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Branched 2-nitroimidazole compound and application thereof in hypoxic selective antitumor prodrugs

A technology for nitroimidazoles and antitumor drugs, applied in the field of compounds, can solve problems such as insufficient targeting and poor effect, and achieve the effects of improving targeting, reducing toxic and side effects, enhancing curative effect and bioavailability

Active Publication Date: 2018-04-10
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TH-302 has the defect of insufficient targeting, which leads to the poor effect of clinical phase III trials

Method used

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  • Branched 2-nitroimidazole compound and application thereof in hypoxic selective antitumor prodrugs
  • Branched 2-nitroimidazole compound and application thereof in hypoxic selective antitumor prodrugs
  • Branched 2-nitroimidazole compound and application thereof in hypoxic selective antitumor prodrugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of compound 3

[0040]

[0041] Cesium carbonate (6.52g, 20mmol) and compound 1 (1.13g, 10mmol) were dissolved in 15mL of N,N-dimethylformamide, the mixture was stirred at room temperature for 15 minutes, and compound 2 (5.12g, 20mmol) was added. Heated to 80°C, stirred overnight, and the reaction was complete. Quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated the organic phase, and separated by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 2.4 g of yellow oil with a yield of 99%. 1 H NMR (400MHz, CDCl 3 )δ7.13(s, 1H), 7.11(s, 1H), 4.74(s, 2H), 4.15(q, J=7.2Hz, 2H), 1.25(t, J=6.7Hz, 3H), 1.21( d,J=5.8Hz,6H).MS(ESI) Calcd for C 10 h 16 N 3 o 4 [M+H] + :242.1, found: 242.1.

Embodiment 2

[0043] Preparation of Compound 4

[0044]

[0045] Compound 3 (4 g, 16.6 mmol) was dissolved in 20 mL of DMF, NBS (5.9 g, 33.2 mmol) was added, and stirred overnight at room temperature. After the reaction was complete, it was quenched by adding water, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 3.5 g of a yellow solid with a yield of 66% and a melting point of 65-67°C. 1 H NMR (400MHz, CDCl 3 )δ7.17(s,1H),4.72(s,2H),4.16(q,J=7.1Hz,2H),1.26(t,J=7.2Hz,4H),1.23(s,6H). 13 CNMR (100MHz, CDCl 3 )δ175.4, 126.2, 115.1, 61.9, 55.6, 44.7, 23.1, 22.2, 14.1. HRMS (ESI): m / z Calcd for C 10 h 14 N 3 BrNa[M+Na] + :342.0006,found:342.0071.

Embodiment 3

[0047] Preparation of Compound 6

[0048]

[0049]Under nitrogen protection, compound 4 (1g, 3mmol), Pd(dppf)Cl 2 DCM (245mg, 0.3mmol), potassium phosphate (1.27g, 6mmol) were suspended in 10mL DMF, compound 5 (0.92g, 6mmol) was added dropwise, heated to 60°C, and stirred overnight. Some raw materials could not react completely, quenched by adding water, extracted with ethyl acetate, dried over anhydrous sodium sulfate. After the organic phase was concentrated, it was separated by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain 0.5 g of a yellow solid with a yield of 62% and a melting point of 58-60°C. 1 H NMR (400MHz, CDCl 3 )δ7.10(s,1H),6.53(dd,J=17.5,11.0Hz,1H),5.94(d,J=17.5Hz,1H),5.32(d,J=11.0Hz,1H),4.70( s,2H), 4.14(q,J=7.1Hz,2H),1.26–1.21(m,9H). 13 C NMR (100MHz, CDCl 3 )δ175.5, 139.1, 126.9, 123.3, 116.7, 61.6, 55.4, 44.6, 23.0, 22.1, 14.1. HRMS (ESI): m / z Calcd for C 12 h 17 N 3 o 4 Na[M+Na] + :290.1111,found:290.1128.

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Abstract

The invention discloses a branched 2-nitroimidazole compound and application thereof in hypoxic selective antitumor prodrugs. The branched 2-nitroimidazole compound has a structure represented by formula I, wherein R1 and R2 include but are not limited to the following structures: hydrogen and methyl. The branched 2-nitroimidazole compound can be targeted to a hypoxic region of tumor, and is reduced by specific enzymes that are highly expressed in hypoxic tumor tissues to release active drugs. The branched 2-nitroimidazole compound can be connected with ligands and anti-tumor drugs, is appliedto the hypoxic selective antitumor prodrugs, improves the solubility of the drugs, improves the targeting, reduces toxic and side effects, and enhances anti-tumor efficacy.

Description

technical field [0001] The present invention relates to a compound, especially a novel 2-nitroimidazole compound represented by general formula I and its application in hypoxic selective antitumor prodrugs. This type of compound has hypoxic selectivity and can be Highly expressed specific enzymes in hypoxic tumor tissue reductively release the original drug, improving targeting and anti-tumor efficacy. [0002] Background technique [0003] Malignant tumors are a major problem that threatens human life and health, and drug therapy is one of the main means of tumor treatment. Cytotoxic drugs are the main body of current tumor treatment drugs. Because they act on tumor cells and normal cells at the same time, they have poor curative effect on solid tumors, high toxicity and side effects, and drug resistance. Therefore, it is a problem to be solved to develop high-efficiency, low-toxicity, and anti-drug-resistant antitumor drugs. [0004] Hypoxia is one of the common chara...

Claims

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Application Information

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IPC IPC(8): C07D233/91A61K31/4178A61K31/7028A61K31/337A61P35/00A61P35/02
CPCC07D233/91
Inventor 吕伟金沉黄颖余家会
Owner EAST CHINA NORMAL UNIV
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