],364....

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Abstract

The invention provides a kind of indole alkaloids possessing a 1,2,4-oxadiazole fragment, and a preparation method and application thereof. The structure of the indole alkaloids is shown as a formula I, and in the formula I, A, R and n are defined as the specification and the claims. The indole alkaloids are novel in structure, the synthetic route is simple in operation, the yield is high, the safety is good, and the indole alkaloids possess obvious protection effect on beta-amyloid protein, hydrogen peroxide and oxygen-glucose deprivation induced nerve cell damage, and are applicable to prepare medicines for preventing and/or treating nervous system degenerative diseases.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to an indole alkaloid with a 1,2,4-oxadiazole fragment structure, a preparation method and application thereof. Background technique [0002] Neurodegenerative diseases are a group of chronic, degenerative nervous system diseases based on primary neuron degeneration, which mainly include Alzheimer's disease (AD), Parkinson's disease (Parkinson's disease) , PD) and so on. At present, the problem of population aging is becoming more and more serious, and the incidence of neurodegenerative diseases is increasing day by day, among which the highest incidence is AD. Scientists pointed out that there will be 22 million AD patients in the world in 2025, and the number of patients will reach 45 million by 2050. AD has become the fourth largest "killer" of the elderly after cardiovascular disease, cancer, and stroke. The incidence of dementia in my country is close to that of European and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14A61K31/4245A61K31/506A61K31/5377A61K31/496A61K31/4439A61P25/28A61P25/16A61P25/14
Inventor 郭跃伟章海燕萧伟王振中江成世傅燕
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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