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Folate receptor binding ligand-drug conjugate

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

Active Publication Date: 2015-07-22
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

[0205] Example 1 Preparation of compound III

[0206] (III)

[0207] According to the conventional steps of the present invention, according to scheme 1, add 1000mg 2Cl-Trt Resin (1.5eq) to a 50ml reaction bottle, then add 234mg Fmoc-Cys(Trt)-OH (1.0eq), 8ml Chloromethane (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% of Piperidine DMF solution, reacted for 20min, after washing with DMF, the ninhydrin test was positive, take 709mg Fmoc-Lys (Fmoc)-OH (3.0eqiv, 178mg HOBT (3.3eqiv), dissolve in 6ml DMF, add 230μL DIC (3.3eq) and mix After adding to the reaction column, after reacting for 1H, ninhydrin is monitored, and after washing with DMF, add 20% piperidine DMF solution. Repeat the above steps, sequentially condense Fmoc-Asp(OtBu)-OH, Fmoc-Asp(OtBu)-OH, Fmoc -Arg(Pbf)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu-OtBu, N 10 -TFA-...

Embodiment 2

[0208] Example 2 Preparation of compound 33

[0209]

[0210] Add 10.0ml DCM, 1.0ml MeOC(O)SCl (1.0eq) to a 100ml three-neck 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- Add mercaptopyridine (1.0eq), 16ml DCM dropwise into the reaction bottle, keep warm at 0°C for 1h, then rise to room temperature for 1h, then TLC raw material reaction is complete, post-treatment: concentrate to about 16ml, filter with suction, the filtrate is washed with DCM to get light yellow Slight odor solid 2.0g.

[0211] 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, the TLC reaction of the raw material...

Embodiment 3

[0213] Example 3 Preparation of compound 15-3

[0214]

[0215] Add 1.5g of vinblastine, 5ml of anhydrous methanol and 5ml of anhydrous hydrazine into a 100ml three-necked flask, heat up to about 60°C, react for 24 hours and then detect the reaction progress by TLC. Washed 3 times with water and 3 times with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain 1.1 g of white solid, namely compound 15-2.

[0216] 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, and keep at room temperature for 2h After the reaction is complete.

[0217] 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, and obtain 750mg of pure product of 15-3 after column chromatography. MS[M] + : 95...

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Abstract

The present invention provides folate receptor binding ligand‐drug delivery conjugates having the formula (F) nL1L2D. The conjugates have high affinity to folate receptor‐positive tumor cells and low toxicity for normal cells. The present invention also relates to preparation methods for such conjugates, pharmaceutical compositions comprising such conjugates, and use of such conjugates for preparing anti‐tumor medicaments.

Description

technical field [0001] The invention relates to a pharmaceutical compound for targeted drug delivery and a preparation method thereof. It specifically relates to folate 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) coupling, forming (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 technique [0002] Although great progress has been made in the research of cancer treatment methods and anticancer drugs, cancer is still one of the major diseases that seriously threaten human health. In the United States, cancer is the second leading cause of death after heart disease. Present representative methods for treating c...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61P35/00C07K7/02
CPCA61K47/65A61K47/64A61P35/00
Inventor 袁建栋宋云松黄仰青朱锐胡晓伟方程
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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