Quinolone derivative as well as preparation method and application thereof

A derivative and quinolone technology, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of insufficient activity and no statistical difference, and achieve the effect of inhibiting tumor cell proliferation, inducing cell apoptosis, and low toxicity

Pending Publication Date: 2021-12-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the existing small-molecule SH2 domain inhibitors all have the dilemma of insufficient activity or no statistical difference compared with the positive control drug

Method used

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  • Quinolone derivative as well as preparation method and application thereof
  • Quinolone derivative as well as preparation method and application thereof
  • Quinolone derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of Diethyl 2-(((4-Hydroxyphenyl)amino)methylene)malonate (Compound 3)

[0044] Add 4-aminophenol (compound 1, 0.5 g, 4.5 mmol) to 2.5 mL of ethanol, then add ethoxymethylene malonate (compound 2, 925 μL, 4.5 mmol), and react at room temperature for 2 hours , until the reaction is complete, spin off ethanol under low pressure, and wash with methyl tert-butyl ether to obtain diethyl 2-(((4-hydroxyphenyl)amino)methylene)malonate (compound 3), white Solid (1.26 g, 98% yield).

[0045] 1 H NMR (500MHz, CDCl 3 )δ10.95(d,J=13.9Hz,1H,NH),8.41(d,J=13.9Hz,1H,CH),7.07–6.95(m,2H,Ar-H),6.92–6.82(m, 2H, Ar-H), 6.62(s, 1H, OH), 4.3(q, J=7.0, 2H, CH 2 ), 4.29 (q, J=7.0, 2H, CH 2 ), 1.35(t, J=7.0Hz, 3H, CH 3 ), 1.32(t, J=7.0Hz, 3H, CH 3 ).

[0046] Synthesis of 2-[(4-acetoxy-phenylamino)-methylene]-diethyl malonate (compound 4)

[0047] Diethyl 2-(((4-hydroxyphenyl)amino)methylene)malonate (compound 3, 0.5 g, 1.7 mmol) and triethylamine (374 μL, 2.6 mmol) were added t...

Embodiment 2

[0059] Synthesis of 6-((4-methylbenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 7b)

[0060] Referring to the synthesis of compound 7a in Example 1, only 4-(trifluoromethoxy)benzyl bromide was replaced with 4-(methyl)benzyl bromide to obtain compound 7b as a white solid with a yield of 85.2%.

[0061] mp>250℃.IR(KBr):3451,2894,1685,1626,1490,1383cm -1 . 1 H NMR (500MHz, DMSO) δ15.47(s, 1H, COOH), 13.52(s, 1H, NH), 8.81(d, J=5.5Hz, 1H, CH), 7.82(d, J=9.1Hz, 1H,Ar-H),7.74(s,1H,Ar-H),7.64(d,J=8.4Hz,2H,Ar-H),7.61(dd,J=9.1,1.6Hz,1H,Ar-H ), 7.41(d, J=8.2Hz, 2H, Ar-H), 5.31(s, 2H, CH 2 ). 13 C NMR (126MHz, DMSO) δ177.42(s), 166.49(s), 156.44(s), 143.32(s), 137.19(s), 134.13(s), 133.35(s), 128.96(s), 127.75 (s), 125.59(s), 124.77(s), 121.40(s), 106.86(s), 105.51(s), 69.66(s), 20.71(s). MS(ESI) m / z 308.1[M-H] - ; HRMS (ESI) calcd for C 18 h 14 NO 4 [M-H] - 308.0928,found 308.0931.

Embodiment 3

[0063] Synthesis of 6-((2-fluorobenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 7c)

[0064] Referring to the synthesis of compound 7a in Example 1, only 4-(trifluoromethoxy)benzyl bromide was replaced by 2-fluorobenzyl bromide to obtain compound 7c as a white solid with a yield of 88.6%.

[0065] mp>250℃.IR(KBr):3439,2901,1694,1622,1492,1387cm -1 . 1 H NMR (500MHz, DMSO) δ15.50(s, 1H, COOH), 13.57(s, 1H, NH), 8.81(d, J=6.3Hz, 1H, CH), 7.83(d, J=9.1Hz, 1H,Ar-H),7.78(d,J=2.8Hz,1H,Ar-H),7.63–7.55(m,2H,Ar-H),7.44(dd,J=9.1,2.8Hz,1H,Ar -H),7.32–7.20(m,2H,Ar-H),5.30(s,2H,CH 2 ). 13 C NMR (126MHz, DMSO) δ177.98(s), 167.01(s), 161.93(s), 159.97(s), 156.78(s), 143.96(s), 134.86(s), 131.17(dd, J= 21.6, 6.1Hz), 126.14(s), 124.82–124.31(m), 123.76(d, J=14.6Hz), 122.06(s), 116.02(s), 115.86(s), 107.46(s), 105.98( s),64.70(d).MS(ESI)m / z 336.0[M+Na] + ; HRMS (ESI) calcd for C 17 h 12 FNO 4 [M+Na] + 336.0643,found 336.0641.

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Abstract

The invention belongs to the fields of medicinal chemistry and pharmacotherapeutics, and discloses a quinolone derivative as shown in a formula I in the description or pharmaceutically acceptable salt or ester thereof. The invention also discloses application of the quinolone derivative or the pharmaceutically acceptable salt or ester thereof in preparation of an STAT3 inhibitor or in preparation of a medicine for preventing and/or treating tumor-related diseases. Pharmacological experiments prove that the quinolone derivative or the pharmaceutically acceptable salt or ester thereof can achieve the anti-tumor purpose by inhibiting proliferation of tumor cells and inducing apoptosis of the tumor cells, and the quinolone derivative or the pharmaceutically acceptable salt or ester thereof has an anti-tumor effect and is relatively low in toxicity. The quinolone derivative can be combined with a target protein STAT3SH2 structural domain, so that formation of an STAT3 homodimer is mediated, and a JAK-STAT3 cellular pathway is selectively inhibited.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and specifically relates to a quinolone derivative, a preparation method thereof, and an application for preparing a small molecule inhibitor of STAT3 and preparing a drug for treating tumors. Background technique [0002] The signal transducer and activator of transcription (STAT) protein family plays an important role in the occurrence of many human diseases. STAT3 (Signal Transducer and Activator of Transcription 3) is a transcription factor that plays an important role in the development of various cancers, including breast cancer, and can be detected in a variety of tumors. Activated STAT3 protein. The activated STAT3 protein will enter the nucleus and promote the expression of various anti-apoptotic protein genes, thereby supporting the occurrence and development of tumors. At present, this target is already an important anti-tumor target. [0003] Binding of c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56C07D409/12A61P35/00A61K31/4709A61K31/47
CPCC07D215/56C07D409/12A61P35/00
Inventor 余文颖查放余大鑫
Owner CHINA PHARM UNIV
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