Novel compound and application thereof

A compound and combination sequence technology, applied in the field of new compounds, can solve problems such as unsuitability, safety hazards, and accumulated toxicity

Active Publication Date: 2020-02-28
KYLONOVA (XIAMEN) BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, anionic liposomes, pH-sensitive liposomes, immunoliposomes, fusogenic liposomes, and cationic lipids, etc., although some progress has been made, liposomes themselves are prone to inflammatory reactions , a variety of antihistamines and hormones such as cilitizine and dexamethasone must be used before

Method used

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  • Novel compound and application thereof
  • Novel compound and application thereof
  • Novel compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0146] Embodiment 1, the synthesis of GBL-0401

[0147] 1. Synthesis of Kys-01

[0148] 1.1. Compounds with 5'YICd-01 structure: Synthesis of 5'YICd-01-PFP

[0149] 1.1.1. Synthesis of 5'YICd-01-c1

[0150]

[0151] Measure 5.0 g (81.9 mmol) of 2-hydroxyethylamine, add 50 mL of dimethyl sulfoxide, 5 mL of sodium hydroxide solution (concentration 1 g / mL), add 12 mL (81.9 mmol) of tert-butyl acrylate dropwise for 1 hour, and After reacting for 24 hours, 100 mL of petroleum ether was added, washed twice with saturated brine, and the organic layer was dried. After passing through the column, 7.5 g of a colorless oily substance was obtained.

[0152] 1.1.2. Synthesis of 5'YICd-01-c2

[0153]

[0154] Weigh 7.5g (39.7mmol) of 5'YICd-01-c1, add 50mL of DCM, 23mL of sodium carbonate solution (25%), add 7.7g (45.0mmol) of benzyl chloroformate dropwise at room temperature, react overnight at room temperature, wash with saturated saline Twice, dried over anhydrous sodium sulfate...

Embodiment 2

[0213] Embodiment two, the synthesis of GBL-0402

[0214] 1. Synthesis of Kys-02

[0215] 1.1. Compounds with 5'YICc-01 structure: Synthesis of 5'YICc-01-PFP

[0216] 1.1.1. Synthesis of 5’YICc-01-c1

[0217]

[0218] Take 7.0g (40.0mmol) of SANC-c8 and 9.2g (34.4mmol) of 5’YICd-01-c3, add 25mL of DMF to dissolve, add 9.0g of TBTU, cool down to 10°C, add 2ml of DIEA, and react overnight at room temperature. Add 30 mL of water and 50 mL of dichloromethane, and wash the organic layer three times with saturated brine. The organic layer was dried and evaporated to dryness under reduced pressure. After passing through a column chromatography (eluent: dichloromethane: methanol = 1%-10%), 10.0 g of a yellow viscous solid was obtained.

[0219] 1.1.2. Synthesis of 5'YICc-01-c2

[0220]

[0221] Take 10.0g of 5'YICc-01-c1, add 15ml of concentrated hydrochloric acid, and react overnight at room temperature. Evaporate to dryness under reduced pressure to obtain 7.3g.

[0222...

Embodiment 3

[0252] Embodiment three, the synthesis of GBL-0403

[0253] 1. Synthesis of Kys-03

[0254]1.1. Compounds with 5’ERCd-01 structure: Synthesis of 5’ERCd-01-PFP

[0255] 1.1.1. Synthesis of 5’ERCd-01-c1

[0256]

[0257] Measure 5.0g (54.9mmol) of 2-amino-1,3-propanediol, add 50mL of DMSO, 5mL of sodium hydroxide solution (concentration: 1g / mL), cool down to 0°C, add dropwise 20mL (137.8mol) of tert-butyl acrylate2 After the addition was completed in 1 hour, react at room temperature for 48 hours, add 100 mL of petroleum ether, wash with saturated brine twice, and dry the organic layer. After passing through a chromatography column (eluent: ethyl acetate: petroleum ether = 25%-75%), add 0.05% triethylamine to the column to obtain 6.2 g of a colorless oil.

[0258] 1.1.2. Synthesis of 5’ERCd-01-c2

[0259]

[0260] Weigh 6.2g (17.9mmol) of 5'ERCd-01-c1, add 50mL of dichloromethane, 23mL of sodium carbonate solution (25%), add 8.2mL of benzyl chloroformate (57.4mmol) dro...

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Abstract

The invention relates to a novel compound and application thereof to inhibition of HBV gene expression. The novel compound structurally comprises an HBV gene expression inhibiting interference nucleicacid, a transition point and a terminal modification chain thereof. By the terminal modification chain, two or three N-acetyl galactosamine can be introduced into a 3' terminal of an antisense strandof siRNA while two or one N-acetyl galactosamine can be introduced into a 5' terminal, and the total number of introduced N-acetyl galactosamine is four. According to in-vivo and in-vitro pharmacological experiments, the novel compound is capable of continuously and efficiently inhibiting HBV gene expression.

Description

technical field [0001] The present invention relates to a new compound and its application for inhibiting HBV gene expression. The structure of the compound contains an interfering nucleic acid for suppressing HBV gene expression, a transition point and a terminal modification chain thereof. By modifying the end of the strand, two to three N-acetylgalactosamines can be introduced at the 3' end of the antisense strand of this siRNA, and two to one N-acetylgalactose can be introduced at the 5' end of the sense strand amines, the total number of N-acetylgalactosamines introduced was four. The drug efficacy experiments on HepG 2 cells and transgenic mice prove that this new compound can continuously inhibit the expression of HBsAg, HBeAg and HBV DNA of HBV. Background technique [0002] RNAi [0003] RNAi (RNA interference) was discovered in 1998 by Andrew Z. Fire et al. when conducting antisense RNA inhibition experiments in Caenorhabditis elegans, and this process was calle...

Claims

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Application Information

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IPC IPC(8): C12N15/113A61K31/713A61P1/16
CPCC12N15/113A61K31/713A61P1/16C12N2310/14C12N2310/31C12N2310/351C12N15/1131A61K47/549A61K47/545A61K47/55A61P31/20C12N2310/11
Inventor卢雪琴穆卓王圣军杜艳春
OwnerKYLONOVA (XIAMEN) BIOPHARMA CO LTD