Monomethyl auristatin E prodrug and preparation method and application thereof

An auristatin and monomethyl technology, applied in the field of monomethyl auristatin E prodrug and its preparation, can solve the problems of large drug side effects, narrow drug treatment window, high chemical toxicity and the like

Active Publication Date: 2021-08-31
THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, due to the high chemical toxicity of MMAE, its drug side effects are very large, which usually leads to a narrow drug treatment window, which limits its wide application.

Method used

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  • Monomethyl auristatin E prodrug and preparation method and application thereof
  • Monomethyl auristatin E prodrug and preparation method and application thereof
  • Monomethyl auristatin E prodrug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] This example provides a monomethyl Astatin E prodrug-shear type TCO axial isomer -mmae (TCO dax -Mmae, its structure is as follows:

[0056]

[0057] The preparation process is as follows:

[0058] (1) The shear type TCO axial isomer of 1.2: 1 is dissolved in tetrahydrofuran in tetrahydrofuran, and triethylamine is added to tetrahydrofuran, and triethylamine and 4-nitrophenol chlorol. The molar ratio of the methyl ester is 1: 1, 25 ° C for 20 h to obtain a shear type TCO axial isomer to nitrophenyl carbonate;

[0059] (2) The shear type TCO axial isomer of 0.5: 1 of the molar ratio is in the presence of nitrophenyl carbonate and Mmae in dimethylformamide, 1-hydroxybenzene triazole (HOBT), wherein The molar ratio of Hobt and shear TCO axial isomers on nitrophenyl carbonate was 0.5: 1, 35 ° C. Anti-lighting reaction 24h to obtain Mmae prodrug;

[0060] (3) Purification of the MMAE prodrug of the MMAE to obtain a refined product and the yield is 85.5%.

[0061] The resulting...

Embodiment 2

[0063] This example provides a monomethyl Astin E prodrug-shear type TCO plane isomer-MMAE (TCO deq -Mmae, its structure is as follows:

[0064]

[0065] The preparation process is as follows:

[0066] (1) The shear type TCO plane isomer of 1.4: 1 is dissolved in tetrahydrofuran in tetrahydrofuran, and pyridine is added to tetrahydrofuran, and the molar ratio of pyridine and 4-nitrophenol chloroform is added. The reaction was obtained from 1: 1, 25 ° C for 48 hours to obtain a shear type TCO plane isomer to nitrobenzene carbonate;

[0067] (2) The shear type TCO plane isomer of 0.6: 1 in the molar ratio is in the presence of nitrophenyl carbonate and Mmae in dimethylformamide, 1-hydroxybenzene triazole (hobt), where Hobt The molar ratio of the shear type Tco plane isomer to nitrobenzene carbonate is 0.6: 1, 30 ° C. Anti-lighting reaction 24h to obtain Mmae prodrug;

[0068] (3) Purification of the MMAE prodrug of the produced MMAE was purified and the yield was 86.1%.

Embodiment 3

[0070] This example provides a monomethyl Astatin E prodrug-coupling TCO axial isomer-Mmae (TCO lax -Mmae, its structure is as follows:

[0071]

[0072] The preparation process is as follows:

[0073] (1) The coupling TCO axial isomer with a molar ratio of 1.6: 1 is dissolved in tetrahydrofuran in tetrahydrofuran to 4-nitrophenol chlorometry, and the pyridine is added to the molar of pyridine and 4-nitrophenol chloroform. The ratio was 1: 1, 25 ° C for 12h to obtain a coupling TCO axial isomer to nitrobenzyl carbonate;

[0074] (2) A conjugated TCO axial isomer of 0.7: 1 of 0.7: 1 is in the presence of nitrophenyl carbonate and Mmae in dimethylformamide, 1-hydroxybenzene triazole (HOBT), wherein The molar ratio of Hobt and coupling TCO axial isomers on nitrophenyl carbonate is 0.7: 1, 30 ° C. Anti-lighting reaction 36h to obtain Mmae prodrug;

[0075] (3) Conducting the MMAE prodrug of MMAE to obtain a refined product with a yield of 89.8%.

[0076] The resulting MMAE prodrug e...

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PUM

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Abstract

The invention relates to a monomethyl auristatin E prodrug and a preparation method and application thereof. The monomethyl auristatin E prodrug comprises any one or a combination of at least two of a compound shown in a formula (I), a compound shown in a formula (II), a compound shown in a formula (III) or a compound shown in a formula (IV). Compared with an original drug, the monomethyl auristatin E prodrug can passivate drug active sites of the original drug in a spatial structure, can significantly reduce the toxicity of the drug to cells, and can be selectively activated in cancer cells. The preparation method is simple to operate, and the prepared prodrug has high chemical purity and high yield.

Description

Technical field [0001] The present invention belongs to the field of biomedicine, involving a monomethyl Astatin E prodrug and preparation methods and applications, in particular, to a monomethyl Astatin E prodrug with low toxic side effects and preparation methods and applications. Background technique [0002] Chemotherapy drugs typically have a large toxic side, which limits the amount of drug usage and its application, which results in cancer recurrence or metastasis. Single-methyl Astatin E (Mmae, Monomethyl Auristatin E, CAS: 474645-27-7) is a novel anti-split Auristatin derivative, commonly used for antibody coupling drugs. [0003] For example, CN109200291A discloses an antibody coupling drug targeted to EGFR and a preparation method thereof and a use thereof, which targets an antibody coupling agent of EGFR, named LR004-VC-MmAe, which is from antibody, cytotoxicity Composition of drugs and linkers. The new antibody coupling drug LR004-VC-MmAe can be targeted to the EGFR ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/023A61K38/07A61P35/00
CPCC07K5/0202A61P35/00A61K38/00
Inventor 姚庆鑫高远
Owner THE NAT CENT FOR NANOSCI & TECH NCNST OF CHINA
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