Bisindole alkaloid compound as well as synthesis method and application thereof

A technology of indole alkaloids and compounds, applied in the direction of active ingredients of heterocyclic compounds, organic chemical methods, drug combinations, etc., can solve many problems such as side effects, improper use, and inability to get rid of physical dependence and psychological dependence at the same time, and achieve inhibition The effect of cell proliferation

Active Publication Date: 2021-08-13
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Drug addiction is a global public hazard and a worldwide medical problem; addictive drug substitution therapy is mainly used in clinical detoxification. Opioids such as methadone and naltrexone cannot simultaneously get rid of physical dependence and psychologi

Method used

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  • Bisindole alkaloid compound as well as synthesis method and application thereof
  • Bisindole alkaloid compound as well as synthesis method and application thereof
  • Bisindole alkaloid compound as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Preparation of compound 1

[0054] 1. Preparation of Monomeric Alkaloid 1i

[0055]

[0056] first step:

[0057] At room temperature, 6-methoxyindole 1a was dissolved in anhydrous ether. After cooling down to 0°C, oxalyl chloride was added dropwise. After reacting for 3 hours, it was raised to room temperature and reacted for 1 hour to produce a red solid. Suction filter and wash with anhydrous ether solution. The filter cake was the crude compound 1b (yield 92%), which could be directly used in the next reaction without further purification.

[0058] Step two:

[0059] At room temperature, compound 1b was dissolved in absolute ethanol, and after cooling down to 0°C, triethylamine was added dropwise, and hydrogen chloride gas generated during the dropwise addition was taken away by argon flow. After the triethylamine was added dropwise, the reaction was heated under reflux for 3 hours. The temperature was lowered to 0°C, a yellow solid precipitated out, and it ...

Embodiment 2

[0108] Preparation of Compound 2

[0109] 1. Preparation of monomeric alkaloid 2d

[0110]

[0111] first step:

[0112] At room temperature, cesium carbonate was added into anhydrous acetonitrile, compound 2a and compound 2b were added, and the temperature was raised to 60°C. After reacting for 10 hours, it was cooled to room temperature, filtered through celite and washed with ethyl acetate. The organic phase was evaporated to dryness of solvent under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain compound 2c (yield 65%).

[0113] Step two:

[0114] Compound 2c was dissolved in nitrogen-nitrogen dimethylformamide at room temperature. Under the protection of argon, sodium formate, triphenylphosphine and palladium acetate were added, and the temperature was raised to 55°C for 6 hours. Water and dichloromethane were added, and the reaction solution was extracted 3 times with dichloromethane. The org...

Embodiment 3

[0141] Preparation of compound 3

[0142]

[0143] first step:

[0144] At room temperature, compound 3a and compound 3b were dissolved in 1% methanolic hydrochloric acid solution, and heated to reflux for 1 hour under the protection of argon atmosphere. Diluted with water, basified with sodium bicarbonate solution, extracted 3 times with dichloromethane. The organic phases were combined and washed with saturated sodium chloride solution. After drying and filtering over anhydrous sodium sulfate, the organic phase was evaporated to dryness under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography to obtain compound 3 (yield 68%).

[0145] Compound 3: 1 H NMR (600MHz, CD 3 OD) δ7.66(d, J=7.7Hz, 1H), 7.23(d, J=8.7Hz, 1H), 7.10(d, J=7.7Hz, 1H), 7.07(1H), 7.07(1H), 6.86(d, J=8.7Hz, 1H), 5.23(dd, J=12.4, 3.3Hz, 1H), 4.03(m, 1H), 3.99(s, 3H), 3.70(s, 3H), 3.52(d ,J=2.1Hz,1H),3.41(overlapped,2H),3.39(1H),3.21(1H),3.03(d...

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Abstract

The invention discloses a bisindole alkaloid compound as well as a synthesis method and application thereof. The compound has a structure as shown in formula I. In the formula I, R1 is independently selected from C1-C4 alkoxy or hydrogen; if R1 is alkoxy, n is 1 or 2; R2 is independently selected from C1-C4 alkyl groups or hydrogen; R3 is independently selected from a group consisting of C1-C4 alkoxy carbonyl groups or hydrogen; R4 is hydrogen; R5 is independently selected from a C1-C4 alkyl group or a C1-C4 hydroxyalkyl group; and R6 is independently selected from carbonyl, hydroxyl or hydrogen. The bisindole alkaloid compound can selectively relax pulmonary artery, inhibit proliferation of pulmonary artery endothelial cells and vascular smooth muscle cells, reduce right ventricular diastolic pressure of mice with pulmonary arterial hypertension and inhibit right ventricular hypertrophy. The bisindole alkaloid compound can resist drug addiction in a dose-dependent manner, has a chemical structure type different from that of an existing anti-addiction drug, and is expected to be developed into a novel anti-addiction drug.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a bisindole alkaloid compound, a synthesis method thereof and an application in preparing medicines for treating pulmonary hypertension and anti-addiction. Background technique [0002] Pulmonary hypertension (Pulmonary hypertension) is a common malignant and progressive pulmonary vascular disease caused by various causes of elevated pulmonary artery pressure, and its pathological features are excessive constriction of pulmonary arterioles and vascular remodeling. Endothelial cell dysfunction is characterized by decreased levels of vasodilation substances such as nitric oxide and prostacyclin, and increased levels of vasoconstrictor substances such as endothelin, resulting in excessive constriction of pulmonary arteries. Vascular remodeling manifests as intimal neogenesis, medial thickening and adventitial fibrosis, etc. The activation and excessive proliferation of...

Claims

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Application Information

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IPC IPC(8): C07D519/00A61K31/55A61P9/12A61P25/30A61P11/00
CPCC07D519/00A61P9/12A61P25/30A61P11/00C07B2200/07Y02P20/55
Inventor 张晓琦叶文才张冬梅李勇敖运林
Owner JINAN UNIVERSITY
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