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Acridine derivative and preparation method and application thereof

A drug and compound technology, applied in the field of 9-benzylamino (benzyloxy) acridine derivatives and its preparation, can solve the problems that acridine derivatives need to be strengthened

Inactive Publication Date: 2013-08-21
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the acridine compounds that have been reported to interact with DNA are anilinoacridine derivatives, but there are few reports on the effect of the connecting chain between the benzene ring and the acridine ring on tumor activity.
[0005] Therefore, at this stage, the development of new acridine derivatives that can be used as topoisomerase inhibitors still needs to be strengthened

Method used

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  • Acridine derivative and preparation method and application thereof
  • Acridine derivative and preparation method and application thereof
  • Acridine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Embodiment 1, preparation 4-chloro-2 (4-methoxy amino) benzoic acid

[0060]In dimethylformamide (DMF) (50.00ml) was added 2,4-dichlorobenzoic acid (2.00g, 10.47mmol), 4-methoxyaniline (0.86g, 6.99mmol), potassium carbonate (2.00g , 14.49mmol) and copper powder (0.20g, 3.15mmol). Stir overnight at 130°C. After the reaction mixture was cooled, it was added to 200 ml of water, and the pH value was adjusted to about 3 with acetic acid. After extraction with ethyl acetate, the organic phase was evaporated to dryness and separated by column chromatography to obtain 1.24 g of a yellow solid (compound represented by formula IV, 4-chloro-2(4-methoxyanilino)benzoic acid). Yield 63.9%; melting point 198-201°C.

[0061] The confirmed data of the compound structure are:

[0062] 1 H NMR (400MHz, CDCl 3 )δ9.16(s,1H),δ7.93(d,J=8.6Hz,1H),δ7.17(d,J=8.7Hz,2H),δ6.95(d,J=8.8Hz,2H ),δ6.87(d,J=1.8Hz,1H),δ6.64(dd,J=8.6,1.7Hz,1H),δ3.84(s,3H); 13 C NMR (100.6MHz, CDCl 3 ) δ 172.79, 15...

Embodiment 2

[0063] Embodiment 2, preparation 6,9-dichloro-2-methoxyacridine

[0064] The 4-chloro-2(4-methoxyanilino)benzoic acid (2.00g, 7.19mmol) prepared in Example 1 was added to anhydrous phosphorus oxychloride (25.00ml), and refluxed at 140°C for 3 hours . After the reaction solution was cooled, it was slowly added to a mixture of ice water, ammonia water and chloroform (volume ratio 1:1:1). Chloroform was separated, extracted with chloroform again, and all chloroform extracts were combined, evaporated to dryness, and dried. 1.98 g of a yellow solid (compound represented by formula V, 6,9-dichloro-2-methoxyacridine) was obtained. Yield 99%; melting point 160-163°C.

[0065] The confirmed data of the compound structure are:

[0066] 1 H NMR (400MHz, CDCl 3 )δ8.34(d,J=9.2Hz,1H),δ8.20(d,J=1.9Hz,1H),δ8.09(d,J=10.2Hz,1H),δ7.56(dd,J =9.2,2.0Hz,1H), δ7.54–7.48(m,2H), δ4.04(s,3H).

Embodiment 3

[0067] Embodiment 3, preparation 6-chloro-2-methoxy-9-benzylamino-acridine

[0068] Add 6,9-dichloro-2-methoxyacridine (50.00mg, 0.18mmol) and various amine compounds (0.97mmol) prepared in Example 2 into 10.00ml of absolute ethanol, add potassium carbonate, Potassium iodide, heated under reflux at 85-100 degrees Celsius and stirred overnight. The reaction solution was evaporated to dryness, extracted with ethyl acetate, and the organic phase was evaporated to dryness and separated by column chromatography to obtain the desired compound (compound shown in formula I):

[0069] 1) Preparation of 6-chloro-2-methoxy-9-(4-trifluoromethyl)benzylamino-acridine (R in formula I 4 =CF 3 , Z is NHCH 2 , and the rest of the substituents are all H)

[0070] Yield 81%; melting point 152-154 ° C; high resolution mass spectrum (ESI): calculated value [C 22 h 16 CIF 3 N 2 O+H] + 417.0981; experimental value: 417.0986.

[0071] The confirmed data of the compound structure are:

[007...

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Abstract

The invention discloses an acridine derivative represented by the formula I and a preparation method and application thereof. The formula I represents a compound or a medically accepted salt, ester and solvent composition thereof; Z is NHCH2, NHCH2CH2, NHCH2CH2CH2 or OCH2; the compound represented by the formula I has a deoxyribonucleic acid (DNA) connection function and inhibition activity to topoisomerase; the compound or the medically accepted salt, ester and solvent composition thereof can be effectively used for preparing a DNA connector, a topoisomerase inhibitor and an eucaryon biological tumor cell multiplication inhibitor and tumor preventing and / or treating medicines.

Description

technical field [0001] The present invention relates to acridine derivatives and their preparation methods and uses. Specifically, the present invention relates to 9-benzylamino (benzyloxy) acridine derivatives represented by formula I and their preparation methods and uses. Background technique [0002] Cancer is the number one cause of human death today, and it is imminent to develop anti-tumor drugs with high efficiency and low toxicity. Drugs designed to target DNA and related enzymes are current research hotspots, and some drugs have been used for cancer treatment or have entered the clinical research stage, such as anthracycline antineoplastic drugs. Drugs acting on DNA targets can interact with DNA to change the structure of DNA, such as unwinding the helical structure of DNA and extending DNA chains, etc., thereby delaying or inhibiting the transcription and translation of DNA. [0003] DNA topoisomerase (divided into DNA topoisomerase I and DNA topoisomerase II) pl...

Claims

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Application Information

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IPC IPC(8): C07D219/10C07D219/06A61K31/473A61P35/00A61P35/02
Inventor 蒋宇扬郎许亮高春梅孙钦生
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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