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Amino lipid as well as preparation method and application thereof

An amino lipid and hydrocarbon-based technology, applied in the field of medicinal chemistry, can solve the problems of cytotoxicity and low efficiency, and achieve the effects of low equipment requirements, high atom economy, and enhanced escape ability.

Active Publication Date: 2022-08-09
SHENZHEN MAGICRNA BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 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 preparation method and 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

[0070] Example 1 as G as G 1 G 2 Selected from-O-C (= O) -The parallel synthesis and representative

[0071]

[0072] Add 3-cymbal-1-propitol (173 μl, 2mmol), Dipea (442 μl, 2.4 mmol) to the THF, -20 ° C in a 50ml reaction bottle (184 mg, 1 mmol) and 10ml. Stir at room temperature to react overnight. You get STEP I solution (1mmol / 10ml), add laurel acid (481mg, 2.4 mmol), EDC.HCL (460mg, 2.4 mmol), DMAP (6mg, 0.05 mmol), and Dipea (442μL, 2.4mmol, 2.4mmol ), Stir at room temperature for 6 hours, and get 0.1 m STEP II solution (1mmol / 10ml).

[0073] Use a pipette to transfer the Step II solution to the 96 -hole plate of 1.5 ml (0.1 ml, 0.01 mmol), each hole, and the THF solution (0.1 ml, 0.02 mmol, 0.2 0.2 of the alcohol (0.1 ml, 0.02 mmol, 0.2 M) Stir at room temperature for 6h, TLC detects STEP II raw materials. After the reaction is over, the normal temperature is volatilized until the basic solvent, that is, the 16 amino lipid compounds are obtained. For mass spectrometry, se...

Embodiment 2

[0077] Example 2 as G 1 G 2 Different from each other from -CH 2 -He-O-C (= O)-Time, the parallel synthesis and representation of the amino lipid compound library of the OX series

[0078]

[0079] Add Sixteen alkyl sulfurnol (308 μl, 1mmol), Dipea (221 μl, 1.2mmol), and 10ml of THF, -20 Add 3-cymbal-1-propylene (87 μl, 1mmol) and Dipea (221 μl, 1.2mmol) after 30 minutes of stirring reaction for 30 minutes. . HCL (230mg, 1.2mmol), DMAP (3mg, 0.025mmol), and Dipea (221 μl, 1.2mmol), stir 6h at room temperature, and get 0.1 m Step II solution (1mmol / 10ml).

[0080] Use a pipette to transfer the Step II solution to the 96 -hole plate of 1.5 ml (0.1 ml, 0.01 mmol), each hole, and the THF solution (0.1 ml, 0.02 mmol, 0.2 0.2 of the alcohol (0.1 ml, 0.02 mmol, 0.2 M) Stir at room temperature for 6h, TLC detects STEP II raw materials. After the reaction is over, the normal temperature is volatilized until the basic solvent, that is, the 16 amino lipid compounds are obtained. For mass s...

Embodiment 3

[0084] Example 3: When G 1 G 2The same on-O-C (= O)-When the DX series, one of the DX series of the parallel synthesis and representation of the amino lipid compound library

[0085]

[0086] Add 6-pyramid-1-hexol (274 μl, 2mmol), Dipea (442 μl, 2.4mmol) when adding a three-gipedis (184 mg, 1 mmol) and 10ml of THF, -20 ° C. Stir at room temperature to react overnight. You get the STEP I solution (1mmol / 10ml), and add cricket acid (463 μl, 2.4 mmol), EDC.HCL (460mg, 2.4 mmol), DMAP (6mg, 0.05mmol), and Dipea (442 μL, 2.4mmol, 2.4mmol ), Stir at room temperature for 6 hours, and get 0.1 m STEP II solution (1mmol / 10ml).

[0087] Use a pipette to transfer the Step II solution to the 96 -hole board of 1.5 ml (0.1 ml, 0.01 mmol), and each hole with THF solution (0.1 ml, 0.02 mmol, 0.2m) with THF in each hole (0.1 ml, 0.02 mmol, 0.2m) Stir at room temperature for 6h, TLC detection does not have Stepii raw materials. After the reaction is over, the normal temperature is volatilized unti...

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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 ionizable amino lipid as shown in a formula (I) or pharmaceutically available salt thereof disclosed by the invention is mild in reaction condition, free of protection and deprotection and high in atom economy in the process of constructing the amino lipid. In in vitro and in vivo delivery studies, excellent ability to deliver nucleic acids into cells is shown. The amino lipid compound has a plurality of degradable groups, the introduction of the groups not only improves the entrapment capacity of nucleic acid, but also significantly enhances the escape capacity of nucleic acid in endosome / lysosome, and can also contribute to release of delivery targets such as target drugs or genes while greatly reducing the cytotoxicity, thereby improving the delivery efficiency. The preparation method of the amino lipid compound has the advantages of easily available raw materials, mild reaction conditions, good reaction selectivity, high reaction yield, low requirements on instruments and equipment and simplicity in operation.

Description

Technical field [0001] The invention is the field of pharmaceutical chemistry, which involves a kind of amino lipid and its preparation methods and applications. Background technique [0002] At present, the extremely broad application prospects of nucleic acid drugs can have development potential in many gene -related diseases such as genetic diseases and cardiovascular diseases, in addition to being used for cancer and infectious diseases. However, because RNA, DNA, and SIRNA are easily degraded, and directly administered through oral or intravenous injection, the biological utilization is extremely low, so the delivery of the carrier is required. [0003] At present, the MRNA vaccine delivery carrier mainly includes two categories: virus vectors and non -virus vectors. The virus vectors mainly reverse the transcript of viruses, adenovirus, adenocyte -related viruses, and acne virus. Although this type of virus carrier has high transit efficiency (95%) and it is not easy to deg...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/12C07C227/18C07D207/16C07D211/34C07D211/60C07D211/62C07D295/15A61P31/00A61P35/00A61P35/02A61P37/08A61P39/02C12N15/87A61K31/713A61K47/18A61K47/22
CPCC07C229/12C07D207/16C07D295/15C07D211/62C07D211/34C07D211/60A61P35/00A61P35/02A61P37/08A61P39/02A61P31/00C12N15/87A61K31/713A61K47/18A61K47/22C07C2601/14Y02A50/30
Inventor 查高峰王静潘逸航
Owner SHENZHEN MAGICRNA BIOTECHNOLOGY CO LTD
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