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Novel CDK9 inhibitor based on benzofuran structure, preparation method and application of novel CDK9 inhibitor

A methyl and ethyl technology, applied in the field of biomedicine, can solve problems such as easily causing diarrhea

Active Publication Date: 2019-07-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Flavopiridol has a certain therapeutic effect on chronic lymphocytic leukemia, breast cancer, liver cancer, prostate cancer and other cancers, and is now approved by the FDA as an orphan drug for the treatment of chronic lymphocytic leukemia, but Flavopiridol is prone to side effects such as diarrhea

Method used

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  • Novel CDK9 inhibitor based on benzofuran structure, preparation method and application of novel CDK9 inhibitor
  • Novel CDK9 inhibitor based on benzofuran structure, preparation method and application of novel CDK9 inhibitor
  • Novel CDK9 inhibitor based on benzofuran structure, preparation method and application of novel CDK9 inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041]

[0042] The first step: the preparation of intermediate I-2

[0043]Add phloroglucinol I-1 (63g, 0.5mol) into 300mL of anhydrous ether, stir to dissolve at room temperature, and then add anhydrous ZnCl 2 (13.4g, 0.1mol) and anhydrous acetonitrile (50g, 1.25mol), feed dry HCl gas reaction 40h under 0 ℃, TLC detects (V 石油醚 :V 乙酸乙酯 =1:2) The reaction is complete, stand still until the temperature of the reaction solution rises to room temperature, filter with suction, dry the filter cake to constant weight, dissolve it in 200mL water, heat and reflux for 6h, a large amount of solid precipitates, cool to room temperature, filter with suction, and dry , 60 g of white solid was obtained, yield 71%. m.p.119-121°C.

[0044] The second step: the preparation of intermediate I-3

[0045] Intermediate I-2 (33.6g, 0.2mol) was added to 350mL anhydrous acetone, stirred and dissolved at room temperature, and then 63.48g K 2 CO 3 (0.46mol), dropwise added dimethyl sulfate (39....

Embodiment 2

[0063] Example 2: Compound L2

[0064]

[0065] m.p.150~153℃.HRMS(ESI),[M+H] + calculated for C 23 h 26 N 2 o 5 410.1842,found 410.1907. 1 H NMR (300MHz, DMSO-d 6 ):δ=12.62(s,1H,5-OH),7.32(m,3H,Ar-H),6.95(d,1H,J=6.0Hz,Ar-H),6.91(s,1H,CHCO) ,6.26(s,1H,Ar-H),4.45(m,1H,C H (CH 3 ) 2 ),3.60(s,4H,Ar-N(C H 2 ) 2 ),2.95(s,2H,NHC H 2 ),2.73(s,2H,NHC H 2 ),1.89(m,2H,NCH 2 C H 2 CH 2 NH), 1.28(d, 6H, J=6.00Hz, CH(C H 3 ) 2 ) ppm. 13 C NMR (75MHz, DMSO-d 6 ):δ=181.8,163.5,159.8,156.0,150.0,148.6,131.9,130.0,125.2,114.9,113.2,108.1,104.5,102.8,99.5,73.9,50.7,48.6,47.2,46.8,28.0×22 C)ppm.IR(KBr)ν3445,2970,1652,1593,1497,1370,1322,1192,1109,1031,842,699,576,548cm -1 .

Embodiment 3

[0066] Example 3: Compound L3

[0067]

[0068] m.p.240~242℃.HRMS(ESI),[M+H] + calculated for C 25 h 28 N 2 o 5 436.1998,found 436.2065. 1 H NMR (300MHz, DMSO-d 6 ):δ=12.58(s,1H,5-OH),10.73(s,1H,7-OH),7.44(m,3H,Ar-H),7.18(d,1H,J=7.2Hz,Ar- H),7.03(s,1H,CHCO),6.33(s,1H,Ar-H),4.83(m,1H,C H (CH 2 ) 4 ),3.25(s,4H,Ar-N(C H 2 CH 2 ) 2 N),2.50(s,4H,Ar-N(CH 2 C H 2 ) 2 N),2.26(s,3H,NCH 3 ),1.68(m,8H,CH(C H 2 ) 4 ) ppm. 13 C NMR (75MHz, DMSO-d 6 ):δ=182.1, 163.4, 157.8, 155.8, 151.4, 150.0, 131.5, 129.8, 125.4, 118.8, 116.6, 112.4, 104.9, 103.7, 99.1, 84.0, 54.4(2×C), 47.7(2×C), 45.6,32.3(2×C),23.2(2×C)ppm.IR(KBr)ν3441,2952,1651,1597,1496,1432,1375,1328,1260,1006,930,862,788,700,571cm -1 .

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Abstract

The invention relates to the field of biological medicine, in particular to a series of derivatives of a novel CDK9 inhibitor with a benzofuran structure and an application of the novel CDK9 inhibitor. A series of compounds are synthesized by modifying a parent nucleus of wogonin since wogonin has the disadvantages of low antitumor activity and poor druggability; particularly, an N-ring containingsubstituent is introduced into a 3' site or a 4' site; the compounds are brand-new and are not reported in literatures; at the same time, the inventor carries out a series of bioactivity evaluation on the synthesized compounds; and in particular, the most compounds have good selectivity for CDK9 and better inhibition activity for cancer cells.

Description

technical field [0001] The present invention relates to the field of biomedicine, specifically including a series of derivatives of novel CDK9 inhibitors with a benzofuran structure and uses thereof, and relates to compounds as CDK9 inhibitors, pharmaceutically acceptable salts, esters, and solvents of the above compounds Compound or prodrug, and the purposes of the pharmaceutical composition of above-mentioned compound. [0002] technical background [0003] Cyclin-dependent kinases (CDKs), a member of the serine / threonine kinase family, form heterodimers with the regulatory subunit cyclins to exert their catalytic functions. CDKs family members can be divided into periodic CDKs and transcriptional CDKs according to their functional differences. The former mainly includes CDK1 / 2 / 4 / 6, which controls the cell cycle process; the latter mainly includes CDK7 / 8 / 9, which regulates the transcription of mRNA and processing (Malumbres M. et al. Genome Biol., 2014, 15:122). The overe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/30C07D405/12C07D407/12C07D417/12C07D405/14C07D405/04A61K31/5377A61K31/551A61K31/496A61K31/541A61P35/00A61P35/02A61P31/18A61P31/16A61P31/20A61P31/14
CPCC07D311/30C07D405/12C07D407/12C07D417/12C07D405/14C07D405/04A61P35/00A61P35/02A61P31/18A61P31/16A61P31/20A61P31/14Y02A50/30
Inventor 卞金磊李志裕赵腾腾王举波吴体智田于成
Owner CHINA PHARM UNIV
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