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Amino lipid as well as preparation method and application thereof

An amino lipid and alkyl technology, applied in the field of medicinal chemistry, can solve the problems of cytotoxicity and low efficiency, and achieve the effects of enhanced degradation ability, high atom economy, and easy availability of raw materials

Active Publication Date: 2022-03-01
SHENZHEN MAGICRNA BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Aiming at technical problems such as low transfection efficiency of cationic liposomes and cytotoxicity caused by positive charges in the prior art, the present invention provides an amino lipid and its application

Method used

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  • Amino lipid as well as preparation method and application thereof
  • Amino lipid as well as preparation method and application thereof
  • Amino lipid as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: Parallel synthesis and characterization of E7C71Ay series amino lipid compound library

[0066]

[0067] In the 25mL reaction tube, add FeCl 3 (4 mg, 0.005 mmol), Py (1 μL, 0.0025 mmol), 2-hexyldecanoic acid (0.3 mL, 1 mmol) and 1,2-epoxydodecane (0.27 mL, 1.2 mmol), stirred at room temperature overnight , to get Step I (1mmol), add 10mL of DCM, dubbed 0.1 M Step I solution.

[0068] Transfer the Step I solution to 1.5 mL of 96-well plate with a pipette gun (0.1 mL each, 0.01 mmol), and add a DCM solution of carboxylic acid with tertiary amine (0.1 mL, 0.02 mmol, 0.2M), DIPEA and EDC·HCl in DCM (0.2 mL, 0.04 mmol, 0.2 M), DMAP in DCM (0.1 mL, 0.005 mmol, 0.05 M) were stirred at room temperature for 6 hours, and no Step I raw materials were detected by TLC. After the reaction was completed, it was waved to dryness at room temperature to obtain 15 amino lipid compounds E7C71Ay. Mass spectrometry was performed, and the results are shown in Table 1 below. ...

Embodiment 2

[0072] Example 2: 2-Hydroxyhexadecyldodecanoate

[0073]

[0074] In the 25mL reaction tube, add FeCl 3 (20mg, 0.025mmol), Py (5μL, 0.0125mmol), lauric acid (1g, 5mmol) and 1,2-epoxyhexadecane (1.7mL, 6mmol), stirred at room temperature overnight, using column Purification by analysis (hexane:EA=20:1 to 5:1) gave 2-hydroxyhexadecanyl dodecanoate (2.0 g, 90%). 1 H NMR (400MHz, CDCl 3 ): δ 0.88 (t, 6H), 1.26-1.45 (m, 40H), 1.47 (m, 2H), 1.63 (m, 2H), 2.02 (m, 1H), 2.34 (t, 2H), 3.82 (m , 1H), 3.95 (m, 1H), 4.13 (m, 1H). ESI-MS calculated for C 28 h 57 o 3 + [M+H] + 441.4, found 441.6.

Embodiment 3

[0075] Example 3: Hexadecyl 2-((4-(dimethylamino)butyryl)oxy)dodecanoate

[0076]

[0077]In a 10 mL reaction tube, add EDC·HCl (192 mg, 1 mmol), DIPEA (174 μL, 1 mmol), DMAP (3.0 mg, 0.025 mmol), 4-(dimethylamino)butyric acid (101 mg, 0.6 mmol) ), 2-hydroxyhexadecanoate (220 mg, 0.5 mmol), 4 mL DCM. Stirring at room temperature for 3 h gave compound E11C7A9 (235 mg, 85%). 1 HNMR (400 MHz, CDCl 3 ): δ 0.88 (t, 6H), 1.25-1.45 (m, 40H), 1.58 (m, 4H), 1.78 (m, 2H), 2.23 (s, 6H), 2.30 (m, 6H), 4.01 (m , 1H), 4.21 (m, 1H), 5.08 (m, 1H). 13 C NMR (400 MHz, CDCl 3 ): δ14.03, 14.08, 22.59, 22.64, 23.35, 25.11, 27.39, 27.43, 29.23, 29.27, 29.29, 29.45, 29.53, 29.59, 30.80, 31.65, 31.85, 31.89, 32.16, 38.39, 47 64.49, 71.53, 171.87, 173.43. ESI-MS calculated for C 34 h 68 NO 4 + [M+H] + 554.5, found 554.7.

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PUM

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Abstract

The invention belongs to the technical field of medical chemistry, and particularly relates to amino lipid as well as a preparation method and application thereof. The invention provides an ionizable amino lipid represented by a general formula (I) or a pharmaceutically acceptable salt thereof. The amino lipid can be used for delivering nucleic acid and small molecule drugs. The amino lipid compound has two ester bonds, so that the lysosomal escape capability of ionizable amino lipid is remarkably enhanced, release of delivery targets such as target drugs or genes is facilitated, the delivery efficiency is further improved, and the amino lipid compound shows excellent capability of delivering nucleic acid into cells in in-vitro and in-vivo delivery studies.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to an amino lipid and its preparation method and application. Background technique [0002] Nucleic acid drugs have extremely broad application prospects in the prevention and treatment of cancer, infectious diseases, genetic diseases and cardiovascular diseases. However, since RNA, DNA, and siRNA are easily degraded in vivo, the bioavailability is extremely low due to direct oral or intravenous administration, so carrier delivery is required. [0003] Commonly used nucleic acid vectors include viral vectors and non-viral vectors. Viral vectors have high transfection efficiency, but viral vectors lack targeting, and there are greater safety concerns, and the vectors have small capacity and high production costs. Non-viral vectors have the advantages of high safety, easy modification of carrier molecules, suitable for mass production, etc., and have broad app...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/12C07D211/62C07C67/26C07C69/28C07C227/18C07D207/16C07D295/15C07D211/34A61K47/18A61K47/22A61K48/00A61K9/51A61P35/00A61P37/08A61P31/00A61P39/02A61P7/06A61P7/04A61P7/00
CPCC07C229/12C07D211/62C07C67/26C07C227/18C07D207/16C07D295/15C07D211/34A61K47/18A61K47/22A61K48/005A61K48/0033A61K9/5123A61P35/00A61P37/08A61P31/00A61P39/02A61P7/06A61P7/04A61P7/00C07C69/28C07D211/60C07D403/12C07D221/18A61K31/131A61K31/401A61K31/44A61K31/5375C07D215/58C07D213/55A61K47/28C07C219/08
Inventor 查高峰潘逸航胡月潇彭星华
Owner SHENZHEN MAGICRNA BIOTECHNOLOGY CO LTD
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