Dihydropteridine ketone type BRD4 (Bromodomain-Containing Protein 4) protein inhibitor as well as preparation method and application thereof

A technology of dihydropteridone and dihydropteridine, which is applied in the fields of organic chemistry, drug combination, antitumor drugs, etc., can solve the problem that there are not many BRD4 small molecule inhibitors.

Active Publication Date: 2019-03-22
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are not many BRD4 small-molecule inhibitors that have entered the clinical stage, and it is urgent t

Method used

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  • Dihydropteridine ketone type BRD4 (Bromodomain-Containing Protein 4) protein inhibitor as well as preparation method and application thereof
  • Dihydropteridine ketone type BRD4 (Bromodomain-Containing Protein 4) protein inhibitor as well as preparation method and application thereof
  • Dihydropteridine ketone type BRD4 (Bromodomain-Containing Protein 4) protein inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Preparation of 2-aminobutyric acid methyl ester hydrochloride:

[0100] Add 2-aminobutyric acid (1.00g, 1.0eq.) into a 50mL eggplant-shaped flask, add 15mL of anhydrous methanol, and slowly add SOCl at 0°C 2 (2.31g, 2.0eq.), after heating to reflux for 1.5 hours, TLC showed that the reaction was complete. Evaporation of the volatiles gave a white solid which was analyzed with Et 2 O ground the solid, obtained the crude product of compound 2 after suction filtration, and could directly carry out the next step reaction without purification, and the yield was 90%.

[0101] White solid, melting point: 120-122℃. 1 H NMR (400MHz,D 2 O)δ4.04(t,J=6.2Hz,1H),3.76(s,3H),1.99–1.82(m,2H),0.97–0.87(m,3H). 13 C NMR (101MHz,D 2 O) δ170.79, 53.99, 53.46, 23.21, 8.42. HR-MS (ESI): Calcd.C 5 h 12 ClNO 2 ,[M+H] + m / z:118.0863,found:118.0867.

Embodiment 2

[0103] The preparation of 2-(cyclopentylamino) methyl butyrate:

[0104] Compound 2 (1.00g, 1.0eq.) and cyclopentanone (548mg, 1.0eq.) were ice-bathed for 10 minutes, and NaOAc (547mg, 1.0eq.) and NaBH(OAc) were added 3 (2.07g, 1.5eq.). The reaction mixture was stirred overnight at room temperature. After TLC showed that the reaction was over, add saturated NaHCO to the reaction system 3 solution to quench the reaction, then CH 2 Cl 2 (20mL×2) extract the aqueous layer, combine the organic layers, wash over anhydrous Na 2 SO 4 Drying, filtration and concentration afforded compound 3 in 65% yield.

[0105] Colorless oily liquid. 1 H NMR (400MHz, DMSO-d 6 )δ3.63(s,3H),3.10(t,J=6.6Hz,1H),2.98–

[0106] 2.84(m,1H),1.80(s,1H),1.67–1.54(m,4H),1.54–1.48(m,2H),1.47–1.39(m,2H),1.32–1.21(m,2H), 0.84(t,J=7.4Hz,3H). 13 C NMR (101MHz, DMSO-d 6 )δ175.71, 60.88, 57.32, 51.19, 33.17, 32.10, 26.25, 23.38, 23.33, 10.21. HR-MS (ESI): Calcd.C 10 h 19 NO 2 ,[M+H] + m / z:186.1494,fou...

Embodiment 3

[0108] Preparation of 2-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)butanoic acid methyl ester:

[0109] Compound 3 (1.00g, 1.0eq.) was added to 15mL of acetone, and after 10 minutes of ice bathing, 2,4-dichloro-5-nitropyrimidine (1.05g, 1.0eq.) was added, and K 2 CO 3 (750mg, 1.0eq.), stirred overnight at room temperature. After the reaction was complete, the solvent was removed, the residue was dissolved with ethyl acetate, and washed with water, the organic layer was collected, dried over anhydrous sodium sulfate, and purified by silica gel flash column chromatography (PE / EA=10:1) to obtain compound 4, yielding The rate is 89%.

[0110] Yellow solid, melting point: 110-111℃. 1 H NMR (400MHz, DMSO-d 6 )δ8.84(s,1H),4.29–4.14(m,1H),3.64(s,3H),3.52–3.48(m,1H),2.28–2.15(m,1H),2.04–1.90(m, 2H),1.85–1.77(m,2H),1.72–1.61(m,3H),1.51–1.35(m,2H),0.94(t,J=7.8Hz,3H). 13 C NMR (101MHz, DMSO-d 6 )δ164.21, 151.73, 151.14, 137.83, 119.27, 61.06, 59.38, 28.30, 28.28, 26.36, 23...

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Abstract

The invention relates to the field of medicine chemicals, in particular relates to a dihydropteridine ketone type BRD4 (Bromodomain-Containing Protein 4) protein inhibitor as well as a preparation method and application thereof, and particularly application as BRD4 protein inhibitors and antitumor medicines. The compound has a structural formula as shown in the specification.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a dihydropteridone-type BRD4 protein inhibitor, their preparation method, a pharmaceutical combination containing these compounds and their use, especially as a BRD4 protein inhibitor and an antitumor drug aspects of use. Background technique [0002] Malignant tumor is the number one major disease threatening the health of our people. In 2017, "China Cancer Research" published by Academician He Jie of the National Cancer Center and others released the cancer data in China in 2013. The report pointed out that cancer is the number one cause of death among urban and rural residents in my country; the number of new cancer cases continues to rise, reaching 3.68 million in 2013, accounting for 1 / 4 of the world's new cases; about 10,000 people are diagnosed with cancer every day in the country. Therefore, research on anticancer drugs and their related target inhibitors has ...

Claims

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Application Information

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IPC IPC(8): C07D475/00A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D475/00
Inventor 刘宏民郑一超孙凯李雯符运栋宋启梦
Owner ZHENGZHOU UNIV
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