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Branched-chain 2-nitroimidazole compound and application thereof in dosing system

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

Active Publication Date: 2017-11-24
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-chain 2-nitroimidazole compound and application thereof in dosing system
  • Branched-chain 2-nitroimidazole compound and application thereof in dosing system
  • Branched-chain 2-nitroimidazole compound and application thereof in dosing system

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0047] Preparation of compound 2

[0048]

[0049] Under nitrogen protection, compound 1 (11.5 g, 50.9 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL), and n-butyllithium (25.5 mL, 61.1 mmol) was slowly added dropwise at -78°C. After stirring at -78°C for 1 hour, p-toluenesulfonyl azide (7.0 g, 45.8 mmol) was added dropwise, and stirring was continued at -78°C for 1 hour. It was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After the organic phase was concentrated, it was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a yellow liquid (10.0 g, 82%). 1 H NMR (400MHz, CDCl 3 )δ6.73(s,1H),4.55(s,2H),3.40(s,3H),0.87(s,9H),0.04(s,6H). 13 C NMR (101MHz, CDCl 3 )δ141.43, 130.31, 125.17, 55.50, 29.57, 25.84, 18.23, -5.26. HRMS (ESI) m / z Calcd for C 11 h 22 N 5 OSi,[M+H] + :272.1907,found:272.1829.

preparation example 2

[0051] Preparation of compound 3

[0052]

[0053] Compound 2 (10.0 g, 37.5 mmol) was dissolved in 1M hydrochloric acid / methanol solution (100 mL), and after stirring at room temperature for 4 hours, triethylamine was added to adjust to neutrality. After the reaction solution was concentrated, it was washed with ether to obtain a yellow solid (5.0 g, 87%). Melting point: 105-107°C. 1 H NMR (400MHz, CDCl 3 )δ6.60(s, 1H), 4.47(s, 2H), 4.06(br, 1H), 3.40(s, 3H). 13 C NMR (101MHz, CDCl 3 )δ141.49, 130.80, 125.06, 54.21, 29.52. MS (ESI) Calcd forC 5 h 8 N 5 O,[M+H] + :154.07,found:154.07.

preparation example 3

[0055] Preparation of Compound 4

[0056]

[0057] Compound 3 (5.0 g, 32.7 mmol) was dissolved in dimethyl sulfoxide (30 mL), and 2-iodobenzoic acid (18.3 g, 65.4 mmol) was added in batches under ice-cooling, and stirred overnight at room temperature. It was quenched by adding water, the solid was filtered off, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give a yellow solid (5.0 g, 100%). Melting point: 103-105°C. 1 H NMR (400MHz, CDCl 3 )δ9.58(s,1H),7.61(s,1H),3.71(s,3H). 13 C NMR (101MHz, CDCl 3 )δ178.4, 148.0, 142.3, 131.2, 31.8. MS (ESI) Calcd for C 5 h 6 N 5 O,[M+H] + :152.05,found:152.05.

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Abstract

The invention discloses a branched-chain 2-nitroimidazole compound and application thereof in a dosing system. The branched-chain 2-nitroimidazole compound is of the structure of formula I as shown in the specification, in the formula, R1 and R2 are H or CH3; X comprises but is limited to the following structures: -OH, -COOH, -CONH2, -C identically equal to CH, -CH2OH, -CH2COOH, -CH2CONH2, -CH2C identically equal to CH, -CH2OCH2C identically equal to CH, C1-C6 alkyl, C1-C6 alkyl with alkenyl, and C1-C6 alkyl with alkynyl. The medicine can target a tumor hypoxia area and is reduced by highly expressed specific enzymes in hypoxia tumor tissue, and thus active compounds can be released. The compound disclosed by the invention can be connected with a ligand, is applied to research on dosing systems and is capable of improving dissolubility of medicines, improving targeting properties, reducing toxic or side effects and improving anti-tumor treatment effects.

Description

technical field [0001] The present invention relates to a compound, especially a novel 2-nitroimidazole compound represented by general formula I, a synthesis method thereof, and an application in a drug delivery system. Background technique [0002] 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. [0003] Hypoxic regions are common in tumor tissues, and hypoxia can cause tumors to produce protective proteins. Therefore, hypoxic tumor tissues have strong resistance and tolerance to traditional radiotherapy and chemotherapy. In additi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/91C07D491/22C08G65/333A61P35/00A61P35/02A61K47/54A61K47/60
CPCC07D233/91C07D491/22C08G65/33396
Inventor 吕伟金沉余家会
Owner EAST CHINA NORMAL UNIV
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