7-fluoro-substituted Isaindigotone derivatives and preparation method thereof, and application of 7-fluoro-substituted Isaindigotone derivatives in preparing anticancer drugs

A derivative and hydroxyl technology, applied in the 7-position fluorine substituted Isaindigotone derivative and its preparation, the application field in the preparation of anti-cancer drugs, to achieve the effect of inhibiting proliferation and widely anti-tumor

Active Publication Date: 2016-12-14
SUN YAT SEN UNIV
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

Patent CN101250189A has disclosed a kind of difatty amino-substituted quinazolones derivatives and its preparation method and its application as anticancer drugs; However, there are very few above-mentioned Isaindigotone derivatives targeting NM23-H2 protein at present, so it is urgent to develop a new class of Isaindigotone derivatives targeting NM23-H2 protein

Method used

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  • 7-fluoro-substituted Isaindigotone derivatives and preparation method thereof, and application of 7-fluoro-substituted Isaindigotone derivatives in preparing anticancer drugs
  • 7-fluoro-substituted Isaindigotone derivatives and preparation method thereof, and application of 7-fluoro-substituted Isaindigotone derivatives in preparing anticancer drugs
  • 7-fluoro-substituted Isaindigotone derivatives and preparation method thereof, and application of 7-fluoro-substituted Isaindigotone derivatives in preparing anticancer drugs

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: the synthesis of compound m1

[0078]

[0079] Put 2-amino-4,5-difluorobenzoic acid (5g, 29mmol) and 2-pyrrolidone (5mL) into a 100mL single-necked flask, and add 20mL of phosphorus oxychloride (POCl3) dropwise under stirring in an ice bath to make After 30 minutes of dripping, heat and reflux at 103°C for 24 hours, add the reaction system dropwise to 200mL of ice water, adjust the pH to weak alkaline with concentrated NaOH solution, and filter with suction to obtain the crude product, which is purified by silica gel column chromatography (eluent: V (Petroleum ether): V (ethyl acetate) = 1:1) to obtain compound m1, 5.4 g, yield 85%.

[0080] 1 H NMR (400MHz, CDCl 3 )δ8.20–7.85(m,1H),7.60–7.34(m,1H),4.42–4.06(m,2H),3.19(td,J=7.9,2.7Hz,2H),2.43–2.16(m, 2H).LC-MS m / z:223[M+H] +.

Embodiment 2

[0081] Embodiment 2: the synthesis of compound m2

[0082]

[0083] Take compound m1 (2.22g, 10mmol) and diethylaminopropylamine (3ml, 24mmol) in a thick-walled pressure-resistant bottle, heat and stir at 100°C overnight to obtain an orange-yellow solution. After the reaction system cools down to room temperature, a large amount of pale A yellow precipitate was precipitated, and 20 ml of diethyl ether was added to the reaction system to further precipitate the solid. After suction filtration, the filter cake was obtained as a milky white solid, which was vacuum-dried to obtain 2.3 g of milky white powder, with a yield of 69%.

[0084] 1 H NMR (400MHz, CDCl 3 )δ7.72(d,J=11.7Hz,1H),6.72(s,1H),6.67(d,J=7.7Hz,1H),4.19–4.12(m,2H),3.31(dd,J=10.6 ,5.8Hz,2H),3.11(t,J=7.9Hz,2H),2.63–2.59(m,2H),2.55(q,J=7.1Hz,4H),2.30–2.19(m,2H),1.89 –1.81(m,2H),1.06(t,J=7.1Hz,6H).

Embodiment 3

[0085] Embodiment 3: the synthesis of compound m3

[0086]

[0087] According to the synthesis method of m2, 2.1 g of light yellow solid was obtained with a yield of 66%. 1 H NMR (400MHz, CDCl 3 )δ7.67(d,J=11.7Hz,1H),6.63(d,J=7.7Hz,1H),4.12–4.05(m,2H),3.24(dd,J=11.6,6.3Hz,2H), 3.04(t, J=7.9Hz, 2H), 2.37(t, J=6.4Hz, 4H), 2.19(s, 6H), 1.77(dt, J=12.8, 6.2Hz, 2H).

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and particularly discloses 7-fluoro-substituted Isaindigotone derivatives. The structural formula of the derivatives is disclosed as Formula (I) or Formula (II), wherein X is C or N; R1 is hydrogen, amino, substituted amino, orpenta- or hexa-heterocyclic radical; R2 is hydrogen, hydroxy, amino, C1-C8 alkyl, or C1-C8 alkoxy or halo; R3, R5 and R6 are defined the same as R2; and R4 is hydrogen, hydroxy, amino, phenyl, C1-C8 cycloalkyl, C1-C8 alkyl, C1-C8 alkoxy, C1-C6 alkyl acyloxy, C1-C6 alkynyl, halo, or penta- or hexa-heterocyclic radical. The fluoro-substituted Isaindigotone derivatives can bebondedwith NM23-H2 protein and block the interaction between the NM23-H2 protein and c-myc G-quadruplex DNA, thereby causing the reduction of protooncogene c-myc transcription and translation, and inhibiting the proliferation of multiple tumor cell strains. The fluoro-substituted Isaindigotone derivatives have wide antitumor effects. The fluoro-substituted Isaindigotone derivatives are a novel NM23-H2-protein-targeted transcription regulation blocker, and have wide application space in preparing anticancer drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a 7-position fluorine-substituted Isaindigotone derivative, its preparation method and its application in the preparation of anticancer drugs. Background technique [0002] Malignant tumors are a large class of diseases that endanger human health. According to the World Health Organization (WHO), 8 million people die of cancer every year in the world, and nearly 2 million people die of cancer every year in China. Although the drug treatment of tumors has made great progress, and has become an indispensable main measure of current clinical treatment. However, problems such as high toxicity and side effects and drug resistance are still the main obstacles to clinical tumor drug treatment. The international medical community regards the development of innovative anti-tumor drugs with new targets and targeted therapy as a new hope for changing the status quo of can...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D221/16A61P35/00
CPCC07D221/16C07D487/04
Inventor 黄志纾谭嘉恒王玉青
Owner SUN YAT SEN UNIV
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