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A compound, its preparation method and its use in the preparation of antibody drug conjugates

A compound and conjugate technology, applied in the field of biochemistry, can solve the problems of decreased protein stability, low therapeutic index, decreased protein expression, etc. Effect

Active Publication Date: 2021-03-19
赵琦
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unable to control the position and number of drug and antibody conjugation, the synthesized antibody-drug conjugates have inhomogeneous structure, poor batch reproducibility, and low therapeutic index
At present, there are methods of using protein sequences to incorporate unnatural amino acids, and then using compounds for site-directed amino acid modification, but unnatural amino acids are likely to reduce protein expression or protein stability.
The existing technology is to link specific drugs to the sugar chains of antibodies through specific enzyme catalysis for site-specific modification, but this method requires specific glycosylation modifications on the protein to achieve the reaction
The reaction of protein modification by compounds often requires organic solvents, and the intervention of organic solvents can easily cause protein inactivation

Method used

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  • A compound, its preparation method and its use in the preparation of antibody drug conjugates
  • A compound, its preparation method and its use in the preparation of antibody drug conjugates
  • A compound, its preparation method and its use in the preparation of antibody drug conjugates

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preparation example Construction

[0048] A second aspect of the present disclosure provides a method for preparing the compound described in the first aspect of the present disclosure, wherein the method comprises the following steps:

[0049] (1) Dissolving the precursor compound in an aprotic polar solvent to obtain a precursor compound solution, contacting the precursor compound solution with an aqueous solution of an alkali metal azide salt in the presence of a phase transfer catalyst to obtain an intermediate product ;

[0050] (2) dissolving the intermediate product in dichloromethane to obtain an intermediate product solution, and contacting the intermediate product solution with pyridinium chlorochromate at 0-10° C. to obtain a reaction product;

[0051] Wherein, the structure of the precursor compound is shown in formula (II), and the structure of the intermediate product is shown in formula (III):

[0052]

[0053] In formula (II), R 2 Is Cl, Br or I; In formula (II) and formula (III), R 1 for (C...

Embodiment 1

[0085] This example is used to illustrate the synthesis of 6-azidomethyl-2-pyridinecarbaldehyde.

[0086] Dissolve precursor compound 6-bromomethyl-2-pyridinemethanol in tetrahydrofuran (that is, R in the precursor compound shown in formula (II) of the present disclosure 1 for CH 2 , R 2 Br) to a final concentration of 0.55mmol / mL to obtain 10ml of precursor compound solution, in the precursor compound solution was added a concentration of 1.1mmol / mL of sodium azide (NaN 3 ) aqueous solution 10mL and tetrabutylammonium bisulfate 0.55mmol. The reaction mixture was stirred at 25° C. in the dark for 3 hours, and the reaction mixture was purified by silica gel chromatography to obtain the intermediate product 6-azidomethyl-2-pyridinemethanol.

[0087] Dissolve the intermediate product 6-azidomethyl-2-pyridinemethanol in dichloromethane and cool to 0°C to obtain 20 ml of an intermediate product solution with an intermediate product concentration of 0.25 mmol / ml, stir for 10 minu...

Embodiment 2-7

[0089] Utilize the method for embodiment 1 to synthesize the compound shown in formula (I) respectively, difference only is, in formula (I), R 1 for (CH 2 ) n And the values ​​of n are 2, 3, 4, 10, 16 and 20 respectively to obtain compound 2-7.

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Abstract

The invention relates to a compound, a preparation method for the compound and application of the compound in preparation of an antibody drug conjugate. According to the compound, the preparation method for the compound and the application of the compound in preparation of the antibody drug conjugate, biomolecules with a modifier are conjugated by using the compound and a conjugation scheme, so that the defects that the protein expression quantity is decreased, and the stability is reduced due to the fact that non-natural amino acid is doped can be overcome; and site-directed pegylation modification can be carried out on polypeptide or protein containing no carbohydrate chain, in addition, an organic solvent is not needed in the coupling process, and the biological activity of the obtainedbiological conjugate is higher.

Description

technical field [0001] The present disclosure relates to the field of biochemistry, in particular, to a compound, its preparation method and its use in the preparation of antibody-drug conjugates. Background technique [0002] Antibody Drug Conjugate (ADC) is a coupling product obtained by coupling a monoclonal antibody with a drug. Anti-tumor antibodies can specifically recognize tumor cells. Although they have certain anti-tumor activity, the effect often cannot meet the requirements for treating tumors. Cytotoxic drugs are coupled with monoclonal antibodies through chemical bonds, and the antibody can specifically recognize the characteristics of tumor cells, and can "precisely" deliver toxic small molecules to tumor cells, increasing the concentration of drugs in tumor sites while reducing the concentration of normal tissues , organ drug concentration, to achieve high efficiency and low toxicity anti-tumor effect. The use of monoclonal antibodies to deliver anticancer ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/48C08G65/333C07K16/32C07K1/113A61P35/00
CPCC07D213/48C07K16/32C08G65/333C08G65/33396C08G2650/04C08G2650/50
Inventor 赵琦
Owner 赵琦