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Hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol

A technology based on nitroimidazole and nitroimidazole, which is applied in the field of hypoxia-activated prodrugs and their synthesis of 2-nitroimidazole-1-alkanols, which can solve the problems of incomplete transformation of the original drug form of the drug , to achieve the effects of enhancing curative effect and bioavailability, improving targeting and increasing selectivity

Inactive Publication Date: 2017-07-25
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the carbonate prodrug cannot be completely converted into the original drug form of the drug in the human body

Method used

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  • Hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol
  • Hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol
  • Hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of compound 3

[0046]

[0047]Cesium carbonate (5.8g, 17.70mmol) was added to the N,N-dimethylformamide solution of compound 1 (1g, 8.85mmol), stirred at room temperature for 5 minutes, and compound 2 (1.4g, 9.73mmol) was added to the system ), the reaction mixture was reacted at 50°C for 12 hours, the reaction system was concentrated by rotary evaporation with an oil pump, and the concentrate was separated and purified by column chromatography (dichloromethane:methanol=60:1) to obtain a light yellow solid (1.3g, 88%). 1 H NMR (400MHz, CDCl 3 )δ7.17(s,1H),7.14(s,1H),4.59(t,J=6.9Hz,2H),3.68(t,J=5.7Hz,2H),2.16-2.05(m,2H), 1.78(s,1H). 13 C NMR (101MHz, DMSO) δ144.7, 128.0, 127.9, 57.6, 47.1, 32.4. MS (ESI) m / z = 172.06 [M+H] + .

Embodiment 2

[0049] Preparation of compound 5

[0050]

[0051] Under ice-cooling, tert-butyldimethylsilyl chloride (6.4g, 42mmol) was added in batches to a dichloromethane solution of compound 4 (5g, 40mmol) and imidazole (5.5g, 80mmol), and reacted at room temperature for 2 hours. The system was diluted with dichloromethane, washed with saturated aqueous sodium carbonate, washed with water, washed with saturated aqueous sodium chloride, the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow oil (6.7g, 70%). 1 H NMR (400MHz, CDCl 3 )δ3.88(t,J=6.5Hz,2H),3.38(t,J=6.5Hz,2H),0.91(s,9H),0.08(s,6H).MS(ESI)m / z=238.04 [M+H] + .

Embodiment 3

[0053] Preparation of compound 6

[0054]

[0055] Add cesium carbonate (7g, 21.24mmol) to the N,N-dimethylformamide solution of compound 1 (1.2g, 10.62mmol), and add compound 5 (2.8g, 11.68mmol) under stirring, and the reaction mixture is 60°C After 12 hours of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, the organic phase was washed with water and saturated aqueous sodium chloride solution, and the organic phase was spin-dried to obtain a yellow solid (2 g, 70%). 1 H NMR (400MHz, CDCl 3 )δ7.38(s,1H),7.25(s,1H),4.67(t,J=4.9Hz,2H),4.07(t,J=4.9Hz,2H),0.95(s,9H),0.06( s,6H).MS(ESI)m / z=272.83[M+H] + .

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Abstract

The invention discloses a hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol. The 2-nitroimidazole-1-alkanol of the prodrug is connected to an antineoplastic drug through a carbonate bond. The prodrug has a structure shown in the formula I and in the formula, n represents 0, 1, 2 or 3, and R1, R2, R3 and R4 include but not limited to hydrogen, hydroxyl, chlorine, bromine, fluorine, C1-C6 alkyl, C1-C6 alkyl containing alkenyl and C1-C6 alkyl containing alkynyl. The prodrug can target the hypoxia region of the tumor and is reduced by the high expressed specific enzyme in the hypoxic tumor tissue so that the original drug is released. The prodrug is stable in vitro and in vivo, and the released drug can be specifically reduced in hypoxic tumor tissue so that the targeting of the anti-tumor drug is improved, toxic or side effects are reduced and the curative effect is improved.

Description

technical field [0001] The present invention relates to a kind of medicine, especially a kind of hypoxia-activated prodrug of 2-nitroimidazole-1-alkyl alcohol represented by general formula I and its synthetic method, and this kind of prodrug has good in vivo and external The stability of the drug can be reduced by specific enzymes highly expressed in hypoxic tumor tissue to release the drug, improving the anti-tumor efficacy and targeting. [0002] Background technique [0003] Malignant tumors are a serious threat to human life and health, and chemists are committed to developing highly efficient and low-toxic anti-tumor drugs. Traditional antineoplastic drugs, such as paclitaxel and camptothecin, act on microtubules and topoisomerases respectively, which have obvious inhibitory effects on rapidly growing and differentiated cells in normal areas with relatively abundant blood vessels, but slow-growing The effect of cells in the hypoxic area is limited, so the clinical ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D491/22C07H15/252C07H19/073C07H1/00A61P35/00A61P35/02
CPCC07D405/12C07D491/22C07H1/00C07H15/252C07H19/073
Inventor 吕伟金沉文帅祝奇文余家会
Owner EAST CHINA NORMAL UNIV
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