Small molecule degradation agent targeting at androgen receptors as well as preparation method and application thereof

A technology of androgen receptor and small molecules, applied in the field of biomedicine

Pending Publication Date: 2020-03-24
CHINA PHARM UNIV
View PDF3 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Fortunately, there is research evidence that when serum testosterone reaches castration levels, the androgen concentration in prostate cancer tissue is still maintained at a low level, which is sufficient to activate AR-mediated signal transduction pathways and the expression of related genes , so the development and deterioration of tumors at this stage still depend on the AR signal transduction pathway for growth

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Small molecule degradation agent targeting at androgen receptors as well as preparation method and application thereof
  • Small molecule degradation agent targeting at androgen receptors as well as preparation method and application thereof
  • Small molecule degradation agent targeting at androgen receptors as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: the synthesis of intermediate Ⅰ-5

[0033]

[0034] The first step: preparation of intermediate Ⅰ-2

[0035] Add 2-fluoro-4-nitrotoluene I-1 (70g, 0.45mol) and tetrabutylammonium chloride (8.01g, 0.025mol) into a mixed solvent of 420mL water and 280mL tert-butanol, heat to reflux, After reflux, it was divided into five batches, slowly adding potassium permanganate (a total of 367.75g, 2.56mol) at intervals of 1.5h each time, reflux reaction for 30h, TLC detection (V 石油醚 :V 乙酸乙酯 =2:1) ​​The reaction is complete, stand still until the temperature of the reaction solution is cooled to room temperature, filter with suction, add 6N HCl to the filtrate to adjust the pH to 1-2, extract with ethyl acetate, spin the ethyl acetate layer to obtain 71g of white solid, and collect rate of 85%. HRMS (ESI), calculated for C 7 h 4 FNO 4 186.0203[M+H] + , found 186.0236.

[0036] The second step: the preparation of intermediate Ⅰ-3

[0037] 1-Ethyl-3 (3-dimeth...

Embodiment 2

[0044] Embodiment 2: the synthesis of intermediate P-1

[0045]

[0046] The first step: the preparation of intermediate II-2

[0047] Add II-1 3-fluorophthalic anhydride (5g, 0.018mol), 3-amino-2,6-piperidinedione (2.31g, 0.018mol) and sodium acetate (1.78g, 0.022mol) into 60mL of acetic acid, Stir at room temperature to dissolve, heat up to 80°C, react at 80°C for 15h, TLC detection (V 二氯甲烷 :V 甲醇 =15:1) react completely, stop reaction, spin dry, polyamide column chromatography (V 二氯甲烷 :V 甲醇 =50:1) 6.7 g of golden yellow solid was obtained, with a yield of 81%. HRMS (ESI), calculated for C 13 h 9 FN 2 o 4 277.0625[M+H] + , found 277.0685.

[0048] The second step: the preparation of intermediate II-3

[0049] Add II-2 (3g, 0.011mol) into 30ml N,N-dimethylformamide, stir and dissolve at room temperature, and add N-tert-butoxycarbonylethylenediamine (2.61g, 0.016mol) and N , N-diisopropylethylamine (7.02g, 0.054mol), warming up to 90°C, reacting for 3h, TLC dete...

Embodiment 3

[0052] Embodiment 3: the synthesis of intermediate P-2

[0053]

[0054] The first step: synthesis of intermediate II-5

[0055] Add II-4 6-bromohexanoic acid (5 g, 0.026 mol) into 5 mL of thionyl chloride, stir at room temperature for 12 h, and spin dry to obtain an orange-yellow oil. HRMS (ESI), calculated for C 6 h 10 BrClO 212.9682[M+H] + , found 212.9661.

[0056] The second step: the synthesis of intermediate II-6

[0057] Add the oil obtained in the previous step into 30 mL of anhydrous N,N-dimethylformamide, stir and dissolve at room temperature, and add pomalidomide (3.50 g, 0.013 mol) after it is completely dissolved, N 2 Replace three times. Heat up to 105°C, react at 105°C for 3.5h, TLC detection (V 二氯甲烷 :V 甲醇 =20:1) The reaction is complete, stop the reaction, add 100mL of water to the reaction solution, extract with ethyl acetate, wash the ethyl acetate layer with saturated brine three times, dry over anhydrous sodium sulfate, spin dry to obtain 3.91g,...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention discloses small molecule degradation agents targeting at androgen receptors, belongs to the field of biological medicines, and particularly relates to a series of compounds for degradingandrogen receptor proteins in a targeted ubiquitination manner, a synthesis method and medical applications of the compounds, in particular in prevention or treatment of androgen receptor related diseases. Meanwhile, a series of in-vitro anti-tumor activity evaluation tests are carried out on the synthesized compounds by invertors of the invention, and the compounds have certain inhibitory activity on cancer cells.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically includes a series of derivatives targeting androgen receptor degradation agents, their preparation methods and applications. [0002] technical background [0003] Prostate cancer (PC) is the second leading cause of cancer-related male death worldwide, and the American Cancer Society predicts that prostate cancer will account for 20% of all new cancer diagnoses in 2019 (R.L.Siegel.et al.Cancer statistics,2019,69: 7-34). Studies have shown that the development and progression of prostate cancer are closely related to the regulation of androgen and androgen receptor signaling. Androgen receptor (AR) belongs to the steroid receptor in the nuclear receptor superfamily and is a ligand-dependent trans-transcriptional regulatory protein. The human AR gene has a full length of about 90kb, a molecular mass of about 110 kD, and encodes a total of 919 amino acids. AR contains four structures: N...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07D401/14A61K38/05A61K31/454A61P35/00A61P13/08
CPCC07K5/06034C07D401/14A61P35/00A61P13/08A61K38/00
Inventor 卞金磊李志裕栾红玉任洁程新颖
Owner CHINA PHARM UNIV
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap