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Iron carrier-dihydrofolate reductase inhibitor conjugate and application thereof

A reductase inhibitor, dihydrofolate technology, applied in the field of compounds, can solve problems such as high toxicity and the use of antibacterial reagents

Pending Publication Date: 2021-07-23
JASAN BIO MEDICINE JIAXING CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to its antitumor activity, methotrexate also has certain antibacterial activity. The MIC values ​​against Enterococcus and Streptococcus pneumoniae are 4 μM and 0.5 μM, respectively, but it cannot be used as an antibacterial agent because of its toxicity to normal human cells. to use

Method used

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  • Iron carrier-dihydrofolate reductase inhibitor conjugate and application thereof
  • Iron carrier-dihydrofolate reductase inhibitor conjugate and application thereof
  • Iron carrier-dihydrofolate reductase inhibitor conjugate and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Synthesis of compound 3-4a: as shown in the scheme below, siderophore fragment 2-81 was condensed with compound 3-5 under HATU and DIPEA conditions to obtain compound 3-1a. Compound 3-1a was deprotected from Boc with trifluoroacetic acid, and then coupled with tert-butyl ester-protected methotrexate 3-8 to obtain compound 3-3a. The same tert-butyl ester protection was removed with trifluoroacetic acid, and then K 2 CO 3 The remaining Bz and Fmoc protecting groups were removed to obtain the target product 3-4a.

[0130]

[0131] 1) Preparation of compound 3-1a

[0132] Under nitrogen protection, compound 2-81 (300 mg, 0.281 mmol, 1.0 equiv), compound 3-5 (45 mg, 0.281 mmol, 1.0 equiv), HATU (160 mg, 0.421 mmol, 1.5 equiv) were dissolved in dry DMF ( 5 mL), placed in a low-temperature reactor at -15°C and stirred, and slowly added DIPEA (93 μL, 0.562 mmol, 2.0 equiv) dropwise. After reacting for 2 hours, the pH of the reaction solution was adjusted to neutral with ...

example 2-11

[0142] The synthesis of example 3-12 is the same as the synthesis route of example 1, and 3-4b, 3-4c, 3-4f, 3-4j, 3-4k, 3-4l, 3-4n, 3-4p, 3- 4r,3-4u.

Embodiment 12

[0144] Synthesis of compound 3-4e: as shown in the scheme below, siderophore fragment 2-81 was condensed with compound 3-5 under HATU and DIPEA conditions to obtain compound 3-1e. Compound 3-1e was deprotected from Boc with trifluoroacetic acid, and then coupled with Boc-protected serine 3-7 to obtain compound 3-2e. Similarly, the Boc protection was removed with trifluoroacetic acid, and then condensed with tert-butyl ester-protected methotrexate 3-8 to obtain compound 3-3e. Finally, use trifluoroacetic acid to remove the protection of tert-butyl ester, and then use K 2 CO 3 The remaining Bz and Fmoc protecting groups were removed to obtain the target product 3-4e.

[0145]

[0146] in:

[0147] 1) Preparation of compound 3-1a

[0148] Under nitrogen protection, compound 2-81 (300 mg, 0.281 mmol, 1.0 equiv), compound 3-5 (45 mg, 0.281 mmol, 1.0 equiv), HATU (160 mg, 0.421 mmol, 1.5 equiv) were dissolved in dry DMF ( 5 mL), placed in a low-temperature reactor at -15°C a...

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Abstract

The invention provides a coupling compound which is a compound as shown in a formula (I) or a stereoisomer, a tautomer, a homologue, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound as shown in the formula (I), A is a linking group, and B is a dihydrofolate reductase inhibitor.

Description

technical field [0001] The present invention relates to the field of compounds, specifically, the present invention relates to siderophore-dihydrofolate reductase inhibitor conjugates and applications thereof. Background technique [0002] The discovery of natural siderophore antibiotics provides ideas for the development of new antibiotics. However, there are only a few types of natural siderophore antibiotics, so chemists have developed a series of siderophore-antibiotic conjugates through artificial synthesis, which enriches the types of siderophore antibiotics. [0003] In 1977, the first synthetic siderophore-antibiotic conjugate was born, which drew on the structural characteristics of Ferrimycin and apomycin to link siderophore with sulfa drugs. Antibacterial activity tests found that the antibacterial spectrum of this class of antibiotics was closely related to siderophore. The authors also found that the tether linking the siderophore to the drug plays a crucial r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P31/04
CPCC07D487/04A61P31/04A61K31/519A61K38/00A61K47/552A61K47/55A61K47/64C07K5/0606C07K5/081C07K5/1013C07K7/06
Inventor 贺耘赵胜王志鹏林子华郭键陆建军
Owner JASAN BIO MEDICINE JIAXING CO LTD
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