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Mitochondria-targeted dihydropyridine derivative as well as preparation method and application thereof

A technology of dihydropyridine and mitochondria, applied in the field of medicine, can solve the problems of scavenging reactive oxygen radicals, NADPH structure aggregation, etc., and achieve the effects of easy product availability and simple preparation method.

Active Publication Date: 2017-09-29
INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Currently, dihydropyridines, due to their low toxicity, have been clinically used as Ca 2+ Antagonists are antihypertensive drugs. Nicotinamide adenine dinucleotide phosphate (NADPH) exists in the organism. As an important dihydropyridine endogenous antioxidant, it can scavenge endogenous free radicals and other oxidative substances, but The particularity of NADPH structure does not efficiently gather in mitochondria to scavenge active oxygen free radicals in mitochondria. Therefore, there is an urgent need for compounds that can gather in mitochondria to effectively play a role in scavenging free radicals and assist mitochondria in scavenging excessively produced free radicals.

Method used

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  • Mitochondria-targeted dihydropyridine derivative as well as preparation method and application thereof
  • Mitochondria-targeted dihydropyridine derivative as well as preparation method and application thereof
  • Mitochondria-targeted dihydropyridine derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] A preparation method for mitochondrial targeting dihydropyridine derivatives (I-1), comprising the steps of:

[0037] (1) Add triphenylphosphine (9.4g, 35.9mmol), 3-bromo-1 propanol (0.5g, 3.6mmol) and 10ml N,N-di Methylformamide (DMF), stirred and refluxed at 100°C for 10h, cooled to room temperature after the reaction, filtered the precipitated solid in the system under reduced pressure and washed the solid with cold DMF 3 times to obtain a white solid, dried overnight at 50°C to obtain a white Powdered solid (3-hydroxypropyl) triphenylphosphine bromide;

[0038] (2) Add NH to a 100ml three-necked flask equipped with magnetic stirring 4 HCO 3 (7.9g, 0.1mol), 40% aqueous formaldehyde solution (containing 0.1mol formaldehyde) and ethyl acetoacetate (26g, 0.2mol) and 60ml volume concentration of 50% ethanol aqueous solution, under the protection of nitrogen, heat and reflux for 20h until Pale yellow precipitate, the reaction system was cooled to room temperature, the ...

Embodiment 2

[0044] A method for preparing mitochondria-targeted dihydropyridine derivatives (I-2), comprising the steps of:

[0045] (1) (1) with embodiment 1;

[0046] (2) replace the formaldehyde in the embodiment (2) with the benzaldehyde of equimolar, other is with embodiment 2;

[0047] (3) Add compound 8 (where R is phenyl) (600mg, 2.0mmol), HOBT (162mg, 1.2mmol) and DMF (15mL) into a 100ml round bottom flask equipped with magnetic stirring and stir for half an hour, then add EDCI (230 mg, 1.2 mmol), (3-hydroxypropyl)triphenylphosphine bromide (514 mg, 1 mmol) obtained in step 1) and triethylamine (202 mg, 2 mmol). Under the protection of nitrogen, it was reacted overnight in the dark, and most of the DMF was evaporated under reduced pressure, and the saturated NaHCO 3 An aqueous solution (20 mL) was added to the reaction system, and a pale yellow solid was precipitated, which was collected by suction filtration under reduced pressure, dried and purified by column chromatography t...

Embodiment 3

[0052] A preparation method for mitochondrial targeting dihydropyridine derivatives (I-3), comprising the steps of:

[0053] (1) (1) with embodiment 1;

[0054] (2) replace the formaldehyde in the embodiment (2) with the thiophene 2-formaldehyde of equimolar, other is with embodiment 2;

[0055] (3) Add compound 8 (where R is thienyl) (307mg, 1.0mmol), HOBT (162mg, 1.2mmol) and DMF (15mL) into a 100ml round bottom flask equipped with magnetic stirring and stir for half an hour, then add EDCI (230 mg, 1.2 mmol), (3-hydroxypropyl)triphenylphosphine bromide (514 mg, 1 mmol) obtained in step 1) and triethylamine (202 mg, 2 mmol). Under the protection of nitrogen, it was reacted overnight in the dark, and most of the DMF was evaporated under reduced pressure, and the saturated NaHCO 3 An aqueous solution (20 mL) was added to the reaction system, and a pale yellow solid was precipitated, which was collected by suction filtration under reduced pressure, dried and purified by column...

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Abstract

The invention discloses a preparation method and application of a mitochondria-targeted dihydropyridine compound. The mitochondria-targeted dihydropyridine compound has structures of a formula (I) and a formula (II) (shown in the description). Experiments prove that the mitochondria-targeted dihydropyridine compound is capable of effectively eliminating reactive oxygen species (ROS) generated by ionization radiation and therefore can be applied to the treatment of free radical-induced relevant diseases such as Alzheimer's disease and ionization damage disease. The preparation method is simple, and the product is easily prepared and pollution-free.

Description

technical field [0001] The invention relates to a mitochondria-targeting dihydropyridine derivative, a preparation method and an application thereof, and belongs to the field of medicine. Background technique [0002] In recent years, due to the rapid development of nuclear science and radiation medicine, ionizing radiation is getting closer to our lives, and the risk of being injured by ionizing radiation is also increasing, especially in the process of nuclear-related workers, medical examinations and treatments In middle-aged patients, exposure to excessive radiation causes ionizing radiation damage to the body, which leads to dysfunction of the body, oxidative stress in the body, and even induces many chronic diseases, eventually leading to aging and death. Ionizing radiation damage is mainly the damage of high-energy rays penetrating the body to produce functional macromolecules. The damage is divided into direct damage and indirect damage. Direct damage is due to the d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/59C07F9/6558A61P25/28A61P25/16A61P39/00
CPCC07F9/59C07F9/65586
Inventor 徐文清张宇睿李园园孔劭凡张源孟媛媛
Owner INST OF RADIATION MEDICINE CHINESE ACADEMY OF MEDICAL SCI
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