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Bifunctional molecule as well as preparation method and application thereof

A technology of heteroatoms and compounds, applied in the field of drug compounding, can solve the problem of single structure of androgen receptor inhibitors, and achieve the effect of inhibiting proliferation

Active Publication Date: 2022-04-01
AUBRAK THERAPEUTICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is that the existing androgen receptor inhibitors have a single structure. Therefore, the present invention provides a class of bifunctional molecules completely different from the prior art, its preparation method and its application

Method used

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  • Bifunctional molecule as well as preparation method and application thereof
  • Bifunctional molecule as well as preparation method and application thereof
  • Bifunctional molecule as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] Embodiment 1: the synthesis of intermediate 1

[0154]

[0155] Dissolve tert-butyl ((1r,3r)-3-hydroxy-2,2,4,4-tetramethylcyclobutane)carbamate (3.1g, 12.86mmol, 1eq) in anhydrous THF at 0°C Sodium hydrogen (617mg, 15.43mmol, 60%, 1.2eq) was added under conditions, and after stirring under nitrogen for 30min, 2-chloro-5-fluorobenzonitrile (2g, 12.86mmol, 1eq) was added and stirred at room temperature for 4h. After the reaction was detected by TLC, water was added to quench the reaction, THF was removed under reduced pressure, diluted with ethyl acetate (100 mL), washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated, the residue 3.5 g of the product was obtained by column chromatography (PE / EA 10:1). Dissolve the above product in 50 mL of dioxane, drop into HCl in dioxane solution (4M, 10 mL), stir overnight at room temperature, filter with suction, wash the filter cake with dioxane and ether, and dry to ...

Embodiment 2

[0156] Embodiment 2: the synthesis of intermediate 2

[0157]

[0158] The above product (compound 1-4) (50mg, 0.13mmol, 1eq) was dissolved in DMSO, and 4-fluoronitrobenzene (21mg, 0.15mmol, 1.2eq) and DIEA (31μL, 0.19mmol, 1.5eq) were added , Stir overnight at 120 degrees. After the reaction was detected by TLC, it was diluted with ethyl acetate (20 mL), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography to obtain 28 mg of the product. Dissolve the above product in THF, add palladium carbon, stir overnight at room temperature under hydrogen, filter with suction, and concentrate the filtrate to obtain 25 mg of the product, ESI MS m / z 490[M+H] + .

Embodiment 3

[0159] Embodiment 3: the synthesis of intermediate 3

[0160]

[0161] The above product (compound 1-4) (50mg, 0.13mmol, 1eq) was dissolved in DMSO, and 3,4-difluoronitrobenzene (24mg, 0.15mmol, 1.2eq) and DIEA (31μL, 0.19mmol, 1.5eq), stirred overnight at 120 degrees. After the reaction was detected by TLC, it was diluted with ethyl acetate (20 mL), washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography to obtain 36 mg of the product. Dissolve the above product in THF, add palladium carbon, stir overnight at room temperature under hydrogen, filter with suction, and concentrate the filtrate to obtain 35 mg of the product, ESI MS m / z 508 [M+H] + .

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Abstract

The invention discloses a bifunctional molecule as well as a preparation method and application thereof. The bifunctional molecule provided by the invention can inhibit proliferation of LNCap cells, and part of the compounds also have an effect of inhibiting proliferation of PC-3 cells, so that the bifunctional molecule provided by the invention has the potential of treating cancers, especially prostatic cancers. In addition, the preparation method of the bifunctional molecule is mild in condition, simple to operate, free of high-temperature and low-temperature extreme reaction conditions, free of high-risk and highly toxic substances, suitable for laboratory synthesis and industrial production and wide in industrial application prospect.

Description

technical field [0001] The invention relates to the field of drug compounding, in particular to a class of bifunctional molecules, a preparation method and application thereof. Background technique [0002] Prostate cancer is a common male malignancy, and its incidence worldwide is second only to lung cancer, ranking second among all male malignancies. The incidence of prostate cancer in China is increasing year by year, and it is estimated that by 2020, prostate cancer will become the third leading cause of cancer deaths among males in my country. Currently, androgen deprivation therapy (ADT) is the main treatment for early prostate cancer, including surgical castration and drug castration. However, ADT cannot cure prostate cancer. After a median treatment time of 14-30 months, almost all patients will gradually develop castration-resistant prostate cancer (CRPC). Patients are no longer sensitive to ADT, and the median survival time is less than 20 years. months. In pros...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61K31/454A61P35/00
Inventor 杨光李文龙
Owner AUBRAK THERAPEUTICS
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