Tissue-targeted protein targeted-degradation compound and application thereof

A compound and solvate technology, applied in the field of pharmaceuticals, can solve problems that have not been reported

Active Publication Date: 2021-10-29
TAI BI DI PHARM TECH SHIJIAZHUANG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, breakthroughs have been made in the liver-targeted delivery of nucleic acid drugs by using the high-affinity ligand GalNAc of ASGPR as a targeting molecule, such as by linking a conjugation moiety containing terminal galactose or its derivatives to Nucleic acid, so that the nucleic acid molecule is targeted to liver cells by binding to ASGPR, see, for example, WO2009 / 073809, WO2011 / 104169 and WO2012 / 083046, but the application and research on other aspects of ASGPR ligands have not been reported yet

Method used

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  • Tissue-targeted protein targeted-degradation compound and application thereof
  • Tissue-targeted protein targeted-degradation compound and application thereof
  • Tissue-targeted protein targeted-degradation compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Embodiment 1, the synthesis of compound WGint2

[0107]

[0108] A solution of 10-hydroxydecanoic acid (10.0 g, 53.2 mmol) in DMF (250 mL) was treated with potassium bicarbonate (5.32 g, 53.2 mmol) and benzyl bromide (9.10 g, 53.2 mmol), then at room temperature in Stir under argon for 18 hours. The solvent was evaporated and the residue was partitioned between EA and water. The aqueous layer was washed with EA, and the combined organic extracts were dried over anhydrous magnesium sulfate. The resulting crude product was purified by flash chromatography on silica gel to give compound WGint2 (8.0 g) as a white solid, LC / MS (ESI) m / z: [M+H] + 279.

Embodiment 2

[0109] Embodiment 2, the synthesis of compound WGint3

[0110]

[0111] To a solution of compound WGint2 (5.0 g, 18.0 mmol) in 100 mL of anhydrous dichloromethane containing tetrazolediisopropylamine (4.6 g, 27.0 mmol) was added 2-cyanoethoxy-N,N,N , N-tetraisopropylammonium diphosphate (9.0 mL, 27.0 mmol), and the mixture was stirred at room temperature for 6 h until TLC showed complete reaction. The dichloromethane was then removed by evaporation and the product was extracted in ethyl acetate, washed with 5% sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and evaporated to a small volume. The product was eluted on a silica gel column with 10-35% ethyl acetate-n-hexane+2% triethylamine to give compound WGint3 (2.5 g). This intermediate was directly used in the next reaction.

Embodiment 3

[0112] Embodiment 3, the synthesis of compound WGint6

[0113]

[0114] A mixture of compound WGint3 (2.5 g, 5.2 mmol) and compound WGint4 (0.5 g, 0.52 mmol) in ACN (25 mL) was added to tetrazole (145 mg, 2.1 mmol) and stirred overnight. tert-Butyl peroxide in decane (2 mL, 5M) was added dropwise at 0 °C, and the mixture was stirred at room temperature for 6 h. The reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated at 40 °C, diluted with EA, washed with water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and the solvent was evaporated to give crude compound WGint6. LC / MS(ESI)m / z:[M+H] + 1360.

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Abstract

The invention discloses a tissue-targeted protein targeted-degradation compound and application thereof, relates to the field of pharmacy, and particularly relates to a compound or pharmaceutically acceptable salt, stereoisomer, solvate or polymorphic substance thereof. The compound is a protein targeted-degradation chimera with tissue targeting ability. A structure of the compound comprises three parts: A-BD-CON, wherein the part A is a protein targeted-degradation chimera (PROTAC), one end of the structure of the part A is a target protein binding ligand, and the other end of the structure of the part A is a ubiquitin ligase ligand; and the part CON is a ligand of an asialoglycoprotein receptor (ASGPR) and has a function of targeting a specific tissue of the PROTAC. On the basis of the protein targeted-degradation chimera (PROTAC) which is very difficult in medicine preparation, the functions of liver tissue enriching and cell targeting are further realized, and the solubility, the cell permeability and the drug effect in specific target tissues of the PROTAC are improved, so that the medicine preparation property of the PROTAC is improved on the whole.

Description

technical field [0001] The invention relates to the field of pharmacy, more specifically to such a compound or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof. The compound is a protein targeting degradation chimera with tissue targeting ability. The structure of the compound consists of three parts: A-BD-CON, wherein part A is a protein-targeted degradation chimera (PROTAC), one end of which is a target protein binding ligand, and the other end is a ubiquitin ligase ligand; the CON part is A ligand for the asialoglycoprotein receptor (ASGPR), which functions to target PROTACs to specific tissues. Based on the protein-targeted degradation chimera (PROTAC), which is very difficult to make into a drug, the present invention further realizes the functions of liver tissue enrichment and cell targeting, and improves the solubility, cell permeability and penetration of PROTAC in specific target tissues. Drug efficacy, thereby improving its druggabili...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062A61K31/47A61K31/44A61K31/496A61K31/4709A61K31/444A61K31/517A61K31/505A61K31/551A61K31/4184A61K31/55A61K31/519A61K47/64A61P35/00A61P1/16
CPCC07K5/06034A61K31/47A61K31/44A61K31/496A61K31/4709A61K31/444A61K31/517A61K31/505A61K31/551A61K31/4184A61K31/55A61K31/519A61K47/64A61P35/00A61P1/16C07K5/06017A61K47/62A61K47/66A61K47/54
Inventor 王金戌苏向东白明杰
Owner TAI BI DI PHARM TECH SHIJIAZHUANG CO LTD
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