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A formulation of a conjugate of a tubulysin analog to a cell-binding molecule

A technology for combining molecules and derivatives, which can be used in medical preparations without active ingredients, medical preparations containing active ingredients, and drug combinations, etc., and can solve problems such as shortening the shelf life of drugs, poor stability, and reducing market value.

Pending Publication Date: 2022-02-11
HANGZHOU DAC BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ADCs and many other complex protein macromolecules are often poorly stable in aqueous environments, which can reduce the drug's shelf life and greatly reduce its market value

Method used

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  • A formulation of a conjugate of a tubulysin analog to a cell-binding molecule
  • A formulation of a conjugate of a tubulysin analog to a cell-binding molecule
  • A formulation of a conjugate of a tubulysin analog to a cell-binding molecule

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0414] Example 1. Synthesis of di-tert-butyl-1,2-bis(2-(tert-butoxy)-2-oxyethyl)hydrazine-1,2-dicarboxylate.

[0415]

[0416]To a solution of di-tert-butyl di-tert-butylhydrazine-1,2-dicarboxylate (8.01 g, 34.4 mmol) in DMF (150 mL) was added NaH (60%, 2.76 g, 68.8 mmol). After stirring at room temperature for 30 minutes, tert-butyl 2-bromoacetate (14.01 g, 72.1 mmol) was added. The mixture was stirred overnight, quenched by the addition of methanol (3 mL), concentrated, diluted with ethyl acetate (100 mL) and water (100 mL), separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with MgSO 4 dried, filtered, concentrated, and passed through SiO 2 Purification by column chromatography (ethyl acetate / hexane 1:5 to 1:3) afforded the title compound (12.98 g, 82% yield) as a colorless oil. MS ESI m / z C 22 h 41 N 2 o 8 [M+H] + : The calculated value is 461.28, and the measured value is 461.40.

Embodiment 22

[0417] Example 2. Synthesis of 2,2'-(hydrazine-1,2-diyl)diacetic acid.

[0418]

[0419] 1, 4 - HCL (12M, 10 mL) was added to dioxane (40 mL). The mixture was stirred for 30 minutes, diluted with dioxane (20 mL) and toluene (40 mL), concentrated and mixed with dioxane (20 mL) and toluene (40 mL) Evaporation to dryness gave the crude product which was used in the next step without further purification (2.15 g, 103% yield, 93% purity). MS ESI m / z C 4 h 9 N 2 o 4 [M+H] + : The calculated value is 149.05, and the measured value is 149.40.

Embodiment 32

[0420] Example 3. Synthesis of 2,2'-(1,2-bis((E)-3-bromoacryloyl)hydrazine-1,2-diyl)diacetic acid.

[0421]

[0422] (E)- 3-Bromoacryloyl bromide (5.01 g, 23.60 mmol). The mixture was stirred for 6 hours, concentrated and purified on a silica gel column eluting with 3% formic acid in water / acetonitrile (1:9) to afford the title compound (2.35 g, 77% yield, -93% purity). MS ESI m / z C 10 h 11 Br 2 N 2 o 6 [M+H] + : The calculated value is 412.89, and the measured value is 413.50.

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Abstract

A formulation of conjugates of a tubulysin analog with a cell-binding molecule has a structure represented by Formula (I), wherein T, L, m, n, ..., R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are as defined herein, can be used for targeted treatment of cancer, autoimmune disease, and infectious disease.

Description

technical field [0001] The application of the present invention relates to a conjugate preparation formed by coupling Tubulysin derivatives for targeted therapy with cell surface receptor binding molecules. The application of the present invention also relates to the application of the composition comprising the cell-binding molecule-Tubulysin derivative conjugate in the treatment of cancer, autoimmune system diseases and infectious diseases. [0002] technical background [0003] Targeted delivery of highly active cytotoxic drugs to specific disease sites in humans via antibodies or other cell surface receptor binding agents can significantly increase the therapeutic window of cytotoxic drugs and has proven to be a promising approach. Targeted therapy (Van den Mooter, T. et al Expert Opin Biol Ther. 2015, 15, 749-60). Especially since the US FDA approved Adcetris (brentuximab vedotin) and Kadcyla (ado-trastuzumab emtansine) in 2011 and 2013, respectively, almost all large p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61K31/426A61K9/08C07D277/56A61P35/00
CPCA61P35/00A61K45/06A61K47/6855A61K47/6811A61K9/19A61K9/0019Y02A50/30A61K9/08A61K47/10A61K47/183A61K47/6889A61P37/00A61P31/00A61K47/548A61K47/65A61K47/545A61K47/55A61K47/64A61K38/08A61K51/088
Inventor R·赵杨庆良黄圆圆盖顺叶杭波赵林尧郭辉辉白露李雯君贾军祥郭芝香郑军陈晓晓孔橡飞杜勇张秀真郑秀红陈斌斌杨焱磊代猛徐怡芳范忠良周晓迈姜杏艳陈苗苗张龄莉李艳华其他发明人请求不公开姓名
Owner HANGZHOU DAC BIOTECH
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