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A 12h-indazol[2,1-a]cinnolin-12-one compound and its application

A technology of ketone compounds and compounds, which is applied in the field of preparation of anti-tumor drugs, can solve problems such as limited curative effect, adverse reactions, and urgent demand for drugs

Active Publication Date: 2020-10-27
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A 12h-indazol[2,1-a]cinnolin-12-one compound and its application
  • A 12h-indazol[2,1-a]cinnolin-12-one compound and its application
  • A 12h-indazol[2,1-a]cinnolin-12-one compound and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]

[0041] Weigh 45.6 mg (0.2 mmol) of 2-(2-fluorophenyl)-indazol-3-one, 34 mg (0.24 mmol) of methyl acetoacetate diazo, 12 mg (0.2 mmol) of acetic acid and 5 mg (0.006 mmol) of [ Cp*Rh(MeCN) 3 (SbF 6 ) 2 ] into a round-bottomed reaction flask, then add 2 mL of DCE to dissolve, and react at 40°C for 3 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 50.6 mg of a yellow solid. Yield 78%.

[0042] 1 H NMR (600MHz, CDCl 3 )δ8.05(d, J=7.8Hz, 1H), 7.67–7.62(m, 1H), 7.55(d, J=8.4Hz, 1H), 7.43(t, J=7.5Hz, 1H), 7.22( td,J=8.2,5.0Hz,1H),7.11–7.04(m,2H),3.91(s,3H),2.56(s,3H). 13 C NMR (150MHz, CDCl 3 )δ166.8, 157.5, 152.8 (d, J=257.4Hz), 144.6, 140.9, 131.9, 128.0 (d, J=8.0Hz), 126.8, 124.8, 124.1, 119.6, 119.1, 118.7 (d, J=12.9Hz) ,116.3(d,J=19.9Hz),115.8,109.4,52.3,17.8.HRMS(ESI)calcd for[M+H] + [C 18 h 14 FN 2 o 3 ] + 325.0988,found 325.0986.

Embodiment 2

[0044]

[0045] Using 2-(4-fluorophenyl)-indazol-3-one (45.6mg, 0.2mmol) and ethyl acetoacetate diazonium (37.5mg, 0.24mmol) as raw materials, prepared according to the same method as in Example 1 57.5 mg of yellow solid was obtained (eluent: petroleum ether: ethyl acetate = 4:1), yield 85%.

[0046] 1 H NMR (600MHz, CDCl 3 )δ8.90(dd, J=9.0,5.4Hz,1H),8.06(d,J=7.8Hz,1H),7.68–7.60(m,2H),7.41–7.32(m,1H),7.04(dd ,J=9.8,2.8Hz,1H),6.98(m,1H),4.42(q,J=7.2Hz,2H),2.70(s,3H),1.42(t,J=7.2Hz,3H). 13 C NMR (150MHz, CDCl 3 )δ166.2, 160.1(d, J=244.8Hz), 156.7, 140.0, 136.8, 132.0, 129.3, 124.1, 123.2, 122.6(d, J=8.8Hz), 117.8(d, J=8.3Hz), 117.4, 114.0 (d, J=22.9Hz), 113.8, 110.7 (d, J=26.0Hz), 108.4, 61.6, 18.4, 14.2.HRMS(ESI)calcd for[M+H] + [C 19 h 16 FN 2 o 3 ] + 339.1145,found 339.1141.

Embodiment 3

[0048]

[0049] Using 2-(4-chlorophenyl)-indazol-3-one (49mg, 0.2mmol) and ethyl acetoacetate diazo (37.5mg, 0.24mmol) as raw materials, prepared according to the same method as in Example 1 57.4 mg of yellow solid (eluent: petroleum ether: ethyl acetate = 4:1), yield 81%.

[0050] 1 H NMR (600MHz, CDCl 3)δ8.87(d, J=9.0Hz, 1H), 8.06(d, J=8.4Hz, 1H), 7.65(m, 2H), 7.36(t, J=7.2Hz, 1H), 7.27(s, 1H), 7.24(d, J=8.4Hz, 1H), 4.43(q, J=7.2Hz, 2H), 2.69(s, 3H), 1.42(t, J=7.2Hz, 3H). 13 C NMR (150MHz, CDCl 3 )δ166.1,156.9,139.7,136.9,132.1,131.7,131.2,127.4,124.2,123.6,123.2,122.1,117.4,117.3,113.8,108.4,61.7,18.5,14.2.H]HRMS(ESI)calcd for[M+ + [C 19 h 16 ClN 2 o 3 ] + 355.0849,found 355.0848.

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Abstract

The invention discloses a 12H-indazolo[2,1-a]cinnolin-12-one compound and an application thereof. The structural formula of the 12H-indazolo[2,1-a]cinnolin-12-one compound is represented by formula I,and the compound and its pharmaceutically acceptable salts or hydrates are applied to the preparation of drugs for treating malignant tumors. The compound particularly has good inhibitory activity onhuman prostate cancer PC-3 cells and human pancreatic cancer PANC-1 cells, can inhibit proliferation of the cells in a dose-dependent manner, and has great application prospects. The compound has theadvantages of simple preparation method, cheap and easily available raw materials, low production cost, and convenience in industrial production.

Description

technical field [0001] The present invention relates to a class of novel 12H-indazol[2,1-a]cinnolin-12-one compounds and applications thereof, specifically, the present invention relates to a class of 12H-indazol[2,1-a ] Cinnolin-12-ketone compounds and their application 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 in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00
CPCA61P35/00C07D487/04
Inventor 侯卫白芮松阮奔放
Owner ZHEJIANG UNIV OF TECH
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