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Auristatin analogues and their conjugates with cell-binding molecules

A technique of combining auristatin and molecules, which is applied in the field of derivatives of methyl auristatin F, which can solve the problems of reduced activity and unfavorable transport across cell membranes

Pending Publication Date: 2018-04-17
HANGZHOU DAC BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The charge on the C-terminus of MMAF hinders its transport across cell membranes, thereby reducing its activity

Method used

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  • Auristatin analogues and their conjugates with cell-binding molecules
  • Auristatin analogues and their conjugates with cell-binding molecules
  • Auristatin analogues and their conjugates with cell-binding molecules

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0187] The preparation of embodiment 1 compound 2

[0188]

[0189] Dissolve Boc-L-proline (10.0 g, 46.4 mmol) in 50 mL of tetrahydrofuran and cool to 0° C., add BH 3 solution in tetrahydrofuran (1.0 M, 46.4 mL). The reaction was stirred at 0°C for 1.5 hours, poured into ice water and extracted with ethyl acetate. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to obtain compound 2 (8.5 g, yield 91%) as a white solid. 1 H NMR (500MHz, CDCl 3 )δ3.94(dd,J=4.9,2.7Hz,2H),3.60(ddd,J=18.7,11.9,9.3Hz,2H),3.49–3.37(m,1H),3.34–3.23(m,1H) ,2.06–1.91(m,1H),1.89–1.69(m,2H),1.65–1.51(m,1H),1.49–1.40(m,9H).

Embodiment 2

[0190] The preparation of embodiment 2 compound 3

[0191]

[0192] To a solution of compound 2 (13.0 g, 64.6 mmol) in dimethylsulfoxide (90 mL) was added triethylamine (40 mL) and stirring was continued for 15 minutes. The mixture was cooled in an ice bath, and sulfur trioxide-pyridine complex (35.98 g, 226 mmol) was added portionwise over 40 minutes. The reaction was warmed to room temperature and stirred for 2.5 hours. After adding ice (250 g), the mixture was extracted with dichloromethane (150 mL×3). The organic phase was washed with 50% citric acid solution (150 mL), water (150 mL), saturated sodium bicarbonate solution (150 mL) and brine (150 mL), and dried over anhydrous sodium sulfate. Filtration and distillation under reduced pressure afforded aldehyde 3 (10.4 g, 81% yield) as a thick oil, which was used without further purification. 1 H NMR (500MHz, CDCl 3 )δ9.45(s,1H),4.04(s,1H),3.53(dd,J=14.4,8.0Hz,2H),2.00–1.82(m,4H),1.44(d,J=22.6Hz,9H ).

Embodiment 3

[0193] The preparation of embodiment 3 compound 5

[0194]

[0195] N 2 Under protection, a solution of n-butyllithium in n-hexane (21.6mL, 2.2M, 47.43mmol) was added dropwise to 4-methyl-5-phenyloxazolidin-2-one (8.0g, 45.17 mmol) in tetrahydrofuran (100 mL). The solution was stirred at -78°C for 1 hour, then propionyl chloride (4.4 mL, 50.59 mmol) was added slowly. The reaction mixture was naturally warmed to -50°C, stirred for 2 hours, and then quenched by adding saturated ammonium chloride solution (100 mL). The organic solvent was distilled off under reduced pressure, and the residual solution was extracted with ethyl acetate (3×100 mL). The organic layer was washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (20% ethyl acetate / n-hexane) to give compound 5 as a thick oil (10.5 g, 98% yield). 1 H NMR (500MHz,...

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Abstract

This invention relates to analogues of auristatins, in particular monomethyl auristatin F (MMAF), as cytotoxic agents, conjugates of such cytotoxic agents with a cell-binding agent, the preparation and the therapeutic uses of these cytotoxic agents and conjugates thereof to arrest or retard abnormal cell growth and / or proliferation.

Description

technical field [0001] The present invention describes a class of auristatin cytotoxic small molecules, in particular derivatives of methylauristatin F (MMAF), their conjugation to cell-binding molecules and their use to block cell growth and proliferation Methods. technical background [0002] Chemotherapy is one of the main means of traditional cancer treatment. Treatment of tumors with chemotherapy drugs is based on the drug's ability to distinguish cancer cells from normal cells and preferentially kill cancer cells. Lack of selectivity and systemic toxicity to humans are the main drawbacks of chemotherapeutic agents. [0003] In order to improve the anti-cancer efficacy of drugs, the activity of drugs can be improved to achieve therapeutic effects without adverse reactions at lower doses, or the selectivity of drugs to tumors can be improved, and higher doses can be used to ensure more effective treatment. good therapeutic effect. [0004] Predecessors have done a lo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/68A61K39/395C07K5/02A61P35/00
CPCC07D403/12C07D405/14A61K47/6855A61K47/6869A61P35/00A61K47/68031
Inventor 杨庆良赵永新叶杭波盖顺贾军祥黄圆圆郭辉辉谢洪生李雯君周晓迈杨成玉卓晓韬赵林尧曹敏君林晨彭杰叶智鸧其他发明人请求不公开姓名
Owner HANGZHOU DAC BIOTECH
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