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Arylnitro-containing linker, antibody-drug conjugate containing linker and application of linker

An aryl and nitro technology, applied in the field of medicinal chemistry, can solve problems such as toxicity and lack of tumor specificity

Inactive Publication Date: 2020-03-10
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For those unavoidable off-target ADCs, drug-releasing enzymes in normal tissue lysosomes can degrade ADCs and release highly lethal cytotoxic drugs such as MMAE, causing toxicity to normal tissues; meanwhile, non-ionic free cytotoxins usually Can further penetrate normal cell membranes and cause systemic toxicity to surrounding tissues through the bystander effect
[0007] At this stage, the drug release process of mainstream enzymatic ADCs generally lacks tumor specificity and off-target toxicity caused by non-specific enzymatic hydrolysis

Method used

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  • Arylnitro-containing linker, antibody-drug conjugate containing linker and application of linker
  • Arylnitro-containing linker, antibody-drug conjugate containing linker and application of linker
  • Arylnitro-containing linker, antibody-drug conjugate containing linker and application of linker

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0321] Example 1: Preparation of ADC-1

[0322] 1) Preparation of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoic acid (MCOH)

[0323]

[0324] Maleic anhydride (4.86g, 49.55mmol) was added to a 500mL three-necked flask, completely dissolved with acetic acid (150mL), 6-aminocaproic acid (5.0g, 38.11mmol) was added, and the reaction solution was heated to 120°C and refluxed for 6h. After the reaction, the reaction solution was cooled to room temperature, poured into distilled water, and extracted with an appropriate amount of ethyl acetate for multiple times. The organic phases were combined, washed with saturated NaCl solution, and subjected to anhydrous NaCl solution. 2 SO 4 It was dried overnight, concentrated, and purified by column chromatography to obtain a white powdery solid (5.92 g, 74% yield). 1 H-NMR(400MHz,DMSO-d6) δ11.98(br,1H),7.01(s,2H), 3.39(t,J=7.3Hz,2H), 2.17(t,J=7.3Hz,2H), 1.51-1.44 (m,2H),1.24-1.17(m,2H).MS(ESI)m / z:210.0[MH] - .

[0325] 2) Preparation of (2,5-di...

Embodiment 2

[0379] Example 2: Preparation of ADC-2:

[0380] 1) Preparation of 4-[(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-methyl]-cyclohexanecarboxylic acid

[0381]

[0382] In a similar synthesis method for the synthesis of MCOH, trans-4-(aminomethyl)cyclohexanecarboxylic acid (7.86g, 50.0mmol) and maleic anhydride (4.90g, 50.0mmol) were added to a 500mL three-necked flask, using DMF (250mL) after dissolution, heat to 120°C and reflux for 6h. After the reaction, the reaction solution was cooled to room temperature, poured into distilled water, and extracted with an appropriate amount of ethyl acetate for multiple times. The organic phases were combined, washed with saturated NaCl solution, and then washed with anhydrous NaCl. 2 SO 4 Dry overnight. The solvent was concentrated to obtain a white solid powder (9.96 g, 84% yield). Used directly in the next reaction.

[0383] 2) 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl-methyl)-cyclohexanecarboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (SMCC) preparatio...

Embodiment 3

[0398] Example 3: Preparation of ADC-3

[0399] 1) Preparation of {[5-hydroxymethyl-2-(4-nitro-benzyloxy)phenylcarbamoyl]methyl}carbamic acid tert-butyl ester

[0400]

[0401] Add [(2-hydroxy-5-hydroxymethyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.15g, 0.50mmol) into a 50mL eggplant-shaped flask, and dissolve in anhydrous DMF (5mL ), add p-nitrobenzyl bromide (0.13mg, 0.60mmol), CsCO 3 (0.26mg, 0.8mmol). After stirring and reacting at room temperature for 5 hours, the mixture was poured into distilled water (40 mL) to precipitate solid insolubles. After multiple extractions with EA, the combined organic phases were washed 3 times with saturated NaCl. 2 SO 4 dry. The solvent was evaporated under reduced pressure to obtain a light yellow solid powder (0.12 g, 95% yield). 1 H-NMR(400MHz,DMSO-d6)δ9.11(s,1H), 8.27(d,J=8.7Hz,2H), 8.02(s,1H),7.77 (d,J=8.7Hz,2H), 7.38(s,1H),7.04(d,J=8.4Hz,1H),6.98(dd,J=8.4Hz,1H),5.36 (s,2H),4.39(s,2H),3.76(d,J =5.9Hz,2H),1.32(s,9H).M...

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Abstract

The invention relates to an arylnitro-containing linker represented by a formula I shown in the specification, relates to an antibody-drug conjugate containing the linker, relates to an application ofthe linker, relates to a drug combination containing the antibody-drug conjugate, and an application of the antibody-drug conjugate for treating and / or preventing diseases.

Description

Technical field [0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to the use of aromatic nitro linkers, linker-containing antibody-conjugated drugs and linkers, and also relates to pharmaceutical compositions containing antibody-conjugated drugs, as well as the use of these antibody-conjugated drugs For the treatment and / or prevention of diseases. Background technique [0002] Antibody-drug conjugate (ADC) organically combines monoclonal antibodies and cytotoxins, combining the advantages of both antibodies and cytotoxic drugs, with strong targeting, high cytotoxicity, and low side effects , Long degradation half-life and other characteristics. ADC structure includes three components: antibody, small molecule cytotoxin and linker. The role of antibody is to achieve targeting, while the role of cytotoxin is to kill target cells. The function is to realize the organic combination of antibody and cytotoxin structure to form an organ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/033C07D401/12A61K47/65A61K47/68A61K45/00A61P35/00
CPCC07K5/021C07D401/12A61K47/65A61K47/68A61K45/00A61P35/00A61K47/68031A61K47/6803C07K5/0205C07D403/12C07D403/14C07D405/14C07D405/12C07D207/452A61K47/6889A61K47/6855C07D233/91A61K47/6811A61K47/6851A61K47/545A61K47/6809A61K31/337A61K31/4745A61K31/537A61K31/5517A61K31/704A61K38/07C07C237/04C07D233/94C07D307/71C07D333/44C07D403/04C07D409/12
Inventor 周辛波王彦明李松钟武樊士勇肖典肖军海郑志兵李行舟谢云德曹瑞源王晓奎
Owner ACADEMY OF MILITARY MEDICAL SCI
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