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Non-peptidic polymeric linker compound, conjugate comprising same linker compound, and methods for preparing same linker compound and conjugate

A technology of non-peptidyl polymers and compounds, applied in the direction of medical preparations and pharmaceutical formulations of non-active ingredients, can solve the problems of reduced stability of reactive groups and reduced yield of conjugates, and achieve high yield and stable sexual effect

Active Publication Date: 2019-12-06
HANMI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the disadvantages of functional groups are the reduced yield of conjugates due to the fact that the entire substance introduced into the reaction may not be converted into conjugates during the reaction targeting specific amino acid sites after conjugation with protein drugs, and some Reactive groups are less stable in blood

Method used

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  • Non-peptidic polymeric linker compound, conjugate comprising same linker compound, and methods for preparing same linker compound and conjugate
  • Non-peptidic polymeric linker compound, conjugate comprising same linker compound, and methods for preparing same linker compound and conjugate
  • Non-peptidic polymeric linker compound, conjugate comprising same linker compound, and methods for preparing same linker compound and conjugate

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preparation example Construction

[0135] The preparation method may include: 1) introducing an amino group (-NH 2 ), introducing R at one end of the non-peptidyl polymer through an amide bond with the amino group; and

[0136] 2) introducing an aliphatic hydrocarbon group comprising a functional group selected from the group consisting of: 2,5-dioxapyrrolidinyl, 2,5-dioxapyrrolyl, Aldehydes, maleimides, C 6 -C 20 Aryl disulfide, C 5 -C 20 Heteroaryl disulfides, vinyl sulfones, mercaptans, haloacetamides, succinimides, p-nitrophenyl carbonate and derivatives thereof, wherein R2 is the same as defined in formula 1 or 1a.

[0137] In a specific embodiment, the non-peptidyl polymer of 1) may be polyethylene glycol.

[0138] In a specific embodiment, the molecular weight of the non-peptidyl polymer of 1) may be in the range of 0.1 kDa to 100 kDa, especially 0.1 kDa to 50 kDa, and more specifically 0.3 kDa to 10 kDa, but is not limited thereto.

[0139] In a specific embodiment, 2) a C including an aldehyde gr...

Embodiment 1

[0335] Embodiment 1: Preparation of linker compound (1)

[0336]

[0337] 1-1: Preparation of Compound 2 (MW=10000)

[0338] 20 g of Compound 1 (MW=10000) and 60 mL of dichloromethane were introduced into the reactor. While keeping the reaction temperature below 10°C, 1.11 g of triethylamine and 1.15 g of methanesulfonyl chloride were added thereto, followed by stirring at room temperature for 3 hours. After the reaction was completed, 100 mL of water and 40 mL of dichloromethane were added, followed by stirring for 5 minutes. The obtained organic layer was separated, and then 100 mL of dichloromethane was added to the aqueous layer for further extraction. The organic layer was collected, washed with 100 mL of water, and dried over magnesium sulfate. Filtration was performed, and the remaining filtrate was distilled under reduced pressure. 20 mL of dichloromethane was added to the concentrate, which was then dissolved, and 300 mL of methyl tert-butyl ether was added dro...

Embodiment 2

[0345] Embodiment 2: Preparation of linker compound (2)

[0346] 2-1: Preparation of Compound 2 (MW=5000)

[0347] 20 g of Compound 1 (MW=5000) and 60 mL of dichloromethane were introduced into the reactor. While keeping the reaction temperature below 10°C, 2.23 g of triethylamine and 2.29 g of methanesulfonyl chloride were added, followed by stirring at room temperature for 3 hours. After the reaction was completed, 100 mL of water and 40 mL of dichloromethane were added, followed by stirring for 5 minutes. The obtained organic layer was separated, and then 100 mL of dichloromethane was added to the aqueous layer for further extraction. The organic layer was collected, washed with 100 mL of water, and dried over magnesium sulfate. Filtration was performed, and the remaining filtrate was distilled under reduced pressure. 20 mL of dichloromethane was added to the concentrate, which was then dissolved, and 300 mL of methyl tert-butyl ether was added dropwise over 20 minutes....

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Abstract

One aspect of the present invention provides a compound in which a functional group capable of binding to a globulin Fc region or a physiologically active polypeptide is introduced at one end of a non-peptidic polymer and a functional group capable of a click reaction is introduced at the other end; a polypeptide conjugate in which a physiologically active polypeptide binds to one end of the compound; a physiologically active polypeptide conjugate in which a physiologically active polypeptide and an immunoglobulin Fc region bind to both ends thereof by using the compound as a linker; and methods for preparing the same compound, polypeptide conjugate, and physiologically active polypeptide conjugate.

Description

technical field [0001] The present disclosure relates to a non-peptidyl polymeric compound, including conjugates of the compound and methods of making the same. More specifically, the present disclosure relates to a non-peptidyl polymer compound that can be used as a linker to increase the half-life of a physiologically active polypeptide, a conjugate linked to a physiologically active polypeptide via the compound as a linker, and a preparation method thereof. Background technique [0002] Protein drugs have a short blood half-life when administered to humans. Therefore, protein drugs are inconvenient in that they need to be administered frequently in order to maintain their efficacy. To solve this problem, PEGylation, which combines polyethylene glycol with protein drugs, has been used to increase the blood half-life of protein drugs. This PEGylation not only increases the blood half-life of protein drugs, but also reduces the antigenicity of protein drugs, so PEGylation ...

Claims

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Application Information

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IPC IPC(8): A61K47/68
CPCA61K47/68A61K47/60A61K47/6803A61K47/6889A61K47/545A61K47/61C07D225/08
Inventor 朴嬿金大振郑圣烨郑容圭尹炫植
Owner HANMI PHARMA
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