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Hydrophilic carbonate type antibody drug conjugate

A technology of antibody drugs and carbonates, which can be used in drug combinations, anti-tumor drugs, anti-infective drugs, etc., and can solve the problem of the reduction of the drug effect of Exitecan ADC, the limited effect of improving hydrophilicity, and the lack of molecular hydrophilicity, etc. question

Pending Publication Date: 2020-04-14
SICHUAN BAILI PHARM CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its drawbacks are obvious. At high DAR, the molecule is not sufficiently hydrophilic, resulting in reduced efficacy of exitecan ADC in vivo
[0007] IMMU132 developed by IMMUNOGEN improves hydrophilicity through long-chain PEG, but it is well known that the introduction of long-chain PEG in the main chain of the molecule has limited effect on improving hydrophilicity and will result in reduced molecular fluidity

Method used

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  • Hydrophilic carbonate type antibody drug conjugate
  • Hydrophilic carbonate type antibody drug conjugate
  • Hydrophilic carbonate type antibody drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-6

[0115]

Embodiment 1

[0116] The synthesis of embodiment 1 compound 1

[0117]

[0118] Fmoc-Lys(MMT)-OH (2g, 3.2mmol, 1eq), PABOH (788.16mg, 6.4mmol, 2eq), HATU (1.34g, 3.52mmol, 1.1eq), DIEA (1.24g, 9.6 mmol, 3eq) and 20ml of DMF, stirring and dissolving, under nitrogen protection, reacted at 25°C; spot plate detection, lysine was completely reacted. 200ml of water was added to the reaction solution, a large amount of solids precipitated out, extracted 3 times with EA (60ml), the organic phase was washed with brine three times, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.85g of a yellow oil. Dissolve the intermediate in the previous step with 20ml of diethylamine, protect it under nitrogen, and react at 25°C; spot plate detection shows that the raw materials have completely reacted. The solvent was spin-dried and dissolved in 100ml of EA, washed three times with brine, dried over anhydrous sodium sulfate, and spin-dried to obtain 2.58g of a light brown oily product. Colum...

Embodiment 2

[0120] The synthesis of embodiment 2 compound 2

[0121]

[0122] Add compound 1 (300mg, 0.574mmol, 1eq) in the one-mouth bottle, N 3( PEG) 8 COOH (350mg, 0.631mmol, 1.1eq), HOBT (85mg, 0.631mmol, 1.1eq), DIEA (149mg, 1.15mmol, 2.0eq) and 4ml of dry DMF, nitrogen protection, cooling and stirring in an ice-water bath to dissolve; add HATU ( 240mg, 0.631mmol, 1.1eq), react at 25°C; dot plate detection until compound 1 is completely reacted.

[0123] Post-processing: add 50ml of water to the reaction solution, extract with EA (50mlx3), wash the organic phase three times with brine, dry over anhydrous sodium sulfate, and spin dry to obtain 920mg of light yellow oil. TLC plate preparation and purification: develop once with DCM:MeOH=15:1 as the developer, and purify to obtain 500 mg of the product as a pale yellow oil.

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Abstract

The invention provides a hydrophilic carbonate type antibody drug conjugate or a pharmaceutically acceptable salt thereof. The hydrophilic carbonate type antibody drug conjugate or the pharmaceutically acceptable salt thereof provided by the invention can be used for effectively releasing drugs in a tumor weakly acidic microenvironment to obtain a better in-vivo drug effect on tumors, and can be used for obtaining very good in-vivo PK under high DAR.

Description

technical field [0001] The invention discloses a hydrophilic carbonate type antibody drug conjugate. More specifically, in the present invention, the linker is linked to the drug with a carbonate bond, and the PK characteristics of the ADC drug are improved through the hydrophilic amino acid in the linker. Background technique [0002] As a new type of targeted drug, antibody-drug conjugate (ADC) generally consists of three parts: antibody or antibody-like ligand, small molecule drug, and a linker that couples the ligand and drug. Antibody-conjugated drugs use the specific recognition of antibodies to antigens to transport drug molecules to the vicinity of target cells and effectively release drug molecules to achieve therapeutic purposes. In August 2011, the US Food and Drug Administration (FDA) approved the new ADC drug Adecteis developed by Seattle Genetics for the treatment of Hodgkin's lymphoma and relapsed degenerative large cell lymphoma (ALCL) TM Listed, clinical a...

Claims

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Application Information

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IPC IPC(8): A61K47/68A61K47/65A61K45/00A61P35/00A61P37/02A61P31/00
CPCA61K47/6851A61K47/6803A61K47/65A61K45/00A61P35/00A61P37/02A61P31/00
Inventor 朱义李杰卓识万维李
Owner SICHUAN BAILI PHARM CO LTD