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Cationic lipid compound, composition containing same and application

A technology of cationic lipids and compounds, applied in the field of medicine, can solve the problems of increasing production, increasing toxicity, and complicating

Active Publication Date: 2022-02-15
BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Notably, the increased complexity of Lipid Nanoparticles (LNPs) complicates their production and may increase their toxicity, a major concern that may limit their clinical application

Method used

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  • Cationic lipid compound, composition containing same and application
  • Cationic lipid compound, composition containing same and application
  • Cationic lipid compound, composition containing same and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0186] Example 1: Synthesis of Cationic Lipid Compounds

[0187] 1. Synthesis of 2-octyldecyl 6-((4-(undecyloxy)-4-oxobutyl)(2-hydroxyethyl)amino)hexanoate (YK-001)

[0188] The synthetic route is as follows:

[0189]

[0190] Step 1: Synthesis of n-undecyl 4-bromobutyrate (YK-001-PM1)

[0191] N-undecyl alcohol (5.00g, 29.02mmol) and 4-bromobutanoic acid (5.14g, 30.78mmol) were dissolved in dichloromethane (40mL), and 1-(3-dimethylaminopropyl) was added to the above solution -3-Ethylcarbodiimide hydrochloride (6.67g, 34.82mmol) and 4-dimethylaminopyridine (177mg, 1.45mmol), stirred and reacted at 30~35°C for 8 hours. After the reaction was completed, the reaction solution was washed with saturated sodium carbonate, saturated brine, and washed with Na 2 SO 4 dry. The mixture was filtered, and the filtrate was concentrated under reduced pressure in vacuo. The residue was purified by silica gel chromatography to obtain n-undecyl 4-bromobutyrate (6.68 g, 20.79 mmol, 71.6...

Embodiment 2

[0324] Example 2: Optimization of Preparation Conditions for Lipid Nanoparticles (LNP Preparations)

[0325] 1. Optimizing the ratio of carrier (liposome) to mRNA

[0326]

[0327] The cationic lipid compound YK-009 synthesized in Example 1 was mixed with DSPC (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.), cholesterol (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.) and DMG-PEG2000 according to 50: Dissolve in ethanol at a molar ratio of 10:38.5:1.5 to prepare an ethanolic lipid solution. Quickly add ethanol lipid solution to citrate buffer (pH=4~5) by ethanol injection method, and vortex for 30s for later use. Dilute eGFP-mRNA in citrate buffer (pH=4~5) to obtain mRNA aqueous solution. A certain volume of liposome solution and mRNA aqueous solution were used to prepare liposomes at a weight ratio of total lipid to mRNA of 4: 1, 10: 1, 16: 1, 24: 1, and 30: 1, respectively. Ultrasound at 25°C for 15 minutes (ultrasonic frequency 40kHz, ultrasonic pow...

Embodiment 3

[0338] Embodiment 3: LNP preparation cell transfection experiment of eGFP-mRNA

[0339] Cell recovery and passage: 293T cells were recovered and cultured in a culture dish to reach the required number of cells.

[0340] Seed plate: Digest and count the cells in the culture dish, spread 10,000 cells per well in 96-well plates, and spread 150,000 cells per well in 12-well plates, and culture overnight until the cells adhere to the wall.

[0341] Cell transfection experiment: the LNP preparation containing 1.5 μg of eGFP-mRNA prepared in Example 2 (the cationic lipid in the carrier is YK-009) and the Lipofectamin2000 preparation of eGFP-mRNA were added to the cell culture medium of the 12-well plate, After continuing to culture for 24 hours, the transfection efficiency of different samples was investigated according to the fluorescence intensity by observing with a fluorescence microscope.

[0342] According to the experimental results, the preparation conditions of lipid nanopa...

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Abstract

The present disclosure provides a compound of formula (I) or an N-oxide, solvate, pharmaceutically acceptable salt or stereoisomer thereof. Compositions comprising the aforementioned compounds and the use for delivering therapeutic or prophylactic agents are also provided.

Description

technical field [0001] The invention belongs to the field of medicine. The present invention specifically relates to a cationic lipid compound, its composition and use. Background technique [0002] Effective targeted delivery of biologically active substances such as small molecule drugs, peptides, proteins and nucleic acids, especially nucleic acids, is a persistent medical problem. Nucleic acid therapeutics face great challenges due to low cell permeability and high susceptibility to degradation of certain nucleic acid molecules, including RNA. [0003] Compositions containing cationic lipids, liposomes and liposome complexes (lipoplexes) have been demonstrated to be effective delivery vehicles for biologically active substances such as small molecule drugs, peptides, proteins and nucleic acids to cells and / or cell in the inner compartment. These compositions generally comprise one or more "cationic" and / or amino (ionizable) lipids, including neutral lipids, structured...

Claims

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Application Information

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IPC IPC(8): C07C229/16A61P35/00A61P37/06A61P3/10A61P25/28A61P9/00A61P13/12A61P3/00A61P31/14A61P31/16A61P31/18A61P11/00A61P31/22A61K31/713A61K31/7105A61K9/51A61K39/00A61K45/00A61K47/18
CPCC07C229/16A61P35/00A61P37/06A61P3/10A61P25/28A61P9/00A61P13/12A61P3/00A61P31/14A61P31/16A61P31/18A61P11/00A61P31/22A61K31/713A61K31/7105A61K47/18A61K9/5123A61K45/00A61K39/00Y02A50/30A61K9/5146A61K9/127A61K2039/53A61K2039/55555
Inventor 宋更申张宏雷陈玺朝余晓文王环宇黄大卫
Owner BEIJING YUEKANGKECHUANG PHARM TECH CO LTD
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