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Bivalent ionizable lipid compound, composition and application thereof

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

Pending Publication Date: 2022-08-09
INST OF BASIC MEDICINE & CANCER CHINESE ACAD OF SCI
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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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  • Bivalent ionizable lipid compound, composition and application thereof
  • Bivalent ionizable lipid compound, composition and application thereof
  • Bivalent ionizable lipid compound, composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] Mon-01 Synthesis:

[0159] The synthetic route of Mon-01 is:

[0160]

[0161] Step 1: Synthesis of a1:

[0162] In a 250mL flask, weigh a0 (10.00g) and NBS (1.1eq) and dissolve them in 100mL DMF, heat up to 100°C, and react for 40min; monitor the progress of the reaction by spotting, the reaction is completely post-treated; cool to room temperature, react The liquid was poured into 300 mL of ice water, stirred, filtered with suction, washed with water, dried, and dried to obtain a bright yellow solid (13.4 g, 96.7% yield). The hydrogen spectrum of the compound is attached figure 1 . 1 HNMR (400MHz, DMSO-d 6 ) δ13.30(s, 2H), 8.06(s, 2H).

[0163] Step 2: Synthesis of a2:

[0164] Weigh a1 (10.00 g) and dissolve it in 100 mL of THF, and stir in an ice bath for 15 min; under the ice bath, add BH dropwise 3 / THF (1.0M, 6eq), return to room temperature after dropwise addition, and stir overnight; spot plate to monitor the progress of the reaction, the reaction is ...

Embodiment 2

[0184] Synthesis of hydrophobic fatty chain tail T-4-7:

[0185] Synthetic route of T-4-7:

[0186]

[0187] Step 1: Synthesis of T-2-2:

[0188] In a 250mL single-neck flask, weigh T-2-1 (2.22g, 10mmol) and dissolve it in 30mL of anhydrous DMSO, stir at 10°C for 5min, add TosMIC (195.03, 0.98g, 5mmol), stir for 5min, and add in batches NaH (0.48g, 12mmol), finally added TBAI (369.37g, 0.37g, 1mmol), slowly raised to room temperature and stirred overnight, the reaction progress was monitored by spot plate (PE:EA=49:1), the reaction was complete, the reaction solution was placed in ice Cool in a 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 (80 mL*2), wash with brine, dry, and concentrate to obtain T-2 -2 Crude product, directly proceed to the next reaction.

[0189] Step 2: Synthesis of T-2-3:

[0190] In a 100mL single-neck bottle, T-2-2 was d...

Embodiment 3

[0200] Synthesis of bivalent cationic lipid compound 010101:

[0201] 010101 Synthetic route:

[0202]

[0203] Step 1: Synthesis of 0101:

[0204]The cationic group compound (450 mg, 6.0 eq) and DIEA (340 mg, 6.0 eq) were weighed and dissolved in 35 mL of DCM, and stirred at room temperature; Mon-01 (300 mg, 0.43 mmol) was weighed and dissolved in 15 mL of DCM and added to the reaction solution. The progress of the reaction was detected by the plate, and the reaction was completed after treatment; washed with water, brine, dried, concentrated, mixed with the sample and passed through the column for purification (160 mg, 53.3% yield). The hydrogen spectrum of the compound is attached Figure 15 . 1 H NMR (400MHz, Chloroform-d) δ 8.17(s, 1H), 8.11(d, J=8.1Hz, 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).

[0205] Step 2: Synthesis of 010101:

[0206] In a 10mL single-neck bottle, weigh 0...

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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, a composition and application of the bivalent ionizable lipid compound, the structural formula of the bivalent ionizable lipid compound is shown in the formula (1), and G0, R0, G1, G1 ', L1, L1', Ra-N-Rb, Ra '-N-Rb', M, L2, G2 and R2 are defined in the specification. The invention provides a plurality of ionizable cationic lipids capable of delivering nucleic acid drugs, the ionizable cationic lipids have strong designability, biodegradability and efficient in-vivo and in-vitro transfection efficiency, and the lipid nano delivery system composed of the ionizable cationic lipids is used for delivering mRNA, is superior to products on the market at present on the cellular level, also has good delivery efficiency on the animal level, and has good application prospects. The method can be used as a novel delivery method of nucleic acid drugs and promotes the development of the nucleic acid drugs.

Description

[0001] This application is a divisional application of the Chinese invention patent application with the application number "2022101594904", the application date "February 22, 2022", and the invention name "A bivalent ionizable lipid compound, composition and application". technical field [0002] The present 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 [0003] Nucleic acid drugs, as a major emerging drug field, 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 themselves, 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 that nucleic acid dr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D249/06A61K9/127A61K47/24A61K47/22A61K47/18A61K39/215A61P31/14
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 INST OF BASIC MEDICINE & CANCER CHINESE ACAD OF SCI
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