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Double-substituted maleic amide connexon for antibody-medicine coupling as well as preparation method and application of connexon

A technology of maleamide and drug conjugates, which is applied in antineoplastic drugs, drug combinations, and pharmaceutical formulations, and can solve unsolved problems such as sulfhydryl exchange, poor chemical stability of coupling reagents, and side reactions

Active Publication Date: 2019-05-28
MABWELL (SHANGHAI) BIOSCIENCE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned technology has a long synthetic route of the coupling reagent, poor chemical stability of the coupling reagent, and messy electrophoresis of the antibody conjugate, suggesting that there may be side reactions in the coupling process, and the existing scheme does not solve the problem of in vivo circulation. Sulfhydryl exchange (reverse Michael addition reaction) and other issues

Method used

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  • Double-substituted maleic amide connexon for antibody-medicine coupling as well as preparation method and application of connexon
  • Double-substituted maleic amide connexon for antibody-medicine coupling as well as preparation method and application of connexon
  • Double-substituted maleic amide connexon for antibody-medicine coupling as well as preparation method and application of connexon

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Embodiment Construction

[0223] Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.

[0224] Embodiment group one, compound synthesis and preparation method

[0225] 1.1 Synthesis of Compound E-1 (Formula Ia-1)

[0226] 1.1.1 Intermediate A-1 (step a)

[0227]

[0228] Triethylene glycol (92 g, 613 mmol) was dissolved in tBuOH (200 ml). KOtBu (22.91g, 204mmol) was added under ice-cooling and stirred for half an hour. Under argon protection, a solution of tert-butyl bromoacetate (39.8g, 204mmol) in tBuOH (40ml) was added dropwise, and stirred overnigh...

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Abstract

The invention provides a double-substituted maleic amide connexon coupled with an antibody as well as a preparation method and application of the connexon. Particularly, a strong cytotoxic activity substance and biological macromolecules are coupled through a kind of new connexon. The kind of connexon can selectively act with a disulfide chain at the same time, so that the substance homogeneity and stability of a conjugate are greatly improved. The conjugate prepared from the connexon has high inhibitory activity for cell strains which express corresponding antigens. The invention further provides a preparation method and application of the conjugate.

Description

technical field [0001] The invention relates to a novel disulfide chain bridging and crosslinking reagent, a macromolecule, a therapeutic conjugate and a synthesis method thereof. More specifically, the present invention relates to a conjugate obtained by cross-linking cytotoxic drugs and macromolecules with a maleamide-based disulfide chain bridging cross-linking reagent, and a preparation method and use thereof. Background technique [0002] As a new type of targeted therapy drug, antibody-drug conjugate (Antibody Drug Conjguate, ADC) ushered in a new era of tumor treatment, and its basic design idea originated from Paul Ehrlich's first The concept of "Magic bullet" and drug targeting is put forward, that is, to deliver the drug to the disease site through an appropriate carrier. However, subject to the constraints of antibody and highly active cytotoxic drug technology, the first antibody-drug conjugate (Mylotarg) for the treatment of acute myeloid leukemia (AML) was rel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/456C07D401/14A61K31/537A61P35/00C07K5/027C07K5/06
Inventor 沈竞康孟韬马兰萍王昕张永良于霆陈驎彭红丽杜志彦王英
Owner MABWELL (SHANGHAI) BIOSCIENCE CO LTD
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