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Di-beta-carboline alkali compound and preparation method, medicinal composition and application thereof

A technology of compound and carboline base, which is applied in the field of application of bis-β-carboline base compound and its pharmaceutically acceptable salt, in the preparation of anti-tumor drugs, and can solve the problems of undisclosed effects, etc.

Active Publication Date: 2012-11-28
XINJIANG HUASHIDAN PHARMA RES
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] [According to the synthesis method of Winckler et al., synthesized 9-position methylene bridge-linked and 11C-labeled bis-3,4-dihydro-β-carboline and bis-β-carboline compounds, and found that such bis-β -Carboline compounds can be used as novel imaging agents for positive emission tomography to image acetylcholinesterase in Alzheimer's disease (AD) patients, but the antitumor effects of such compounds have not been disclosed

Method used

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  • Di-beta-carboline alkali compound and preparation method, medicinal composition and application thereof
  • Di-beta-carboline alkali compound and preparation method, medicinal composition and application thereof
  • Di-beta-carboline alkali compound and preparation method, medicinal composition and application thereof

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preparation example 1

[0128]

[0129] Ethyl 1-(pyridin-3-yl)-β-carboline-3-carboxylate:

[0130] (a) Synthesis of ethyl 1-(pyridin-3-yl)-1,2,3,4-tetrahydro β-carboline-3-carboxylate

[0131] Add L-tryptophan ethyl ester (8.04 g, 30 mmol) and isopropanol (84 mL) into a 250 ml round bottom flask, and stir at room temperature until the solution is clear. Subsequently, 3-pyridinecarbaldehyde (36 mmol) was added, and the mixture was heated to reflux for reaction, followed by TLC detection. After the reaction was completed, it was concentrated to dryness under reduced pressure to obtain a light yellow solid. Dissolve the above solid in water, NaHCO 3 Alkalinization, extraction with ethyl acetate, combined organic phases, washing with water, washing with saturated brine, drying over anhydrous sodium sulfate, and concentrating to dryness under reduced pressure to obtain an oily product, which can be directly used in the next step without purification.

[0132] (b) Synthesis of ethyl 1-(pyridin-3-yl)-...

preparation example 2

[0135]

[0136] 1-(pyridin-3-yl)-β-carboline:

[0137] L-tryptophan (10mmol) and glacial acetic acid (20ml) were mixed, heated until completely dissolved, then 3-pyridinecarbaldehyde (10.6mmol) was added, the reaction mixture was heated to reflux, followed by TLC detection. After the reaction is completed, the reaction mixture is poured into boiling water, then potassium dichromate (20mmol) is added, heating is continued for 20 minutes, the heating is stopped, the reaction solution is cooled to room temperature, and then anhydrous Na 2 SO 3 (2.7g) with constant stirring, then adjust the pH value to about 10 with solid NaOH, extract with ethyl acetate, combine the organic phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain yellow Solid, recrystallized from ethyl acetate to obtain 1.97 g of light yellow solid, yield 80%. 1 H NMR (300MHz, CDCl 3 ): δ10.11 (1H,...

preparation example 3

[0139]

[0140] 1-(thiophen-3-yl)-β-carboline:

[0141] Mix L-tryptophan (10 mmol) and dichloromethane (100 ml), add phenylacetaldehyde (1.05 ml) and trifluoroacetic acid (1.5 ml) under stirring at room temperature, continue stirring at room temperature, and track and detect by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to about 30 ml, filtered, and carefully washed with ether to obtain a solid. The solid was subsequently dissolved with glacial acetic acid, and KMnO 4 (30mmol) reflux, TLC tracking detection. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was poured into water, alkalized with sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, anhydrous Na 2 SO 4 Dry, decolorize with activated carbon, filter, and concentrate the filtrate to dryness under reduced pressure, and perform sili...

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Abstract

The invention discloses a di-beta-carboline alkali compound and a preparation method, a medicinal composition and application thereof. The di-beta-carboline alkali compound and pharmaceutical salt thereof are shown as a general formula I. The di-beta-carboline alkali compound is prepared by condensing a beta-carboline intermediate and dihalogenated alkane. The medicinal composition comprises an effective dose of di-beta-carboline alkali compound shown as the formula I and a pharmacodynamically acceptable carrier. The invention also discloses application of the di-beta-carboline alkali compound to preparation of medicines for resisting tumors such as melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermal carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostatic cancer and colon cancer.

Description

technical field [0001] The invention relates to a class of bis-β-carboline base compounds and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition of such compounds, and an application thereof in the preparation of antitumor drugs; it belongs to the technical field of medicine. Background technique [0002] Cook et al. (2005, 2010) reported the synthesis of bis-β-carbolines linked by 6-alkyne bridges, and subsequently confirmed that such bis-β-carboline bases are sensitive to benzodiazepine receptors (Bz) and γ-aminobutyric acid Acid (GABA) receptors have good affinity. [0003] Winckler et al. (2010) designed bis-3,4-dihydro-β-carboline and bis-β-carboline compounds connected by 2 methylene bridges and 9 methylene bridges and confirmed that these compounds have Better acetylcholinesterase and butyrylcholinesterase inhibitory activity. [0004] [According to the synthesis method of Winckler et al., synthesized 9-position met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00C07D471/04A61K31/437A61K31/444A61P35/00
Inventor 王子厚武嘉林尚靖马芹施步席郭亮范文玺孙洁
Owner XINJIANG HUASHIDAN PHARMA RES
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