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Benzoic acid nitrogen mustard fragment-containing compound and preparation method and use thereof

A technology of chlorambucil and compound, which is applied in the field of medicinal chemistry and can solve problems such as large toxic and side effects

Active Publication Date: 2019-01-04
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the clinical application of nitrogen mustards has relatively high toxicity and side effects, and they are non-selective to normal and tumor cells.

Method used

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  • Benzoic acid nitrogen mustard fragment-containing compound and preparation method and use thereof
  • Benzoic acid nitrogen mustard fragment-containing compound and preparation method and use thereof
  • Benzoic acid nitrogen mustard fragment-containing compound and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] Add scutellarin 1 (10g, 21.6mmol) to 120mL of absolute ethanol, 120mL of concentrated hydrochloric acid and 10mL of H 2 O in the mixture. In N 2 Under protection conditions, reflux for 36 hours. After cooling at room temperature, the reaction solution was poured into an equal volume of water, filtered with suction, washed with water until neutral, dried, and the crude product was separated by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) to obtain yellow solid scutellarin glycoside Yuan 5 1.05g, the yield is 17%. 1 H NMR(DMSO-d 6 ,400MHz)δ(ppm): 12.80(s,1H,5-OH), 10.47(s,1H,7-OH), 10.32(s,1H,4′-OH), 8.75(s,1H,6- OH),7.91(d,2H,J=8.9Hz,H-2′,6′),6.92(d,2H,J=8.9Hz,H-3′,5′),6.75(s,1H,H -8), 6.57(s, 1H, H-3).

Embodiment 2

[0028]

[0029] Dissolve 5 (286mg, 1mmol) in 5mL DMF, add K 2 CO 3 (207 mg, 1.5 mmol) and 1,2-dibromoethane (130 μL, 1.5 mmol). In N 2 Protected, reacted for 3h at 115℃. After cooling to room temperature, the reaction solution was poured into 50 mL of H 2 Extract with ethyl acetate (3×30 mL) in O, wash with saturated aqueous salt solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate by silica gel column chromatography (petroleum ether: ethyl acetate 3:1) to obtain light yellow powder 6 90mg, yield 29%. 1 H NMR(DMSO-d 6 ,400MHz)δ(ppm): 13.03(s,1H,5-OH),10.37(s,1H,4′-OH),7.93(d,2H,J=8.7Hz,H-2′,6′) ,6.92(d,2H,J=8.7Hz,H-3′,5′),6.80(s,1H,H-8),6.73(s,1H,H-3),4.39(t,2H,J =4.7Hz,-CH 2 -), 4.29(t,J=4.7Hz,2H,-CH 2 -).

Embodiment 3

[0031]

[0032] Intermediate 6 (312 mg, 1 mmol) was dissolved in 30 mL of acetone, and K was added 2 CO 3 (417mg, 3mmol) and 1,3-dibromopropane (420μL, 3mmol) were refluxed for 8h. After cooling to room temperature, it was filtered with suction, the filtrate was concentrated, and separated by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain 290 mg of light yellow powder 7a with a yield of 67%. Intermediate 7a (108mg, 0.25mmol) was dissolved in 5mL DMF, and K was added 2 CO 3 (68mg, 0.5mmol) and chlorambucil 4 (76mg, 0.25mmol) were reacted at room temperature for 24h. Pour the reaction solution into 30mL of H 2 Extract with ethyl acetate (3×20 mL) in O, wash with saturated aqueous salt solution, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) to obtain light yellow powder 8a55mg, yield 36%. 1 H NMR(DMSO-d 6 , 400MHz)δ(ppm): 12.32(s,1H,5-OH),8....

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Abstract

The invention relates to the field of natural medicine and medicine chemistry, and particularly relates to a compound containing benzoic acid nitrogen mustard fragment and a preparation process and use, in particular to a compound which introduces a benzoic acid nitrogen mustard fragment at a 4'-OH through a linking group after derivatization of the 6, 7-position of scutellarin, and a pharmaceutically acceptable salt thereof. The method also relates to the preparation process and antitumor activity of these compounds. The method of the benzoic acid nitrogen mustard fragment-containing compoundis shown in the general formula I, wherein m, n are as described in the claims and the specification. The formula is shown in the description.

Description

Technical field [0001] The present invention relates to the field of medicinal chemistry, and relates to a class of compounds containing chlorambucil fragments and preparation methods and uses thereof, and specifically relates to the 6,7-position derivatization of scutellarin aglycon, and the 4′-OH pass through a linker The group introduces the compound of the chlorambucil fragment. The invention also relates to the preparation method of these compounds and their application in the preparation of anti-tumor drugs. Background technique [0002] Malignant tumors are one of the main diseases threatening human health. In recent years, the incidence and mortality of cancer have been increasing year by year. However, the clinically used anti-tumor drugs have relatively large side effects, which seriously affect the therapeutic effect of tumor diseases. Therefore, it is particularly important to find and develop effective and low-toxic anti-tumor drugs. Natural products are one of th...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61P35/00A61P35/02A61K31/357
Inventor 李达翃华会明韩通李占林田康涛胡旭高祥
Owner SHENYANG PHARMA UNIVERSITY
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