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Application of 12H-indazole [2, 1-a] cinnoline-12-ketone compound

A ketone compound and indazole technology, which is applied in the application field of 12H-indazo[2,1-a]cinnoline-12-one compounds, can solve the problems of adverse reactions, limited curative effect, urgent drug demand and the like, Achieving significant application prospects and good inhibitory activity

Active Publication Date: 2020-02-04
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, specific therapeutic drugs and strategies for pancreatic cancer have not yet been developed. The pyrimidine nucleoside analog gemcitabine is still the basis of first-line chemotherapy for patients with pancreatic cancer. Its curative effect is limited and there are many adverse reactions. Urgent need

Method used

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  • Application of 12H-indazole [2, 1-a] cinnoline-12-ketone compound
  • Application of 12H-indazole [2, 1-a] cinnoline-12-ketone compound
  • Application of 12H-indazole [2, 1-a] cinnoline-12-ketone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032]

[0033] Weigh 42mg (0.2mmol) 2-phenylindazol-3-one, 53mg (0.24mmol) ethyl benzoylacetate diazo, 12mg (0.2mmol) acetic acid and 5mg (0.006mmol) [Ru(p-cymene) (MeCN) 3 (SbF 6 ) 2 ] into a round-bottomed reaction flask, then add 2 mL of DCE to dissolve, and react at 60°C for 6 hours. The reaction solution was mixed with silica gel, and separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain 72.6 mg of a yellow solid with a yield of 95%.

[0034] 1 H NMR (600MHz, CDCl 3 )δ9.05(d, J=8.4Hz, 1H), 8.00(d, J=7.8Hz, 1H), 7.59(d, J=7.8Hz, 1H), 7.55–7.49(m, 3H), 7.44( d,J=7.2Hz,2H),7.35(td,J=7.2,1.2Hz,1H),7.21(td,J=7.2,1.2Hz,1H),7.18(t,J=7.2Hz,1H), 7.16–7.12(m,1H),5.61(d,J=8.4Hz,1H),3.94(q,J=7.2Hz,2H),0.84(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl 3)δ165.4, 157.3, 138.9, 136.3, 133.9, 131.6, 131.2, 130.5, 129.9, 129.1, 128.4, 125.9, 123.8, 123.5, 122.4, 120.0, 116.6, 116.1, 112.9, 110.4, 61. for[M+H] + [C 24 h 19 N 2 o 3 ...

Embodiment 2

[0036]

[0037] Using 2-phenyl-5-fluoroindazol-3-one (45.6mg, 0.2mmol) and ethyl benzoyl acetate diazo (53mg, 0.24mmol) as raw materials, according to the method of Example 1, 70.4mg was prepared Yellow solid (eluent: petroleum ether: ethyl acetate = 4:1). Yield 88%.

[0038] 1 H NMR (600MHz, CDCl 3 )δ9.02(dd,J=8.4,1.2Hz,1H),7.64–7.58(m,2H),7.53(m,3H),7.42(m,2H),7.39–7.33(m,1H),7.23 (td,J=7.8,1.2Hz,1H),6.90(td,J=9.0,3.0Hz,1H),5.56(dd,J=9.6,4.2Hz,1H),3.94(q,J=7.2Hz, 2H), 0.84(t, J=7.2Hz, 3H). 13 C NMR (150MHz, CDCl 3 )δ165.3, 158.2(d, J=242.9Hz), 156.5, 138.8, 133.6, 132.8, 131.4, 130.7, 129.9, 129.3, 128.4, 126.2, 123.9, 120.2, 120.0(d, J=2.3Hz), 117.4(d ,J=9.0Hz),116.3,114.7(d,J=7.8Hz),110.4,108.3(d,J=23.9Hz),61.0,13.5.HRMS(ESI)calcd for[M+H] + [C 24 h 18 FN 2 o 3 ] + 401.1296,found 401.1294.

Embodiment 3

[0040]

[0041] Using 2-phenyl-5-methoxyindazol-3-one (48.0mg, 0.2mmol) and ethyl benzoylacetate diazo (53mg, 0.24mmol) as raw materials, prepared according to the method of Example 1 70.1 mg of yellow solid (eluent: petroleum ether: ethyl acetate = 4:1). Yield 85%.

[0042] 1 H NMR (600MHz, CDCl 3 )δ9.04(d, J=7.8Hz, 1H), 7.60(t, J=7.8Hz, 1H), 7.54(m, 3H), 7.42(d, J=7.8Hz, 2H), 7.38–7.33( m, 2H), 7.22(t, J=7.8Hz, 1H), 6.78(dd, J=9.6, 3.0Hz, 1H), 5.50(d, J=9.6Hz, 1H), 3.93(q, J=7.2 Hz,2H),3.83(s,3H),0.83(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl 3 )δ165.5, 157.1, 155.7, 139.4, 133.6, 131.8, 131.3, 130.5, 129.9, 129.2, 128.2, 125.9, 123.8, 122.3, 120.3, 117.3, 116.3, 114.4, 109.3, 102.8, IES.55, 60.9 )calcd for[M+H] + [C 25 h 21 N 2 o 4 ] + 413.1496,found 413.1501.

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Abstract

The invention discloses application of a 12H-indazole [2, 1-a] cinnoline-12-ketone compound, and application of the 12H-indazole [2, 1-a] cinnoline-12-ketone compound and pharmaceutically acceptable salts or hydrates of the compound in preparing drugs for treating malignant tumors. The compound has good inhibitory activity especially on PC-3 cells of human prostate cancer and PANC-1 cells of humanpancreatic cancer, can inhibit the proliferation of the above cancer cells in a dose-dependent manner, and has great application prospects.

Description

technical field [0001] The invention relates to the application of a class of 12H-indazol[2,1-a]cinnolin-12-one compounds or pharmaceutically acceptable salts or hydrates in the preparation of antitumor drugs. Background technique [0002] Cancer is one of the major diseases that seriously affect human health and threaten human life. The World Health Organization (WHO) and the health departments of governments all over the world have listed the fight against cancer as a top priority. [0003] Prostate cancer is one of the common male malignancies. In 2017, there were 161,360 new cases of prostate cancer in the United States, accounting for the first (19%) incidence of male malignant tumors; 26,730 new deaths from prostate cancer, accounting for the third (8%) of male malignant tumor mortality. There were 60,300 new cases of prostate cancer in my country in 2015, and the incidence of prostate cancer is increasing at a rate of 10% per year. Current prostate cancer treatment...

Claims

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Application Information

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IPC IPC(8): A61K31/5025A61K31/5377A61K31/675A61P35/00
CPCA61K31/5025A61K31/5377A61K31/675A61P35/00
Inventor 侯卫白芮松阮奔放
Owner ZHEJIANG UNIV OF TECH
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