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Aza-acridine compound and preparation method and application thereof

A compound and solvate technology, applied in the field of azaacridine parent nucleus synthesis

Active Publication Date: 2017-05-24
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, in many tumor cells in humans, Src-EGFR synergy can lead to tumorigenesis

Method used

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  • Aza-acridine compound and preparation method and application thereof
  • Aza-acridine compound and preparation method and application thereof
  • Aza-acridine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0107] Example 1A: (Compound I) Preparation

[0108] Step 1a, 1b prepares 2-aminoquinoline-3-carbonitrile (2)

[0109] O-nitrobenzaldehyde (3.02g, 20mmol) was dissolved in EtOH (20ml), then iron powder (3.0g) and ammonium chloride (1.07g, 20mmol) aqueous solution (5ml) were added thereto, and the reaction was refluxed. After completion of the reaction, filter while hot, collect the filtrate, directly add malononitrile (1.32g, 20mmol) and Et 3 N (2ml), heated to reflux for reaction. Then the reaction solution was cooled to room temperature, and the solid was collected by filtration as compound 2. Yield 79.6%.

[0110] The confirmed data of the compound structure are:

[0111] 1 H NMR (400MHz, DMSO) δ8.69(s, 1H), 7.65(d, J=8Hz, 1H), 7.66(dd, J 1 =J 2 =8Hz,1H),7.51(d,J=8Hz,1H),7.28(dd,J 1 =J 2 =8Hz,1H),7.21(s,3H).

[0112] Step 1c, preparation of 2-aminoquinoline-3-carboxamide (3)

[0113] Compound 2 (1.69 g, 10 mmol) was dissolved in concentrated H 2 SO 4 (10ml), ...

Embodiment 1

[0120] Example 1: (Compound 14a) Preparation

[0121] Step 2a, 2b prepare 2-aminoquinoline-3-formonitrile (2)

[0122] O-nitrobenzaldehyde (3.02g, 20mmol) was dissolved in EtOH (20ml), then iron powder (3.0g) and ammonium chloride (1.07g, 20mmol) aqueous solution (5ml) were added thereto, and the reaction was refluxed. After completion of the reaction, filter while hot, collect the filtrate, directly add malononitrile (1.32g, 20mmol) and Et 3 N (2ml), heated to reflux for reaction. Then the reaction solution was cooled to room temperature, and the solid was collected by filtration as compound 2. Yield 79.6%.

[0123] Step 2c, preparation of 2-aminoquinoline-3-carboxamide (3)

[0124] Compound 2 (1.69 g, 10 mmol) was dissolved in concentrated H 2 SO 4 (10ml), stirred for 24h, cooled the reaction solution and added it dropwise to ice water, adjusted the pH to about 8 with 20% NaOH solution, collected the precipitate by filtration, and dried to obtain compound 3. Yield 9...

Embodiment 2

[0141] Example 2: (Compound 14b) Preparation

[0142] Compound 14b was prepared according to the steps of Example 1, except that:

[0143] 1. Preparation of 1-(3-fluorophenyl)-3-(4-nitrophenyl)urea (7b)

[0144]The aniline in step 1g in Example 1 was replaced with 3-fluoroaniline for reaction. Yield 83.9%.

[0145] 2. Preparation of 1-(4-aminophenyl)-3-(3-fluorophenyl)urea (8b)

[0146] Replace 7a in step 1h in Example 1 with 7b for reaction. Yield 87.1%.

[0147] 3. Preparation of 1-(4-((5,10-dihydropyrimidinone[4,5-b]quinoline-4-)amino)phenyl)-3-(3-fluorophenyl)urea (14b)

[0148] 8a in Step 2i in Example 1 was replaced with 8b for reaction. Yield 77.5%, HRMS (ESI): [M+H] + 427.1683.

[0149] The confirmed data of the compound structure are:

[0150] 1 H NMR (400MHz,DMSO)δ10.58(s,1H),10.27(s,1H),9.49(s,1H),8.68(s,1H),8.40(s,1H),7.60(d,J= 8Hz, 2H), 7.51(d, J=8Hz, 1H), 7.39(d, J=8Hz, 1H), 7.34-7.28(m, 3H), 7.12(d, J=8Hz, 1H), 7.06(d , J=8Hz, 2H), 7.01(d, J=8Hz, 2...

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Abstract

The invention discloses a method for efficiently preparing an aza-acridine compound. The structural formula of the aza-acridine compound is shown as a formula I; the preparation method comprises the following steps: adding a 2-aminoquinoline-3-methanamide compound and a solvent under an air condition, and heating to reaction temperature; after the reaction is ended, separating and purifying to obtain multisubstituted acridine derivatives shown as the following formula, wherein the reaction temperature is 100 to 200DEG C, and the reaction time is 1 to 24 hours. A synthetic method of the aza-acridine compound, disclosed by the invention, has the advantages of scientificity, reasonability, simple and easily-operated synthesis process and high synthetic yield; a product is easy to purify. The invention also relates to the aza-acridine compound which can be used for inhibiting EGFR (Epidermal Growth Factor Receptor) and SrC, a preparation method of the aza-acridine compound, activity of a drug containing the aza-acridine compound and the application of the drug. The compound is shown in a formula II and can be used for preparing an EGFR and SrC activity inhibitor and a disease treatment medicine activated and mediated by the EGFR and the SrC.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a simple and effective method for synthesizing azaacridine parent nuclei and its application. Background technique [0002] The discovery of a new acridine compound as the mother core of kinase inhibitors, especially the optimization of the synthesis method, has important research significance. Azacridine derivatives are compounds of great research and application value, which can be widely used in dyes, fluorescence, and medicinal chemistry, and also have certain effects on anticancer. The research on azaacridine compounds is still one of the hot spots in organic synthesis and medicinal chemistry, so the efficient and convenient synthesis of azaacridine derivatives is of great significance. The simple and direct method of synthesizing azaacridine derivatives is still not much reported so far. [0003] The high coplanarity of acridine makes it excellent in anti-tumor, and it...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P35/00A61P35/04A61P35/02
CPCC07D471/04
Inventor 蒋宇扬崔至闪高春梅陈少鹏
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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