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Hypoxic activation prodrug based on 2,2-dimethyl-3-(2-nitroimidazolyl) propionic acid

A nitroimidazolyl and dimethyl technology, applied in the field of hypoxia-activated prodrug of 2,2-dimethyl-3-propionic acid and its synthesis, can solve the problems of unstable structure and low synthesis yield , to achieve the effects of improving targeting, enhancing curative effect, and convenient and efficient synthesis

Inactive Publication Date: 2017-12-01
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Recently, a patent has disclosed a class of 3-(2-nitroimidazole) propionic acid prodrugs. However, due to the following reversible Michael addition reaction of this type of prodrug, the synthesis yield of this type of compound is low and the structure is unstable. The problem

Method used

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  • Hypoxic activation prodrug based on 2,2-dimethyl-3-(2-nitroimidazolyl) propionic acid
  • Hypoxic activation prodrug based on 2,2-dimethyl-3-(2-nitroimidazolyl) propionic acid
  • Hypoxic activation prodrug based on 2,2-dimethyl-3-(2-nitroimidazolyl) propionic acid

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Experimental program
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Effect test

Embodiment 1

[0038] Preparation of compound 2

[0039]

[0040] Diisopropylamine (15.4 mL, 0.11 mol) was dissolved in anhydrous tetrahydrofuran (100 mL), the mixture was cooled to -30°C, and n-butyllithium (44.0 mL, 0.106 mol) was slowly added dropwise to the system. After the dropwise addition, the reaction system was reacted at 0°C for 30 minutes, cooled to -78°C again, compound 1 (13.6mL, 0.10mol) was added dropwise to the reaction system, and reacted at this temperature for 1 hour and then added to the mixed system Diiodomethane (5.20 mL, 0.065 mol) was added dropwise, and the reaction mixture was reacted at room temperature for 16 hours, and compound 1 was completely reacted. The reaction mixture was poured into saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was distilled by an oil pump under reduced pressure to obtain compound 2 (25.0...

Embodiment 2

[0042] Preparation of Compound 4

[0043]

[0044] Cesium carbonate (2.88g, 8.84mmol) was added to a solution of compound 3 (0.500g, 4.42mmol) in N,N-dimethylformamide (15mL), the mixture was stirred at room temperature for 15 minutes, and the compound was added to the system 2 (2.26 g, 8.84 mmol). The reaction mixture was reacted at 100° C. for 16 hours, the color of the reaction solution changed from yellow to brownish red, and the compound 3 was completely reacted. The reaction solution was cooled to room temperature, ethyl acetate (60 mL) was added to the system, filtered, the filtrate was washed with saturated sodium bicarbonate (30 mL), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the concentrate was passed through column chromatography ( Petroleum ether:ethyl acetate=3:1) Separation and purification gave light yellow oil 4 (1,1 g, 98%). 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), ...

Embodiment 3

[0046] Preparation of compound 5

[0047]

[0048] Lithium hydroxide monohydrate (418 mg, 9.96 mmol) was added in batches to a mixed solution of compound 4 (600 mg, 2.49 mmol) in methanol (20 mL) and water (4 mL), and the reaction system was stirred at room temperature for 16 hours to complete the reaction. The methanol in the system was removed by a water pump, the pH of the mixed system was adjusted to 4.0 with dilute hydrochloric acid (2N) solution, the aqueous phase was extracted with ethyl acetate (30mL*2), the organic phase was washed with saturated aqueous sodium chloride solution, anhydrous sulfuric acid Dry over sodium, filter and concentrate to give 5 (448 mg, 84%) as a pale yellow solid. 1 H NMR (400MHz, CDCl 3)δ7.21(s,1H),7.16(s,1H),4.76(s,2H),1.27(s,6H), MS(ESI)m / z=213.08[M+H] + .

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Abstract

The invention discloses a hypoxic activation prodrug based on 2,2-dimethyl-3-(2-nitroimidazolyl) propionic acid. The hypoxic activation prodrug is connected with an antitumor drug by using 2,2-dimethyl-3-(2-nitroimidazolyl) propionic acid by virtue of an ester bond and has a structure shown as a formula I, wherein R1 and R2 include, but are not limited to the following structures: hydrogen, hydroxyl, chlorine, bromine, fluorine, C1-C6 alkyl, C1-C6 alkyl containing alkenyl and C1-C6 alkyl containing alkynyl; and the antitumor drug comprises paclitaxel and docetaxel. The hypoxic activation prodrug has the characteristics that a hypoxic region of a tumor can be targeted, the hypoxic activation prodrug can be reduced by a specific enzyme highly expressed in a hypoxic tumor tissue, and a crude drug is released by a reduced amino imidazolidine acid compound under the action of intramolecular cyclisation. The prodrug provided by the invention is stable in vitro and vivo and capable of releasing a drug by specific reduction in the hypoxic tumor tissue, improving the targeting ability of the antitumor drug, reducing toxic or side effects and improving the curative effect.

Description

technical field [0001] The present invention relates to a kind of medicine, especially a hypoxia-activated prodrug of 2,2-dimethyl-3-(2-nitroimidazolyl)propionic acid represented by general formula I and its synthesis method. The prodrug has good stability in vivo and in vitro, and can be reduced and released by specific enzymes highly expressed in hypoxic tumor tissues, thereby improving antitumor efficacy and targeting. [0002] Background technique [0003] Traditional antitumor drugs, such as paclitaxel, act on both tumor cells and normal cells at the same time, so they have poor curative effect on solid tumors, high toxicity and side effects, low bioavailability, and drug resistance. At the same time, there are generally hypoxic areas in tumor tissue, and hypoxic tumor tissue has strong resistance and tolerance to traditional radiotherapy and chemotherapy. [0004] 2-nitroimidazolidinic acid compounds belong to 2-nitroimidazole compounds, which can target hypoxic tu...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/337A61P35/00A61K47/54
Inventor 吕伟金沉文帅余家会
Owner EAST CHINA NORMAL UNIV
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