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Androgen receptor antagonist, its preparation method and application

A reaction and compound technology, applied in the field of medicine, can solve problems such as low biological activity and increased metabolic burden of patients

Active Publication Date: 2021-09-14
KUNMING JIDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Marcella Bassetto, Salvatore Ferla, etc. in "Design and synthesis of novel bicalutamide and enzalutamide derivatives as antiproliferative agents for the treatment of prostate cancer (European Journal of Medicinal Chemistry118 (2016) 230-243)" showed that bicalutamide in 22Rv1, DU The geometric mean IC50 of anticancer activity of -145, LNCaP and VCaP cell lines is 52.42 μM, and the geometric mean of enzalutamide activity is 28.10 μM. Their biological activity is generally not high, and a larger dose is required to achieve therapeutic purposes use, thereby increasing the patient's metabolic burden

Method used

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  • Androgen receptor antagonist, its preparation method and application
  • Androgen receptor antagonist, its preparation method and application
  • Androgen receptor antagonist, its preparation method and application

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preparation example Construction

[0043] The compounds of the present invention can be produced by the following methods in addition to the production methods described above.

[0044]

[0045] where R 1 , R 2 , R 3 and R 4 The definition is the same as above, R 5 For tert-butyl or methyl.

Embodiment 1

[0047] Embodiment 1 (preparation of compound JD1001-2053)

[0048]

[0049] Add 5.0g (15.4mmol, 1.0eq) Fmoc-1-aminocyclopropanecarboxylic acid to a 200mL three-necked flask under nitrogen protection, then add 50mL of DCM, 4 drops of DMF, and add 9.8g of oxalyl chloride (76.9 mmol, 5.0eq), stirred and reacted at room temperature for 4 hours, took out two drops of the reaction solution and added methanol to treat it as methyl ester, detected the completion of the reaction by TLC (developing solvent: PE:EA=1:1), and distilled off the oxalyl chloride under reduced pressure and DCM to obtain a pale yellow solid, which was stored under nitrogen gas for subsequent use.

[0050] Take the light yellow solid obtained in the previous step reaction, add 90mL dry THF, 1.9g (22.6mmol, 1.5eq) NaHCO 3 , 3.4g (18.3mmol, 1.2eq) 5-amino-3-trifluoromethyl-2-cyanopyridine, heated to 60°C, maintained the temperature and stirred for 2 hours, and the reaction was completed by TLC detection (devel...

Embodiment 2

[0053] Embodiment 2 (preparation of compound JD1001-2054)

[0054]

[0055] Add JD1001-002-9 solid 0.10g (0.37mmol, 1.0eq), THF 3.2mL, DMAP 0.14g (1.11mmol, 3.0eq), 3,5-difluorobenzenesulfonate into a 25mL round bottom flask under nitrogen protection Acyl chloride 0.24g (1.11mmol, 3.0eq), stirred and reacted at room temperature for 3 hours, the completion of the reaction was detected by TLC (developing solvent: PE:EA=1:1), adding saturated NaHCO 3 Quench the reaction with aqueous solution, extract with ethyl acetate to obtain the organic phase, wash the organic phase twice with 0.5N hydrochloric acid aqueous solution, dry over anhydrous sodium sulfate, filter, concentrate the organic phase to obtain a solid, and prepare the liquid phase (CH 3 CN:H 2 O=60:40) separation and purification, and about 24 mg of the product JD1001-2054 was obtained by freeze-drying, with a yield of 16%.

[0056] 1 H NMR: (DMSO,ppm,400MHz)δ1.07(2H,m),1.40(2H,m),7.51(2H,m),7.57(1H,m),8.60(1H,d),8...

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Abstract

The present invention relates to a kind of androgen receptor antagonist, its preparation method and application thereof, and the androgen receptor antagonist is a compound represented by general formula (1) and a pharmaceutically acceptable salt thereof (R in the general formula 1 , R 2 , R 3 and R 4 The definition is as shown in the manual).

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel androgen receptor antagonist, its preparation method and its application. Background technique [0002] The incidence of prostate cancer ranks second among all malignant tumors in men. Androgen receptor (Androgen receptor, AR) is an important target for the treatment of prostate cancer, and the use of androgen receptor antagonists to block the combination of androgen and AR can achieve therapeutic purposes. Commonly used clinical non-steroidal androgen receptor antagonists include bicalutamide (R-bicalutamide) and enzalutamide (Enzalutamide), the structures of which are shown below. [0003] [0004] These compounds are all used for the treatment of prostate cancer. Bicalutamide (US4636505) was developed by AstraZeneca and launched in 1995 under the trade name of Casodex. Enzalutamide (MDV3100, US2007254933), trade name Xtandi, was jointly developed by Medivation an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/84A61K31/44A61P35/00A61P13/08A61P17/10A61P17/14A61P17/00
CPCA61P13/08A61P17/00A61P17/10A61P17/14A61P35/00C07D213/84
Inventor 肖绪枝张朴永卢法冠王志朋陈梦然郭昆周蕊张云
Owner KUNMING JIDA PHARMA
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