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Beta-carboline derivatives, and preparation method and application thereof

A compound and pharmaceutical technology, applied in the field of beta-carboline derivatives, can solve the problems of limited effectiveness, poor bioavailability of anticancer drugs, and poor bioavailability

Inactive Publication Date: 2012-09-19
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Due to the poor solubility of β-carboline compounds, previous pharmacokinetic studies revealed that the bioavailability of β-carbolines is relatively low (<20%), resulting in extremely poor bioavailability, which is a serious limitation. Poor bioavailability of anticancer drugs often limits their effectiveness

Method used

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  • Beta-carboline derivatives, and preparation method and application thereof
  • Beta-carboline derivatives, and preparation method and application thereof
  • Beta-carboline derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0046] Preparation Example 11- Preparation of (4-hydroxy-3-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid

[0047]

[0048] Weigh 8g (39.2mmol) of L-tryptophan and 10g (65.8mmol) of 3-methoxy-4-hydroxybenzaldehyde into a 250ml eggplant bottle, add 150ml of glacial acetic acid, stir, heat to reflux at 70°C, and react first It was turbid, and clarified after a period of reaction, and finally a large amount of white solids were precipitated. Monitored by TLC plate, the raw material spots disappeared, stopped the reaction and cooled down to room temperature, under ice bath, added ammonia water to adjust the pH to 5, a large amount of white solid precipitated, filtered. The title compound of 3 was obtained as a white solid (3.5 g, 10.4 mmol, 27%).

[0049] [α] 25 D -20.36(c 0.1,MeOH);

[0050] IR (cm -1 ,KBr,neat):3325,1716,763;

[0051] 1 HNMR (300MHz, DMSO-d 6 ):δ10.79(1H,s,NH),7.48(1H,d,J=7.8Hz,Ar-H),7.27(1H,d,J=7.8Hz,Ar-H),7.06(3H,m ,Ar-H),6.75(1H,d...

preparation example 2

[0055] Preparation Example 21- Preparation of (4-hydroxy-3-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester

[0056]

[0057] Gradually add 8ml of thionyl chloride dropwise to 100ml of methanol under ice bath. After dropping, stir for 20 minutes. Then add 3.5g (10.36mmol) 1-(4-hydroxy-3-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylate acid. The reaction mixture was heated at reflux at 60° C. and stirred for 6 hours, and TLC detection showed that the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The residue was crystallized from methanol / ether to give the title compound 4 (1 g, 2.57 mmol, 25%) as a white solid.

[0058] [α] 25 D +186.3(c 0.1,MeOH);

[0059] IR (cm -1 ,KBr,neat):3097,1747,740;

[0060] 1 HNMR (300MHz, DMSO-d 6 ):δ10.80(1H,s,NH),9.58(1H,s,NH),7.54(1H,d,J=7.5Hz,Ar-H),7.31(1H,d,J=7.8Hz,Ar -H),7.10(3H,m,Ar-H),6.94(2H,s,Ar-H),5.84(1H,s,CH),4.74(1H,m,CH),3.85(3H,s, OCH...

preparation example 3

[0064] Preparation Example 31- Preparation of (4-hydroxy-3-methoxyphenyl)-β-carboline-3-carboxylic acid methyl ester

[0065]

[0066] Weigh 1g (2.57mmol) 1-(4-hydroxy-3-methoxyphenyl)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid methyl ester and 2.86g (25.8 mmol) SeO 2 , add to 250ml eggplant bottle, add 100ml dioxane, heat and reflux at 60°C for 4 hours, TLC board detects that the raw material spots disappear, stop the reaction and drop to room temperature, spin dry under reduced pressure, add 100ml distilled water, under ice bath, Add ammonia to adjust the pH to 9, filter, and rinse the filter cake with distilled water. Drying gave the title compound 5 as a brown solid (500 mg, 1.44 mmol, 56%).

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Abstract

The invention relates to beta-carboline derivatives, and a preparation method and the application thereof. More particularly, the invention relates to compounds in formula (I), wherein AA, n, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are defined by the specification. The invention also relates to the preparation method of the compounds shown in the formula (I), a pharmaceutical composition containing the compounds shown in the formula (I), and the application of the compounds to the preparation of antineoplastic drugs. The compounds have special inhibitory activity for the cell proliferationof four cancer cells including K562, HT-29, HL60 and A549.

Description

technical field [0001] The present invention relates to a kind of β-carboline derivatives with anti-tumor activity, their preparation method, the pharmaceutical composition containing the compound and the above-mentioned compounds on A549 (human lung adenocarcinoma epithelial cell line), HL60 (human premature Myeloid leukemia cells), K562 (human chronic myelogenous leukemia cells), HT-29 (human colon cancer cells) four tumor cell proliferation inhibitory activities and the application for the preparation of anti-tumor drugs. Background technique [0002] It is an important way to discover high-efficiency and low-toxic anti-tumor drugs by taking natural-sourced active ingredients with anti-tumor activity as lead compounds and modifying their structures. In the 1960s and 1970s, after people found that carboline alkaloids-Harman (Harman) had various biological activities in the seeds of Camelaceae plant camel, it caused the research of carboline derivatives. upsurge. β-carbol...

Claims

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Application Information

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IPC IPC(8): C07K5/078C07K5/097C07K1/06C07K1/02A61K38/05A61K38/06A61P35/00A61P35/02
Inventor 张建伟彭师奇赵明陈浩
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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