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Folate receptor binding ligand-drug conjugate

A technology of a drug, folic acid, applied in the field of folic acid receptor binding ligand-drug conjugates

Active Publication Date: 2019-02-12
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the main disadvantage of chemotherapy drugs is that while inhibiting the growth of tumor cells, it also severely inhibits the proliferation of normal cells. These unavoidable side effects make the development of new specific anticancer drugs particularly important.

Method used

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  • Folate receptor binding ligand-drug conjugate
  • Folate receptor binding ligand-drug conjugate
  • Folate receptor binding ligand-drug conjugate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0158] The preparation of embodiment 1 compound III

[0159]

[0160] According to the routine procedure described in the present invention, according to the scheme of scheme 1, in the 50ml reaction bottle, add 1000mg2Cl-Trt Resin (1.5eq), then add 234mg Fmoc-Cys(Trt)-OH (1.0eq), 8ml dichloro Methane (DCM), 640μL DIEA (2.0eq), completely dissolved, reacted for 50min, added 8ml DCM, 1ml MeOH, 1ml DIEA, reacted for 20min, transferred to a self-made solid-phase synthesis reaction column, added 10ml 20% piperazine after washing with DMF Pyridine DMF solution, reacted for 20min, after washing with DMF, the ninhydrin test was positive, took 709mg Fmoc-Lys(Fmoc)-OH (3.0eqiv, 178mg HOBT (3.3eqiv), dissolved in 6ml DMF, added 230μL DIC (3.3eq) and mixed Add the reaction column, monitor the ninhydrin after reacting 1H, add 20% piperidine DMF solution after DMF washing.Repeat the above steps, successively condense Fmoc-Asp(OtBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc- Arg(Pbf)-OH, Fmoc-Asp(OtBu...

Embodiment 2

[0161] The preparation of embodiment 2 compound 33

[0162]

[0163] Add 10.0ml DCM, 1.0ml MeOC(O)SCl (1.0eq) to a 100ml three-necked flask and cool down to 0°C in an ice bath, add 0.76ml mercaptoethanol (1.0eq) dropwise, keep warm at 0°C for 30min, add 1.22g 2- Mercaptopyridine (1.0eq) and 16ml DCM were added dropwise into the reaction flask, kept at 0°C for 1 hour, then raised to room temperature for 1 hour, and then the reaction of TLC raw materials was completed. Post-treatment: Concentrate to about 16ml, filter with suction, and wash the filtrate with DCM to obtain light yellow micro Odor solid 2.0 g.

[0164] Add 3.0ml DCM and 0.46g diphosgene (0.55eq) to a 100ml three-neck flask, cool down to 0°C in an ice bath, dissolve 1.0g compound 33-2 (1.1eq) in 13ml DCM, and add 0.45g Triethylamine (1.0eq) was dissolved and added dropwise to the reaction flask. During the dropwise addition, the temperature was controlled below 0°C. After rising to room temperature for 1 hour, ...

Embodiment 3

[0166] The preparation of embodiment 3 compound 15-3

[0167]

[0168] Add 1.5g of vinblastine, 5ml of anhydrous methanol and 5ml of anhydrous hydrazine into a 100ml three-neck flask, raise the temperature to about 60°C, react for 24 hours and then detect the reaction progress by TLC. After the reaction, pour into 50ml of water, extract with DCM for 3 times, and wash with water 3 times, washed 3 times with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 1.1 g of white solid, namely compound 15-2.

[0169] Add 0.98g (1.0eq) of compound 15-2, 0.67g (1.5eq) of compound 33, and 10g of DCM into a 100ml three-necked flask, stir and dissolve, then add 0.44ml of triethylamine (2.5eq) dropwise to the reaction flask, room temperature for 2h After the reaction is complete.

[0170] Post-treatment: add 50ml of DCM, wash with water 3 times, wash with saturated brine 3 times, dry over anhydrous sodium sulfate, concentrate to obtain 1.2g of crude product, ...

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Abstract

The invention provides a folate receptor binding ligand-drug conjugate. The conjugate is formed by a vitamin receptor binding part (F)n, a connector (L) and a drug or an analogue or a derivative (D) thereof, wherein n is an integer from 2 to 4. The vitamin receptor binding part is preferably selected from folic acid or pteroic acid. The connector (L) contains a multivalent connector L1 and at least contains one releasable connector L2. The (F)n is covalently connected to the multivalent connector L1. The drug or the analogue or the derivative (D) thereof is in covalent connection with the releasable connector of L2. The L1 and L2 are in covalent connection. The provided conjugate is capable of greatly improving affinity for a positive tumor cell of a folate receptor, and has remarkable anti-tumor activity, and the side effect is apparently reduced.

Description

[0001] This application is a divisional application with the applicant Borui Biomedicine (Suzhou) Co., Ltd., the application number is 201410024349.9, the application date is 2014.01.20, and the invention name is "folate receptor binding ligand-drug conjugate". technical field [0002] The invention relates to a pharmaceutical compound for targeted drug delivery and a preparation method thereof. Specifically relates to folic acid receptor binding ligand-drug conjugates, more specifically, the present invention relates to two or more folic acid receptor binding ligands (F) and drugs or their analogs or derivatives through linkers (L) (D) coupled to form (F) n The present invention also relates to LD conjugates for use in the treatment of disease conditions caused by pathogenic cell populations, as well as methods for the preparation of such conjugates and pharmaceutical compositions thereof. Background of the invention [0003] Although great progress has been made in the re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/65A61K47/64A61K47/54A61K45/00A61P35/00
CPCA61K47/65A61K47/64A61P35/00
Inventor 袁建栋宋云松黄仰青
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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