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3-Position diamine beta-carboline alkali compound, and preparation method, medicinal composition and use thereof

A technology of compounds and medicinal salts, applied in the application field of 3-position diamine β-carboline base compounds, in the preparation of anti-tumor drugs, which can solve the problems of not disclosing anti-tumor effects

Active Publication Date: 2014-12-03
XINJIANG HUASHIDAN PHARMA RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] According to the synthesis method of Winckler et al., Zheng et al. (2011) synthesized the 9-position methylene bridge link and 11 C-labeled bis-3,4-dihydro-β-carbolines and bis-β-carbolines, which were found to be useful as novel imaging agents for positive emission tomography Imaging of acetylcholinesterase in Alzheimer's disease (AD) patients, but no disclosure of antitumor effects of this class of compounds

Method used

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  • 3-Position diamine beta-carboline alkali compound, and preparation method, medicinal composition and use thereof
  • 3-Position diamine beta-carboline alkali compound, and preparation method, medicinal composition and use thereof
  • 3-Position diamine beta-carboline alkali compound, and preparation method, medicinal composition and use thereof

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Experimental program
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Effect test

preparation example 1

[0146]

[0147] 1. Preparation of 1-substituted-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid 2a-h:

[0148] 1,2,3,4-Tetrahydro-β-carboline-3-carboxylic acid (2a):

[0149] Mix L-tryptophan (102g, 0.5mol) and NaOH (20g, 0.5mol), add 800ml of water, and stir magnetically. After the solution is clarified, add 37-40% formaldehyde (37.5ml, 0.54mol), and rinse the measuring device with about 100ml of water. Reaction at room temperature for 3.5h, then changed to heating under reflux for 2.5h. After the reaction is complete, cool it down, adjust the pH to about 6 with concentrated HCl, and put it in the refrigerator overnight. Filter, rinse the solid with water several times, and finally bring the water once with a small amount of acetone. After drying, a white solid was obtained with a yield of 98.5%.

[0150] 1-Methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2b):

[0151] L-tryptophan (0.4mol) and 600mlH 2 O mixed, then added 7.5ml H 2 SO 4 (0.5mol / L), after ...

preparation example 2

[0258]

[0259] General preparation of intermediates 9a-e:

[0260] Add ethyl β-carboline-3-carboxylate 8a or 8b (10mmol) and 30ml DMF to a 100ml round bottom flask, stir at room temperature until the solution is clear, then add 60% NaH (0.8g, 20mmol), and stir at room temperature for 15 minutes , and then added haloalkane (30mmol), stirred at room temperature, TLC tracking detection. After the reaction is complete, pour the reaction solution into ice water, extract with ethyl acetate (100ml×3), combine the organic phases, wash with water, wash with saturated brine, dry, filter, and concentrate to dryness under reduced pressure, silica gel column chromatography, ethyl acetate: Petroleum ether = 1:2 elution, the target product was collected and concentrated to dryness under reduced pressure to obtain a white solid.

[0261] Ethyl 9-isopropyl-β-carboline-3-carboxylate (9a)

[0262] Starting from ethyl β-carboline-3-carboxylate and 2-bromopropane, a white solid (1.8g, 64%) w...

Embodiment 1

[0298]

[0299] General Preparation Process of 3-Aminoalkyl Chain Linked Bis-β-Carboline Base 1-39

[0300] Add the corresponding β-carboline-3-carbaldehyde (2mmol) and anhydrous methanol (30ml) in a 100ml round bottom flask, stir at room temperature for 10 minutes, then add the corresponding diamine (1mmol), and the reaction mixture is heated to reflux 2 hours. Reflux was stopped, methanol was distilled off under reduced pressure, and absolute ethanol was taken with water twice. The reaction residue was dissolved in anhydrous methanol (30ml), then sodium borohydride (5mmol) was added, the reaction was stirred at room temperature for 4-6 hours, followed by TLC detection. After completion of the reaction, carefully add concentrated hydrochloric acid (10ml) to the reaction solution, stir at room temperature for 15 minutes, then basify with concentrated sodium hydroxide solution, extract twice with dichloromethane (100ml), combine the organic phases, wash with water, and wash...

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Abstract

The invention discloses a 3-position diamine connected beta-carboline alkali compound, and a preparation method, a medicinal composition and a use thereof. The above di-beta-carboline alkali compound and its medicinal salt are represented by general formula I, and the preparation method of the di-beta-carboline alkali compound comprises the following steps: carrying out a condensation reaction on two molecules of beta-carboline-3-formaldehyde and one molecule of diamine NH2(CH2)nNH2, and hydrogenating. The invention also discloses the medicinal composition, and an application of the di-beta-carboline alkali compound in the preparation of antitumor medicines. The medicinal composition comprises an effective amount of the di-beta-carboline alkali compound represented by the formula I and a pharmacodynamically acceptable carrier. The antitumor medicines are used for treating melanoma, stomach cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermal cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and colon cancer.

Description

technical field [0001] The invention relates to a class of 3-position diamine 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; belonging to medicine technology field. Background technique [0002] Jiang et al. (2002) reported the design and synthesis of bis-3,4-dihydro-β-carbolines and bis-β-carboline compounds linked by a methylene bridge at the 1-position, and found that such bis-β-carbolines Alkali is cytotoxic to the L1210 cell line. [0003] Cook et al. (2005, 2010) reported the synthesis of bis-β-carbolines linked by 6-alkyne bridges, and subsequently confirmed that the bis-β-carboline bases are sensitive to benzodiazepine receptors (Bz) and γ-aminobutyric acid Acid (GABA) receptors have good affinity. [0004] Winckler et al. (2010) designed bis-3,4-dihydro-β-carboline and bis-β-carboline compounds ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00A61K31/437A61P35/00
CPCC07D519/00
Inventor 王子厚武嘉林郭亮范文玺尚靖马芹刘利周凡
Owner XINJIANG HUASHIDAN PHARMA RES
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