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A kind of divalent ionizable lipid compound, composition and application thereof

A compound and composition technology, applied in the field of bivalent ionizable lipid compounds, to achieve the effects of promoting development, good delivery efficiency, and convenient operation

Active Publication Date: 2022-05-20
中国科学院基础医学与肿瘤研究所(筹)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although several domestic pharmaceutical companies have announced their patent applications, there is no ionizable cationic lipid with good transfection effect that can efficiently deliver nucleic acid drugs such as mRNA

Method used

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  • A kind of divalent ionizable lipid compound, composition and application thereof
  • A kind of divalent ionizable lipid compound, composition and application thereof
  • A kind of divalent ionizable lipid compound, composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Synthesis of Mon-01:

[0160] The synthetic route of Mon-01 is:

[0161] .

[0162] Step 1: Synthesis of a1:

[0163] In a 250mL flask, weigh a0 (10.00g) and NBS (1.1eq) and dissolve them in 100mL of DMF, raise the temperature to 100°C, and react for 40min; spot the plate to monitor the progress of the reaction, and perform post-treatment after the reaction is complete; cool to room temperature, and react The liquid was poured into 300mL of ice water, stirred, filtered with suction, washed with water, dried, and dried to give a bright yellow solid (13.4g, 96.7% yield). The hydrogen spectrum of the compound is attached figure 1 . 1 HNMR (400 MHz, DMSO- d 6 ) δ 13.30 (s, 2H), 8.06 (s, 2H).

[0164] Step 2: Synthesis of a2:

[0165] Weigh a1 (10.00g) and dissolve it in 100mL of THF, stir in ice bath for 15min; under ice bath, add BH dropwise 3 / THF (1.0M, 6eq), return to room temperature after the dropwise addition, and stir overnight; spot the plate to monitor ...

Embodiment 2

[0185] Synthesis of hydrophobic aliphatic chain tail T-4-7:

[0186] The synthetic route of T-4-7:

[0187]

[0188] Step 1: Synthesis of T-2-2:

[0189] In a 250mL single-necked bottle, weigh T-2-1 (2.22g, 10mmol) and dissolve it in 30mL of anhydrous DMSO, 10 o C and stirred for 5min, added TosMIC (195.03, 0.98g, 5mmol), stirred for 5min, added NaH (0.48g, 12mmol) in batches, and finally added TBAI (369.37, 0.37g, 1mmol), slowly raised to room temperature and stirred overnight, and plated Monitor the progress of the reaction (PE: EA = 49: 1), the reaction is complete, cool the reaction solution in an ice-water bath, slowly add 80 mL of ice water to quench, extract with DCM (60 mL*3), combine the organic phases, wash with 80 mL of water, Wash with saturated sodium bicarbonate (80mL*2), wash with brine, dry, and concentrate to obtain the crude product T-2-2, which is directly carried out to the next reaction.

[0190] Step 2: Synthesis of T-2-3:

[0191] In a 100mL singl...

Embodiment 3

[0201] Synthesis of Divalent Cationic Lipid Compound 010101:

[0202] 010101 synthetic route:

[0203]

[0204] Step 1: Synthesis of 0101:

[0205] Weigh cationic group compound (450mg, 6.0eq) and DIEA (340mg, 6.0eq) dissolved in 35mL of DCM, stir at room temperature; weigh Mon-01 (300mg, 0.43mmol) dissolved in 15mL of DCM to add to the reaction solution, point The progress of the reaction was detected on a plate, and the reaction was completed after treatment; washed with water, washed with brine, dried, concentrated, and mixed with a column for purification (160 mg, 53.3% yield). The hydrogen spectrum of the compound is attached Figure 15 . 1 H NMR (400 MHz, Chloroform- d ) δ 8.17 (s, 1H), 8.11 (d, J = 8.1 Hz,1H), 7.74 (s, 2H), 7.51 (s, 3H), 6.37 (s, 2H), 5.60 (s, 2H), 5.05 (s, 4H),3.50 (s, 8H), 3.20 (s, 4H), 3.10 (s, 1H), 2.62 – 2.47 (m, 12H).

[0206] Step 2: Synthesis of 010101:

[0207] In a 10mL single-necked bottle, weigh 0101 (20mg, 0.028mmol) and T-4-7 (...

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Abstract

The invention relates to the technical field of nucleic acid drug delivery, in particular to a bivalent ionizable lipid compound, composition and application thereof. The invention provides a variety of ionizable cationic lipids capable of delivering nucleic acid drugs, which have strong designability, biodegradability and high transfection efficiency in vivo and in vitro, and the lipid nano-delivery system composed of them is used to deliver mRNA , at the cell level, it is superior to the currently marketed products, and it also has good delivery efficiency at the animal level, which can be used as a new method for the delivery of nucleic acid drugs and promote the development of nucleic acid drugs.

Description

technical field [0001] The invention relates to the technical field of nucleic acid drug delivery, in particular to a bivalent ionizable lipid compound, composition and application thereof. Background technique [0002] Nucleic acid drugs, as a large category of emerging drug fields, have the characteristics of fast design, wide application, and high safety, and are one of the main directions of future drug development. However, due to the poor cell penetration and easy degradation of nucleic acid drugs, the in vivo application of nucleic acid drugs faces great challenges. Therefore, it is necessary to develop specific compounds and delivery systems to improve this situation, so as to promote nucleic acid drugs as an important means of disease prevention and treatment. At present, liposomes prepared from ionizable cationic lipids are a relatively safe and effective means of delivering nucleic acid drugs, but there are still few ionizable lipids available on the market, and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D249/06
CPCC07D249/06A61K9/127A61K47/22A61K47/18A61K47/24A61K39/12A61P31/14A61K2039/53C12N2770/20034
Inventor 谭蔚泓张鹏晖李岩邓旭倩符婷谢斯滔甘绍举
Owner 中国科学院基础医学与肿瘤研究所(筹)
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