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Beta-carboline and thio-analogues subsitituted by amino-acid radical/acyl, preparing method and application thereof

An acyl substitution and amino technology, applied in the field of drug synthesis, can solve the problem of the lack of ability to stabilize the DNA-intercalator-topoisomerase II ternary complex

Inactive Publication Date: 2006-04-26
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But they do not have the ability to stabilize the DNA-intercalator-topoisomerase II ternary complex

Method used

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  • Beta-carboline and thio-analogues subsitituted by amino-acid radical/acyl, preparing method and application thereof
  • Beta-carboline and thio-analogues subsitituted by amino-acid radical/acyl, preparing method and application thereof
  • Beta-carboline and thio-analogues subsitituted by amino-acid radical/acyl, preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Example 1: Synthesis of compound 1 4-propylamino-9-propyl-β-carboline (1)

[0052] 1) Synthesis of 1,2,3,4-tetrahydro-β-carboline (4)

[0053]Add 20.0g of tryptamine (0.125mol) and 100mL of glacial acetic acid into a 250mL round-bottomed flask, stir at room temperature to dissolve them, add 9ml of formaldehyde solution dropwise, heat up and reflux for 1 hour after the addition, stop the reaction, cool, add 500ml of water to dilute, 2N sodium hydroxide was adjusted to make it alkaline, and a large amount of solid precipitated was filtered, washed, and dried to obtain a crude product, which was recrystallized in chloroform to obtain 415.4 g (71.6%) of the product, m.p: 209-210°C. 1 H-NMR (CDCl 3 )δ: 2.75(t, 2H, 4-CH 2 , J=5.5, 6.0Hz), 3.05(t, 2H, 3-CH 2 , J=5.5, 6.0Hz), 3.85(s, 2H, 1-CH 2 ), 7.05(t, 1H, 6-H, J=7.4, 7.7Hz), 7.10(t, 1H, 7-H, J=7.4, 8.1Hz), 7.22(d, 1H, 5-H, J= 7.7 Hz), 7.40 (d, 1H, 8-H, J = 8.1 Hz), 9.04 (m, 1H, 9-NH).

[0054] 2) Synthesis of 2-benzoy...

Embodiment 2

[0062] Example 2: Synthesis of compound 2 1-(3-dimethylamino)propylamino-β-carboline (2)

[0063] 1) Preparation of 2,3-diketone-3-phenylhydrazone piperidine (8)

[0064] In a 1000mL round bottom flask, add 32mL of aniline, 200mL of water and 75mL of concentrated hydrochloric acid, cool in an ice-salt bath to below minus 5°C, add dropwise a sodium nitrite / water (26g / 52mL) solution, and stir for 5 minutes after the addition is complete.

[0065] In a 2000mL round-bottomed flask, add 62g of 3-carboxylate-2-piperidone and 730mL of 3% potassium hydroxide solution, react at 25°C for 8 hours, let stand overnight at room temperature, cool to 0°C, and add diazo Saline solution, kept at 0°C and adjusted to pH 3-4 with 10% sodium bicarbonate, maintained at 0-5°C for 12 hours. The precipitated solid was filtered and washed to obtain 858.8 g (80%) of the product, m.p 243-245°C.

[0066] 2) Preparation of 1-keto-1,2,3,4-tetrahydro-β-carboline (9)

[0067] In a 250mL round bottom flask, ...

Embodiment 3

[0075] Synthesis of compound 34-methyl-3-methoxycarbonyl-1-(3-dimethylaminopropyl)carbamoyl-β-carboline (3)

[0076] 1) synthesis of ethylidene isopropylamine (12)

[0077]Add 29ml (0.34mol) of isopropylamine to a 100ml dry round bottom flask, cool in an ice-water bath, add 19ml (0.34mol) of anhydrous acetaldehyde dropwise, stir at 0°C for 0.5 hours after the addition, add 10g of potassium hydroxide, and let stand After 0.5 hours, separate the organic phase, add 5g of potassium hydroxide, let stand overnight, separate the organic phase, add 5g of potassium hydroxide, and distill to obtain b.p 60-62°C fraction 12 22g (76%).

[0078] 2) Synthesis of α-methyl-N-isopropyl-1H-indole-3-methylamine (13)

[0079] Add 3.5g of indole (30mmol) and 15ml of glacial acetic acid into a 50ml dry round bottom flask, stir to dissolve, cool in an ice-water bath, add 2.6g (30mmol) of 12 benzene solution 5ml dropwise, and stir at 0°C for 24 hours after the addition is complete , post-treatment a...

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Abstract

The invention relates to a novel amino / acyl substituted β-carboline compound, a preparation method and application of antitumor activity. The invention transforms the structure of the gamma-carboline mother core to obtain the beta-carboline derivatives with basic side chain substitution. The compound of the present invention shows good antitumor activity through pharmacodynamic HL60 human leukemia and P388 mouse leukemia cell line antitumor activity tests, and can prepare novel antitumor drugs.

Description

Technical field: [0001] The invention belongs to the field of drug synthesis, and specifically relates to novel amino / acyl substituted β-carboline compounds, preparation methods and applications. Background technique: [0002] Malignant tumor has become a common disease that seriously endangers people's life and health. According to incomplete statistics, there are about 20 million new cases in the world every year; in my country, there are about 1.6-2 million new cases and 1.3 million deaths each year. Because the tumor has the ability to metastasize in the early stage, about 50% of the patients with clinically diagnosed primary tumors have developed distant metastases. More than % is related to the multidrug resistance of tumor cells, and the antitumor drugs currently used in clinical practice are far from meeting the requirements of treatment. [0003] Anti-tumor new drug research is an important field of new drug research in the 21st century, and the research on embedd...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D495/04A61K31/4365A61K31/437A61P35/00
Inventor 闻韧林志刚蒋为群余凡董肖椿缪宇平王浩黄磊青岛均
Owner FUDAN UNIV
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