3-position bis-beta-carboline alkali compound, and preparation method, pharmaceutical composition and application thereof

A technology of compound and carboline base, which is applied in the field of preparation of anti-tumor drugs by 3-position bis-β-carboline base compounds and their pharmaceutically acceptable salts, and can solve the problems of not disclosing anti-tumor effects

Active Publication Date: 2013-03-06
XINJIANG HUASHIDAN PHARMA RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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-carboline and bis-β-carboline compounds, found that such bis-β-carboline compounds can be used as new 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 bis-beta-carboline alkali compound, and preparation method, pharmaceutical composition and application thereof
  • 3-position bis-beta-carboline alkali compound, and preparation method, pharmaceutical composition and application thereof
  • 3-position bis-beta-carboline alkali compound, and preparation method, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example

[0153] Preparation Example: Preparation of Intermediates

[0154]

[0155] Methyl 1-(4-methoxy)phenyl-9-ethyl-β-carboline-3-carboxylate (32)

[0156] Methyl 1-(4-methoxy)phenyl-β-carboline-3-carboxylate (3.32g, 10mmol), DMF (50ml) were mixed, stirred at room temperature until clear, then added 60% NaH (1.2g , 30mmol), stirred and reacted at room temperature for 5 minutes, then added bromoethane (15mmol), continued to stir the reaction at room temperature, TLC tracking detection, the reaction was completed, the reaction solution was poured into ice water, extracted with ethyl acetate, the combined extracts, washed , washed with saturated brine, dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, concentrated to dryness under reduced pressure, silica gel column chromatography, eluted with ethyl acetate to obtain 3.0 g of white solid, yield 84%. FAB-MS (M+1): 361.

[0157] Methyl 1-(4-methoxy)phenyl-9-(3-phenyl)propyl-β-carboline-3-carboxylate (...

Embodiment 1

[0173]

[0174] The preparation method of double β-carboline (1-3):

[0175] 1,9-Dimethyl-β-carboline-3-carboxylic acid (2.1mmol), DMF (30ml), anhydrous potassium carbonate (3.0mmol), dibromoalkane (1mmol) were mixed, stirred at 80°C for 8 -20h, TLC follow-up detection (developing solvent: methanol), the reaction is completed, the reaction mixture is poured into 100% water, extracted with dichloromethane, combined extracts, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure , silica gel column chromatography, eluting with dichloromethane:ethyl acetate=10:1, and concentrating to dryness under reduced pressure to obtain the target product.

[0176] 1,3-Bis(1,9-dimethyl-β-carboline-3-carboxylic acid)propylene glycol (1): The above-mentioned dibromoalkane is 1,3-dibromopropane. 0.36 g of white solid was obtained, the yield was 69%. 1 H NMR (300MHz, CDCl 3 ): δ8.36(2H, s), 7.83(2H, d, J=7.8Hz), 7...

Embodiment 2

[0180]

[0181] The preparation method of double β-carboline (4-6):

[0182] 9-Ethyl-1-methyl-β-carboline-3-carboxylic acid (2mmol), DMF (30ml), anhydrous potassium carbonate (3.0mmol), dibromoalkane (1mmol) mixed, stirred at 80°C 8-20h, TLC follow-up detection (developer: acetone:petroleum ether=1:2), after the reaction is complete, pour the reaction mixture into 100% water, extract with dichloromethane, combine the extracts, wash with water, wash with saturated brine, anhydrous sulfuric acid Dry over sodium, concentrate to dryness under reduced pressure, perform silica gel column chromatography, elute with dichloromethane: ethyl acetate = 10:1, and concentrate to dryness under reduced pressure to obtain the target product.

[0183] 1,6-bis(9-ethyl-1-methyl-β-carboline-3-carboxylic acid)hexamethylene diester (4): The above-mentioned dibromoalkane is 1,6-dibromohexane. 0.38 g of white solid was obtained, the yield was 64%. 1 H NMR (300MHz, CDCl 3 ): δ8.68(2H, s), 8.14(2H...

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Abstract

The invention discloses a bis-beta-carboline alkali compound, and a preparation method, a pharmaceutical composition and application thereof. Specifically, the bis-beta-carboline alkali compound and a pharmaceutically acceptable salt thereof are shown in the general formula I. The bis-beta-carboline alkali compound is prepared by condensation of beta-carboline intermediates and dihaloalkane hydrocarbons. The invention further discloses a pharmaceutical composition and application of the bis-beta-carboline alkali compound in preparing anti-tumor drugs. The pharmaceutical composition comprises an effective dose of bis-beta-carboline alkali compound shown in the formula I and a pharmaceutically acceptable carrier, and the tumor comprises melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermoid carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer and colon cancer.

Description

technical field [0001] The invention relates to a class of 3-position double 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 medical 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 such 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 c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00C07D471/04A61K31/437A61P35/00
Inventor 武嘉林王子厚马芹范文玺郭亮孙洁魏露露喇润菲
Owner XINJIANG HUASHIDAN PHARMA RES
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