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PEG connecter and ligand drug conjugates

A technology of drug conjugates and linkers, used in drug combinations, anti-infective drugs, pharmaceutical formulations, etc., can solve problems such as limiting activity, accelerating the efflux of hydrophobic compounds, and increasing activity.

Active Publication Date: 2017-12-15
JENKEM TECH CO LTD (LIAONING)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, drug-resistant tumor cells may limit the activity of ADCs, most of which are caused by increased expression or activity of drug transporters and accelerated efflux of hydrophobic compounds
Therefore, a challenge in the design and development of ADCs is to generate hydrophilic linkers suitable for antibody and drug conjugation

Method used

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  • PEG connecter and ligand drug conjugates
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  • PEG connecter and ligand drug conjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0156] Embodiment 1: Synthesis of four-arm polyethylene glycol hydroxy-monoacetic acid (III-1)

[0157]

[0158] step:

[0159] In a three-necked round-bottomed flask, pass nitrogen gas, add 100g of four-armed polyethylene glycol (4ARM-PEG-5K) and 800mL of tetrahydrofuran (THF), heat to dissolve, evaporate about 20% of the solvent, cool down, and add 4.48g of potassium tert-butoxide , reacted at room temperature for 2 hours, added dropwise 5.17mL tert-butyl bromoacetate, reacted overnight at room temperature, filtered the next day, concentrated the reaction solution to viscous, added 500mL alkaline solution (add 8.16g sodium hydroxide and 77.52g sodium hydroxide to 500mL water Sodium phosphate), alkali hydrolysis at 80°C for 2 hours, adjust the pH of the solution to 2-3 with 2N hydrochloric acid solution, add 15% sodium chloride to the solution, extract three times with dichloromethane, combine the organic phases, and dry with anhydrous sodium sulfate , filtered, concentra...

Embodiment 2

[0162] Embodiment 2: Four-arm polyethylene glycol hydroxy-methyl monoacetate (IVA-1)

[0163]

[0164] step:

[0165] In a single-necked round-bottomed flask, add 3.2g of four-armed polyethylene glycol hydroxy-monoacetic acid (III-1), dissolve it with 16mL of anhydrous methanol, put it in an ice-water bath, add 0.64mL of concentrated sulfuric acid dropwise, and react at room temperature for 3 hours. % sodium bicarbonate aqueous solution to adjust the pH of the system to 7.0, extract three times with dichloromethane, combine the organic phases, dry the organic phases with anhydrous magnesium sulfate, filter, concentrate at 40°C until viscous, precipitate with ether, and dry in vacuo to obtain four arms Polyethylene glycol hydroxy-methyl monoacetate (IVA-1).

[0166] NMR(DMSO)δ: 3.32(s,3H,CH 2 COOCH 3 ), 4.13 (s,2H,CH 2 COOCH 3 ), 4.57(t,3H,CH 2 OH).

Embodiment 3

[0167] Embodiment 3: four-arm polyethylene glycol sulfonate-methyl monoacetate (IVB-1)

[0168]

[0169] step:

[0170] In a three-neck round bottom flask, nitrogen gas was added, 3.0 g of four-armed polyethylene glycol hydroxy-methyl monoacetate was added, dissolved in 50 mL of toluene, 38 mL of toluene was evaporated by heating until the distillate was clear, and cooled to room temperature, and 5 mL of dichloro methane, stirred for 10 minutes, added 188 μL of triethylamine, stirred for 5 minutes, added dropwise 94 μL of methanesulfonyl chloride, sealed and reacted overnight, the next day, added 720 μL of absolute ethanol, stirred for 15 minutes, filtered, concentrated at 60°C until viscous, Dissolve in 60 mL of isopropanol and precipitate in an ice-water bath, filter, wash the filter cake once with isopropanol, and dry in vacuo to obtain four-armed polyethylene glycol sulfonate-methyl monoacetate (IVB-1).

[0171] NMR(DMSO)δ: 3.17(s,9H,CH 2 OSO 2 CH 3 ), 4.13 (s,2H,CH...

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Abstract

The invention provides a PEG connector. The product comprises a general formula shown in the following formula (I), wherein PEG connecter comprises 1-49 binding sites. The invention also provides ligand drug conjugates, the PEG connector improves medicament capacity and medicament kinds of the ligand drug conjugates, so that connection of ligand drug conjugates and medicament molecules with hypotoxicity becomes possible, and treatment windows are expanded; in addition, binding sites in the PEG connecter are uniformly distributed, and the problem of drug effect reduction due to hydrophobic aggregation caused by local dense distribution of medicament is avoided. Y1 PEG1 {R1 PEG2 {Y4}n}m (I).

Description

technical field [0001] The present invention relates to the field of Ligand Drug Conjugates (LDC), in particular to a Ligand Drug Conjugate with a PEG linker, a pharmaceutical composition comprising the Ligand Drug Conjugate and a preparation method thereof and apply. Background technique [0002] The advent of Antibody-Drug Conjugates (ADC) has revolutionized the treatment of cancer. ADC connects a biologically active small molecule drug to a monoclonal antibody (Monoclonal Antibody, MAb) through a linker, and the MAb acts as a carrier to target and transport the small molecule drug into the target cell, which not only improves the anti It can also reduce the toxicity of small molecule drugs. Currently, two commercial ADCs and It has achieved good results in the treatment of Hodgkin's lymphoma and breast cancer, among which, Using the sulfhydryl group of the antibody cysteine ​​to couple to the maleimide linker, The amino group of the antibody lysine is used to fo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/60A61K31/4745A61P35/00A61P31/00A61P37/02
CPCA61K31/4745A61P31/00A61P37/02A61P35/00C07K2317/94C07C69/708A61K47/60A61K47/6849A61K47/6883C08G65/33303C08G65/33317C08G65/3332C08G65/334C08G65/3344A61K47/6803C07C59/125C07D207/452C07D207/46C07K16/2809C07K16/32C08G65/48A61K47/6855A61K31/436A61K47/10A61K47/34C07C247/04C07C309/65
Inventor 宋艳萍李文汪进良刘岩郑昆林美娜魏真冯泽旺赵宣
Owner JENKEM TECH CO LTD (LIAONING)
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