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AKR1C3 selective inhibitor as well as preparation method and application thereof

A selective and inhibitory technology, applied in the preparation of sulfonic acid amides, organic chemistry, anti-tumor drugs, etc., to achieve good application prospects, rich structural types, good inhibitory activity and selectivity.

Active Publication Date: 2021-06-18
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are few reports on AKR1C3 biological function research and inhibitor research, and the development of inhibitors specifically targeting AKR1C3 can provide a new therapeutic strategy for tumor treatment

Method used

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  • AKR1C3 selective inhibitor as well as preparation method and application thereof
  • AKR1C3 selective inhibitor as well as preparation method and application thereof
  • AKR1C3 selective inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] (1) Synthesis of methyl 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (intermediate 2a)

[0040] Methyl 2-hydroxybenzoate 1a (130 μL, 1.21 mmol) was dissolved in acetonitrile (6.57ml), and 4-(chloromethyl)-3,5-dimethylisoxazole (163 μL , 1.21mmol), potassium carbonate solid (268mg, 1.97mmol), potassium iodide solid (114mg, 0.66mmol), heated and stirred overnight at 80°C. After the reaction was complete, 20 mL of water was added, extracted three times with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography (eluent: PE / EA=15 / 1, v / v) was performed. The intermediate methyl 2-((3,5-dimethylisoxazol-4-yl)methoxy)benzoate (white solid, 100 mg, yield 30%) was obtained. 1 H NMR (300MHz, DMSO-d 6 )δ7.67(dd, J=7.7,1.8Hz,1H),7.59(ddd,J=9.1,7.4,1.8Hz,1H),7.31(d,J=8.1Hz,1H),7.08(td,J =7.6,0.8Hz,1H),5.02(s,2H),3.77(s,3H),2.43(s,3H),2.27(s,3H).

[0041]...

Embodiment 2

[0047] Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-sulfamoylbenzyl)benzamide

[0048] To a DMF solution (12 mL) of intermediate 3a (200 mg, 0.8 mmol) was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylureahexa Fluorophosphate (460mg, 1.2mmol) and N,N-diisopropylethylamine (400μL, 2.4mmol) were activated for half an hour and then added 4-(aminomethyl)benzenesulfonamide hydrochloride (270mg, 1.2mmol) . After the reaction was complete, 60 mL of water was added to the reaction liquid, and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After the solvent was distilled off under pressure, the solid obtained was recrystallized to obtain 2-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(4-sulfamoylbenzyl)benzamide (Compound 2, off-white solid, 170 mg, yield 53%), detected by TLC as one spot, with dark spots under 254nm UV lamp, no fluorescence under 365nm. 1 H NMR (300MHz, DMSO-d6) δ8.67(...

Embodiment 3

[0050] Synthesis of 2-((3,5-dimethylisoxazol-4-yl)methoxy)-4-methyl-N-(4-sulfamoylphenethyl)benzamide

[0051] Referring to the synthetic method of Example 1, the 2-hydroxybenzoate methyl ester in Example 1 is replaced by 2-hydroxyl-4-methylbenzoate methyl ester to obtain 2-((3,5-dimethylisoxan Azol-4-yl)methoxy)-4-methyl-N-(4-sulfamoylphenethyl)benzamide (compound 3), TLC detected as one point, dark spot under UV lamp 254nm, 365nm No fluorescence. 1 H NMR (300MHz, DMSO-d6) δ8.03(t, J=5.5Hz, 1H), 7.77–7.70(m, 2H), 7.55(d, J=7.8Hz, 1H), 7.38–7.28(m, 4H), 7.11–7.05(m, 1H), 6.87(d, J=7.8Hz, 1H), 5.03(s, 2H), 3.48(q, J=6.8Hz, 2H), 2.79(t, J=7.1 Hz,2H),2.41(s,3H),2.34(s,3H),2.19(s,3H).HPLC(80%methanol in water with 0.1%HCOOH):t R =14.091min, 96.153%.

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Abstract

The invention discloses an AKR1C3 selective inhibitor as well as a preparation method and application thereof, and discloses an AKR1C3 selective inhibitor with a benzamide structure as shown in a formula (I) and a preparation method of the AKR1C3 selective inhibitor. A target activity test proves that the compound disclosed by the invention has the activity of obviously inhibiting AKR1C3, and can be further developed into a medicine for treating and / or preventing diseases by inhibiting the aldoketoreductase AKR1C3, and has an opportunity to lay a molecular foundation for research on tumor drug resistance related mechanisms.

Description

technical field [0001] The present invention relates to an AKR1C3 inhibitor and its preparation method and use, in particular to an AKR1C3 selective inhibitor and its preparation method and use. Background technique [0002] Aldoketone reductase 1C (AKR1C) is a subfamily of the aldoketone reductase (AKR) superfamily. The human AKR1C subfamily consists of four isoforms (AKR1C1-AKR1C4) as phase I metabolic enzymes that rely on nicotinamide adenine dinucleotide phosphate (NADPH) to play a key role in steroid reduction. These enzymes have a wide range of substrates, including endogenous steroids, prostaglandins, and exogenous compounds. [0003] AKR1C3 shares high sequence identity (>86%) with AKR1C1, AKR1C2, and AKR1C4, but they display different distribution preferences and biological functions. AKR1C1 and AKR1C2 are widely expressed in different tissue types. Among them, AKR1C1 can promote the inactivation of progesterone and mainly functions as a 20-ketosteroid reducta...

Claims

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Application Information

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IPC IPC(8): C07D261/08C07C311/46C07C303/40A61P35/00A61K31/42A61K31/18
CPCC07D261/08C07C311/46A61P35/00
Inventor 孙昊鹏刘阳何思雨褚相霖郭青龙赵丽冯锋柳文媛
Owner CHINA PHARM UNIV
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