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Quinazoline substituted 1, 2, 3-triazole derivative as well as pharmaceutical composition, preparation method and application thereof

A technology of triazole and quinazoline, applied in the application field of 1,2,3-triazole derivatives and anti-tumor drugs, can solve the problem of subG1 cell accumulation and so on

Active Publication Date: 2022-03-25
SHENZHEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Han et al. designed and synthesized chalcone analogues with A and B rings at the quinazoline-2-base position respectively, and the IC50 value of compound VIIId on HCT-116 cells was 3.36 μM, Has no obvious effect on cell cycle distribution, but sub G1 cells show obvious accumulation with increasing concentration

Method used

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  • Quinazoline substituted 1, 2, 3-triazole derivative as well as pharmaceutical composition, preparation method and application thereof
  • Quinazoline substituted 1, 2, 3-triazole derivative as well as pharmaceutical composition, preparation method and application thereof
  • Quinazoline substituted 1, 2, 3-triazole derivative as well as pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0059] Preparation of 2,4-diamino-6-bromoquinazoline (1)

[0060] Add 2-amino-5-bromobenzonitrile (0.98g, 5mmol), chloroformamidine hydrochloride (1.73g, 15mmol) and dimethylsulfone (15g, 160mmol) in a 100mL three-necked flask, heat to 120- 125°C, reacted for 30 minutes, and a yellow solid precipitated out. Cool to room temperature, add distilled water to dissolve completely, and adjust pH to 8-9 with concentrated ammonia water, a large amount of yellow solid precipitates out. Filtered, dried, and the crude product was purified by column chromatography (eluent: CH 2 Cl 2 / CH 3 OH=95:5to 90:10, v / v), 0.95 g of yellow solid was obtained, yield 86%, mp 285-287°C. 1 H NMR (600MHz, DMSO-d 6 )δ: 7.42 (d, J = 8.4Hz, Quin 8-H), 7.93 (dd, J = 8.4, 1.8Hz, 1H, Quin 7-H), 8.57 (d, J = 1.8Hz, 1H, Quin 5 -H).EI-MS m / z:238,240(M + ).

[0061] Preparation of 2,4-diamino-6-((trimethylsilyl)ethynyl)quinazoline (2)

[0062] 2,4-diamino-6-bromoquinazoline (1) (0.14g, 0.5mmol), trimethyls...

preparation example 2

[0069] Preparation of Phenyl and Substituted Phenylazides 4a-q

[0070] Dissolve aniline or substituted aniline (1 mmol) in a mixture of hydrochloric acid and water (concentrated hydrochloric acid: H 2 O=1:1, 1mL), stirred for 30min under ice-bath cooling, then added dropwise sodium nitrite (0.10g, 1.5mmol) dissolved in water (3.5mL), and cooled in ice-water bath (0-5°C) , stirred for 10 min. Sodium azide (0.26 g, 4 mmol) dissolved in water (5 mL) was added dropwise to the resulting diazonium salt solution, and stirring was continued for 1 h under ice cooling. The reaction solution was extracted with ethyl acetate (20 mL×3), the combined extracts were dried overnight over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was removed by rotary evaporation, and the residue was purified by column chromatography (eluent: PE / EtOAc=95:5, v / v) to obtain different phenylazides 4a-q.

[0071] Yields, melting points and properties of compounds of compound 4a-q

...

Embodiment 1

[0076] 2,4-Diamino-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-4-yl)quinazoline (5a)

[0077]Yield 43% (0.16g), pale yellow solid, mp 207-208°C.HPLC, rt=3.126min. 1 H NMR (600MHz, DMSO-d 6 )δ:3.74(s,3H,OCH 3 ),3.92(s,6H,2OCH 3 ),6.88(br s,2H,NH 2 ),7.27(s,2H,Ph 2′-H,6′-H),7.42(d,J=8.4Hz,1H,Quin 8-H),8.12(br s,2H,NH 2 ), 8.13(d, J=8.4Hz, 1H, Quin 7-H), 8.76(s, 1H, Quin 5-H), 9.24(s, 1H, triazole 5-H). 13 C NMR (150MHz, DMSO-d 6 )δ:56.76(2C),60.68,98.50(2C),110.86,119.59,120.94,122.46,125.03,130.56,133.04,137.83,147.91,152.57 154.01(2C),161.21,163.05.ESI m / ESI C 19 h 20 N 7 o 3 Theoretical value: 394.1628([M+H] + ), measured value: 394.1620.

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Abstract

The invention discloses a quinazoline substituted 1, 2, 3-triazole derivative, the derivative is shown as a general formula (I), and the definition of each substituent group is shown in the specification. In addition, the invention also discloses a preparation method of the compound. The compound shown in the general formula (I) has an inhibiting effect on proliferation of tumor cells, also has an inhibiting effect on proliferation of human colon cancer (HCT-116) and human lung cancer cell strain (A549) cells, and can be used as an antitumor drug.

Description

technical field [0001] The present invention relates to but not limited to the field of medicinal chemistry, and more specifically relates to quinazoline-substituted 1,2,3-triazole derivatives, pharmaceutical compositions, preparation methods thereof and their application in antitumor drugs. Background technique [0002] Quinazoline is an important nitrogen-containing heterocyclic parent, and its derivatives can exert antitumor activity through different mechanisms. The folic acid analog (antifolate) obtained by replacing the pterin ring of folic acid with quinazoline can be used as dihydrofolate reductase (dihydrofolate reductase, DHFR), thymidylate synthase (thymidylate synthase) , TS) inhibitors occupy an important position in antitumor drug research (Gangjee, A.; Jain, H.D.; Kurup, S. Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: Part II. Anti-Cancer Agent Me 2008, 8, 205-231.). DHFR and TS inhibitors in...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/517A61P35/00
CPCC07D403/04A61P35/00
Inventor 许兴智曹胜利王甫城彭斌任婷婷刘少鹏陈子昊杜净睿
Owner SHENZHEN UNIV
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