Dibenzonaphthyridinone compounds, preparation method, and applications thereof

A kind of technology of benzonaphthyridone and compound, applied in the field of antitumor compounds, can solve the problems such as cumbersome steps, not easy to obtain, etc.

Active Publication Date: 2016-12-07
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although there have been reports on the synthesis and antitumor activity of such compounds in the above literature so far, the synthetic routes they adopt all start from intermediate 2 (Scheme 1), and the synthesis of intermediate 2 generally uses aromatic aldehydes as raw materials. Nitration, reaction of aldehyde group with methyl Grignard reagent, oxidation of alcohol, reduction of nitro group, cyclization of o-aminoaryl ethyl ketone with formate to quinolinone and the action of quinolinone and phosphorus oxychloride, etc. -6-step reaction, the steps are very cumbersome
In addition, another raw material o-iodo (bromo) arylformic acid 4 required for its synthesis is not easy to obtain, which limits the substituent R of the product. 1 , R 2 and R 3 diversification

Method used

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  • Dibenzonaphthyridinone compounds, preparation method, and applications thereof
  • Dibenzonaphthyridinone compounds, preparation method, and applications thereof
  • Dibenzonaphthyridinone compounds, preparation method, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 1

[0033] Preparation Example 1: Preparation of Compound H1: 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-3-chlorodibenzo[c,h][1,6]-naphthyridin-6-one

[0034]

[0035] (1) Add 3,4-dimethoxyphenylacetic acid (1.96g, 10mmol), absolute ethanol (5mL), cyclohexane (5mL) and concentrated sulfuric acid (1mL) to a 50mL round bottom flask in turn under stirring , after installing the water separator and straight condenser tube, reflux at 100°C until there is no more water in the water separator; after the reaction is completed, remove cyclohexane and excess ethanol under reduced pressure, and add ethyl acetate to the flask ester (30mL), the mixture was washed twice with ice water, 30mL each time, then washed twice with saturated sodium bicarbonate solution, 30mL each time, extracted with organic solvent for 3 times, the organic layers were combined, and the organic layer was dried with anhydrous magnesium sulfate , filtered, the solvent was removed under reduced pressure, and silica ...

preparation Embodiment 2

[0043] Preparation Example 2: Preparation of Compound H2 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-1-chlorodibenzo[c,h][1,6]-naphthyridin-6-one

[0044]

[0045] Using o-chloroaniline instead of p-chloroaniline, other preparation methods were the same as in Preparation Example 1 to obtain the target compound H2 in the form of white powder.

[0046] Compound H2: Yield 36%, m.p.222~223℃; 1 H NMR (500MHz, CDCl 3 )δ:2.26(s,6H,N(CH 3 ) 2 ), 2.94(t, J=7.10Hz, 2H, CH 2 ),4.05(s,3H,OCH 3 ),4.11(s,3H,OCH 3 ), 4.67(t, J=7.10Hz, 2H, CH 2 ),7.49(dd,J=8.70Hz,7.45Hz,1H,ArH),7.69(s,1H,ArH),7.85(dd,J=7.45Hz,0.95Hz,1H,ArH),7.89(s,1H , ArH), 8.41(d, J=8.70Hz, 1H, ArH), 9.65(s, 1H, CH=N); 13 C NMR (125MHz, CDCl 3)δ:45.89,49.47,56.38,56.43,57.77,102.16,108.87,112.63,119.91,120.13,120.50,123.78,125.55,127.08,129.52,134.52,141.26,144.89,146.09,150.91,154.42,163.89;HRMS(ESI ): m / z calculated value [M+H] + 412.1428 (C 22 h 22 ClN 3 o 3 ), the experimental value is 412.1443.

preparation Embodiment 3

[0047] Preparation Example 3: Preparation of Compound H3 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2-chlorodibenzo[c,h][1,6]-naphthyridin-6-one

[0048]

[0049] Using m-chloroaniline instead of p-chloroaniline, the other preparation methods were the same as in Preparation Example 1 to obtain the target compound H3 as a white powdery solid.

[0050] Compound H3: Yield 14%, m.p.235~236℃; 1 H NMR (500MHz, CDCl 3 )δ:2.31(s,6H,N(CH 3 ) 2 ),2.99(t,J=7.25Hz,2H,CH 2 ),4.03(s,3H,OCH 3 ),4.10(s,3H,OCH 3 ), 4.61(t, J=7.25Hz, 2H, CH 2 ),7.52(dd,J=9.25Hz,2.30Hz,1H,ArH),7.63(s,1H,ArH),7.84(s,1H,ArH),8.10(d,J=2.30Hz,1H,ArH) ,8.45(d,J=9.25Hz,1H,ArH),9.48(s,1H,CH=N); 13 CNMR (125MHz, CDCl 3 )δ:45.87,49.01,56.38,56.43,57.68,102.02,108.73,111.91,117.32,119.53,126.15,126.75,127.27,129.34,135.06,140.78,146.71,149.32,150.71,154.35,163.59;HRMS(ESI): m / z calculated value [M+H] + 412.1428 (C 22 h 22 ClN 3 o 3 ), the experimental value is 412.1434.

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Abstract

The invention discloses dibenzonaphthyridinone compounds represented by the formula (I), which is shown in the description. In the formula (I), R1a is independently chosen from -H and -CH3O, R1b is -CH3O; when R2a is -Cl, R2b and R2c are both -H; when R2b is -Cl, R2a and R2b are both -H; when R2c is independently chosen from -F, -Cl, -Br, -CH3, -CH3O, and -CF3, R2a and R2b are both -H; and R3 is (CH2)2N(CH3)2 or (CH2)3N(CH3)2. The invention further discloses a preparation method of dibenzonaphthyridinone compounds and an application of dibenzonaphthyridinone compounds in the preparation of anti-tumor drugs. The test results show that dibenzonaphthyridinone compounds have a good effect on inhibiting the activity of cells such as human stomach cancer cell (MGC-803), human lung cancer cell (NCI-H460), human liver cancer cell (HepG-2), human liver cancer cell (BEL-7404), and the like, and thus has a good application prospect in antitumor industry.

Description

technical field [0001] The present invention relates to the research field of anti-tumor compounds, and more specifically relates to dibenzonaphthyridinone compounds, their preparation methods and their application in the preparation of anti-tumor drugs. Background technique [0002] Dibenzonaphthyridinones are a class of very important topoisomerase I poisoning agents, have strong antitumor activity, and have good prospects for the development of new antitumor drugs targeting topoisomerase I. The research group of Lavoie and Edmond J. from the State University of New Jersey, who reported the synthesis and anti-tumor activity of this kind of compound, they began to report the synthesis and anti-tumor activity of this kind of compound since 2002, and related research results have been published in many Papers, and applied for many patents (Bioorganic & Medicinal Chemistry Letters (2002), 12 (22), 3333-3336; Bioorganic & Medicinal Chemistry (2003), 11 (9), 2061-2073; Journal o...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/4375A61P35/00
CPCC07D471/04
Inventor 苏桂发胡伟伟潘成学张国海袁静梅朱海妙
Owner GUANGXI NORMAL UNIV
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