Dibenzonaphthyridinone compounds and their preparation methods and applications

A technology of benzonaphthyridone and compounds, which is applied in the field of anti-tumor compounds, and can solve the problems of not being easy to obtain and cumbersome steps

Active Publication Date: 2018-04-06
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 and their preparation methods and applications
  • Dibenzonaphthyridinone compounds and their preparation methods and applications
  • Dibenzonaphthyridinone compounds and their preparation methods and applications

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 under stirring. After installing the water trap and straight condenser, reflux at 100℃ until there is no more water in the water trap; after the reaction is completed, remove the cyclohexane and excess ethanol under reduced pressure, and add ethyl acetate to the flask Ester (30 mL), the mixture was washed twice with ice water, 30 mL each time, and then washed twice with saturated sodium bicarbonate solution, 30 mL each time, and extracted with organic solvent three times. Combine the organic layers and dry the organic layers with anhydrous magnesium sulfate , Filter, remove the solvent under reduced pressure, use silica gel column chromatography (eluent: ...

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] O-Chloroaniline was used instead of p-chloroaniline, and other preparation methods were the same as those in Preparation Example 1, to obtain the target compound H2 in white powder form.

[0046] Compound H2: yield 36%, m.p. 222~223°C; 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] Meta-chloroaniline was used instead of p-chloroaniline, and the other preparation methods were the same as those in Preparation Example 1, to obtain the target compound H3 in white powder form.

[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 to dibenzonaphthyridone compounds, a preparation method thereof and application in the preparation of anti-tumor drugs. Background technique [0002] Dibenzonaphthyridone compounds are a very important class of topoisomerase I toxicants. They have strong anti-tumor activity and have a good prospect for the development of new anti-tumor drugs targeting topoisomerase I. The earliest The Lavoie, Edmond J. research group of the State University of New Jersey in the United States who reported the synthesis and anti-tumor activity of such compounds. They have reported the synthesis and anti-tumor activity of such compounds since 2002, and many related research results have been published. Papers and applied for many patents (Bioorganic&Medicinal Chemistry Letters(2002), 12(22), 3333-3336; Bioorganic&Medicinal Chemistry(2003), 11(9), 2061-2073; Journal of Medicinal C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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