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Aromatic ring ureidindole derivatives and their preparation methods and applications

A technology of aromatic ring ureidindole derivatives and alkyl groups, which is applied in the field of aromatic ring ureidindole derivatives and their preparation, can solve the problems of low overall yield, poor stability, and long steps in the synthesis route, and achieve improved Sensitivity, reversal of drug resistance, and simple synthetic route

Active Publication Date: 2020-10-30
SUN YAT SEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

John D and others synthesized compounds Ko132, Ko134, and Ko143 with similar structures to fumagillin C, among which Ko143 is currently the best ABCG2 reversal agent, and the reversal effect is 10 times higher than that of fumagillin C, but follow-up studies found that Ko143 It is poorly stable in mouse plasma, and the synthesis route of this type of compound has long steps and low overall yield, which is difficult to meet the needs of research and application. The specific reaction process is as follows:

Method used

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  • Aromatic ring ureidindole derivatives and their preparation methods and applications
  • Aromatic ring ureidindole derivatives and their preparation methods and applications
  • Aromatic ring ureidindole derivatives and their preparation methods and applications

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preparation example Construction

[0019] The present invention also provides a preparation method of aromatic ring ureidindole derivatives, comprising:

[0020] The compound of formula (II) structure and the compound of formula (III) structure are reacted, obtain the compound of formula (I) structure,

[0021]

[0022] where the R 1 , R 2 are independently selected from hydrogen, C1-C8 alkyl or C1-C8 alkoxy.

[0023] According to the present invention, the present invention reacts the compound of formula (II) structure and the compound of formula (III) structure, obtains the compound of formula (I) structure, wherein, the compound of described formula (II) structure and described formula (III) The molar ratio of the compound of ) structure is preferably 1: (0.9~1.1), more preferably 1: 1; The auxiliary agent of described reaction is preferably triethylamine; The solvent of described reaction is preferably ethanol, methanol and propanol One or more of them; the reaction is preferably carried out at room t...

Embodiment 1

[0033] Synthesis of Intermediate Compounds II-3, II-4

[0034] In a 25 mL double necked round bottom flask, add 2 mL of Na 2 CO 3 solution (1mol / L), 5mL of Toluene-C 2 h 5 OH (v / v, 1:1), 1.0mmol of IV-1 or IV-2, 2.0mmol of 3-aminophenylboronic acid-hydrate, 0.05mmol of Pd(PPh 3 ) 4 , remove the O in the system by vacuuming 2 , N 2Reflux reaction at 80°C under protection until the reaction of raw materials is complete. The reaction solution was cooled, filtered with suction, and the filtrate was collected, dried, and column chromatographed to obtain compound II-3 (yield 78.3%) or II-4 (yield 72.9%).

Embodiment 2

[0036] The synthetic method of target compound I-a~I-d

[0037] Synthesis of Compound I-a

[0038] In a 25 mL double necked round bottom flask, add 1.0 mmol of II-3, 1.0 mmol of III-c, 3.0 mmol of Et 3 N, 10 mL of C 2 h 5 OH, react at room temperature, and stop the reaction until the conversion of raw materials is complete. The reaction solution was concentrated and dried, and 224 mg of the product was obtained by column chromatography, with a yield of 57.8%.

[0039] Compound I-a provided by the invention is a white solid, molecular formula C 23 h 21 N 3 o 3 , molecular weight 387.15829. Chinese name 1-(3-(1H-indol-5-yl)phenyl)-3-(2,4-dimethoxyphenyl)urea, English: 1-(3-(1H-indol-5 -yl)phenyl)-3-(2,4-dimethoxyphenyl)urea; 1 H NMR (400MHz, Acetone-d 6 )δ10.26(s, 1H), 8.58(s, 1H), 8.12(d, J=8.9Hz, 1H), 7.89(t, J=1.9Hz, 1H), 7.81(dd, J=1.8, 0.9 Hz, 1H), 7.67(s, 1H), 7.50-7.36(m, 3H), 7.34-7.21(m, 3H), 6.58-6.43(m, 3H), 3.82(s, 3H), 3.73(s, 3H); 13 C NMR (100MHz, Ac...

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Abstract

The invention provides an aromatic-ring ureido indole derivative and a preparation method and application thereof. The aromatic-ring ureido indole derivative with a structure shown in formula (I) cansignificantly improve the sensitivity of drug-resistant tumor cells to an anti-tumor drug Mitoxantrone, can well reverse the drug resistance of the tumor cells mediated by ABCG2, and has the potentialto become a novel ABCG2 tumor drug-resistant reversal agent drug; the synthetic route is simple and clear, a target product can be obtained simply through two steps of reactions, and no complicated operation is needed.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an aromatic ring ureidindole derivative, a preparation method and application thereof. Background technique [0002] Tumor drug resistance is one of the main reasons for clinical chemotherapy failure. According to reports, more than six million people die from cancer every year in the world, and more than half of the deaths occur in developing countries. Although the research on tumor treatment continues to advance, less than 50% of tumors are sensitive to chemotherapeutic drugs, and more than 50% of tumors rapidly develop resistance to chemotherapeutic drugs. Once drug resistance occurs, the treatment will be directly ineffective. Drugs, the patient is likely to die as a result. Therefore, it has important theoretical value and potential application prospect to find and develop drugs that can reverse tumor drug resistance. [0003] There are many factors that cause tumor ce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08A61P35/00
CPCA61P35/00C07D209/08
Inventor 汪波叶高杰陈哲生蔡超云谢敏利程小宁
Owner SUN YAT SEN UNIV
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