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Thiohydantoin ternary fused cyclic androgen receptor antagonist and application thereof

A halogen and haloalkyl technology, applied in the field of medicinal chemistry, can solve the problems of ineffective treatment of CRPC, etc., and achieve the effect of novel structure, simple reaction route, and easy-to-obtain reagents

Active Publication Date: 2017-06-09
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, traditional AR antagonists cannot effectively treat CRPC. In view of this situation, new AR antagonists have emerged as the times require.

Method used

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  • Thiohydantoin ternary fused cyclic androgen receptor antagonist and application thereof
  • Thiohydantoin ternary fused cyclic androgen receptor antagonist and application thereof
  • Thiohydantoin ternary fused cyclic androgen receptor antagonist and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Synthesis of compounds of general formula I (CPU102-CPU113).

[0069]

[0070] Preparation of 4-cyano-3-fluorobenzyl bromide (2)

[0071] 3-Fluoro-4-cyanotoluene 1 (10g, 74.07mmol) was dissolved in 200mL of chloroform, 1g of BPO was added, stirred to dissolve, NBS (19.77g, 11.11mmol) was added in batches, refluxed for 12h, and the temperature was lowered. The sodium hydrogen aqueous solution was washed three times, an appropriate amount of water was washed three times, and an appropriate amount of saturated saline was washed three times, and the solvent was evaporated under reduced pressure. Column chromatography gave 14.00 g of a light yellow liquid with a yield of 88.79%. HRMS(ESI):m / z, calcd for C 8 h 5 BrFN 213.9678(M+H) + , found 213.9667.

[0072] Preparation of Diethyl 2-(3-fluoro-4-cyanobenzyl)-2-acetamidomalonate (3)

[0073] Add 100 mL of ethanol to a 250 mL three-necked flask, add sodium metal (0.76 g, 33.16 mmol) in batches, and stir at room temperat...

Embodiment 2

[0089] Preparation of Compound CPU103

[0090] Dissolve CPU102 (0.20g, 0.43mmol) in 5mL of tetrahydrofuran and 5mL of 1N aqueous sodium hydroxide solution, stir at room temperature for 50min, TLC detects that the reaction is complete, distill off the organic solvent under reduced pressure, adjust to pH = 6 with 1N HCl, precipitate a solid, and statically Set crystallization, suction filtration, column chromatography to obtain 0.15g yellow solid, yield 76.53%. m.p.160-162℃; 1 H-NMR (300MHz, DMSO-d 6 ):δ13.26(s,1H,-COOH),8.13(t,J=8.1Hz,1H,Ar-H),7.91(m,1H,Ar-H),7.71(d,J=8.1Hz, 1H,Ar-H),7.56(d,J=7.8Hz,1H,Ar-H),7.35(d,J=8.1Hz,1H,Ar-H),5.46(d,J=17.4Hz,1H, -CH-),4.75-4.84(m,2H,-CH 2 -),3.50-3.64(m,2H,-CH 2 -) ppm; 13 C-NMR (75MHz, DMSO-d 6 ):δ172.7,171.1,165.1,158.9,142.9,139.9,134.7,132.7,130.9,129.6,119.6,118.1,115.8,115.7,115.7,114.4,105.0,72.5,53.8,28.1ppm) HRMS( z, calcd for C 20 h 11 f 4 N 3 o 3 S 450.0456(M+H) + ,found 450.0530;IR(KBr):3413,2235,1718,1627,1443,13...

Embodiment 3

[0092] Preparation of compound CPU104

[0093] Dissolve CPU103 (0.10g, 0.22mmol) in 10mL of dichloromethane, ice bath, add DMTMM (0.09g, 0.33mmol), stir for 30min, add triethylamine (0.09g, 0.88mmol), 30% methylamino alcohol solution (0.03g, 0.33mmol), stirred at room temperature for 3h, TLC detected that the reaction was complete, evaporated the solvent to dryness under reduced pressure, added 1N HCl 20mL, extracted 3 times with 30mL ethyl acetate, combined the organic layer, divided 3 times with 30mL saturated sodium bicarbonate After washing, 30 mL of saturated brine was washed three times, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was chromatographed to obtain 0.08 g of a yellow solid with a yield of 80.00%. m.p.329-333°C; 1 H-NMR (300MHz, DMSO-d 6 ): δ8.38(d, J=8.4Hz, 1H, Ar-H), 8.32(s, 1H, -NH-), 8.22(s, 1H, Ar-H), 8.02(d, J=8.4Hz ,1H,Ar-H),7.65(d,J=8.4Hz,1H,Ar-H),7.33(d,J=7.5Hz,1H,Ar-H),5.39(d,J=7.5Hz,1H ,-CH-...

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Abstract

The invention relates to the field of medicinal chemistry, in particular to prostatic cancer resisting compounds (I) and (II) with thiohydantoin diindyl as skeletons and a preparation method of the compounds. The compounds are capable of molecularly antagonizing androgen receptors and excellent in prostatic cancer resisting effect in cellular level and animal level and can be used for preparation of antitumor medicines.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a class of compounds with thiohydantoindoline as the skeleton and anti-prostate cancer effect, including the preparation method of these compounds, and these compounds can antagonize the androgen receptor at the molecular level , exhibits good anti-prostate cancer effect at the cell level and animal level, and can be used to prepare anti-tumor drugs. Background technique [0002] Prostate cancer is a common tumor that threatens the health of middle-aged and elderly men in Europe and the United States. In recent years, with the improvement of living standards in my country and changes in lifestyles, the incidence of prostate cancer in my country is on the rise. Huggins and Hodges first reported that prostate cancer is androgen-dependent in 1941. As more and more evidence shows that all stages of prostate cancer are regulated by the androgen signaling pathway, blocking th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4745A61P35/00
CPCC07D471/04
Inventor 李志裕卞金磊徐熙葛饶玲
Owner CHINA PHARM UNIV
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