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Novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof

A metabolite and extraction technology, applied in drug combinations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of poor patient tolerance, high toxicity, and large individual differences in targeted drugs, and achieve good inhibition. Active, non-toxic effect

Active Publication Date: 2018-04-17
XIHUA UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these drugs have good clinical efficacy in the treatment of various tumors, the clinical use of cytotoxic drugs has been limited due to the shortcomings of high toxicity and poor patient tolerance; targeted drugs are usually also affected by individual differences. Large, serious drug resistance and other deficiencies can not achieve a very satisfactory clinical efficacy

Method used

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  • Novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof
  • Novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof
  • Novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The synthesis of embodiment 1 target compound

[0048] 1. Synthesis of Intermediate 2

[0049]

[0050] At 0°C, POCl 3 (9.2ml, 98.5mmol) was added dropwise to DMF (9.5ml, 123.1mmol), and after stirring for 0.5h, 5-nitro-1H-indole (compound 1, 2.0g, 12.3mmol) was added to the reaction solution, Then react at room temperature for 1.5h. Then the reaction solution was poured into a large amount of ice water and adjusted to pH 7 with 6N NaOH, then extracted with ethyl acetate (×3), and concentrated to obtain 2.34 g of gray solid with a yield of 98% and a purity of 95.2%. LCMS m / z:191.0[M+H] + .

[0051] 2. Synthesis of Intermediate 3

[0052]

[0053] Compound 2 (2.34g, 12.3mmol), di-tert-butyl dicarbonate (2.95g, 13.5mmol), and 4-dimethylaminopyridine (75.8mg, 0.62mmol) were added to 50ml of tetrahydrofuran, and reacted at room temperature After 3 hours, it was concentrated and recrystallized from ethyl acetate to obtain 3.3 g of a light yellow solid with a yiel...

experiment example 1

[0165] 1. Experimental materials

[0166] DMEM: DMEM medium

[0167] 10% FBS: Fetal Bovine Serum

[0168] DMSO: dimethyl sulfoxide

[0169] Experimental tumor cell lines: pancreatic cancer BxPC-3 cell line, normal human liver cells HL-7702

[0170] 2. Cell preparation and processing

[0171] First, the cell lines were inoculated into 96-well plates containing DMEM+10% FBS medium, at 37°C, 5% CO 2 conditions overnight. On the next day, add the compound to be tested at gradient concentrations diluted in the culture medium and a blank control for 72 hours, then add 20 μl of MTT reagent at a concentration of 5 mg / mL to each well, and continue to incubate for 2-4 hours. After the formation of formazan, the supernatant was sucked off, and then 150 μL of DMSO was added to each well, shaken to fully dissolve the formed formazan, and the absorbance value (OD570) at a wavelength of 570 nm was measured with a microplate reader.

[0172] Finally, according to the inhibition rate=(bl...

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Abstract

The invention discloses a novel 3,5-di-substituted 1H-indole derivative and synthesis and application thereof. The structural formula of the novel 3,5-di-substituted 1H-indole derivative is shown in formula 11, in the formula, R is selected from halogen, C1-C6 methyl, C1-C6 methoxyl, -OH, -COOH, -SO3H or -SO2NH2. The invention further provides a method for preparing the compound. The method has eight steps, the reaction yield of every step is higher than 60%, the reaction yields of four of the eight steps are higher than 90%, and the purities of all compounds are greater than 95%, and conformto purity required for later-period anti-tumor cell activity test. The prepared compound 11a-11h has good inhibition activity to pancreatic cell lines BxPC-3, wherein the activity of the compound as shown in formula 11 e is the best, IC50 reaches up to 2.28 mu mol / L, and the compound hardly has toxic or side effects to normal cells of people.

Description

technical field [0001] The present invention relates to a novel 3,5-disubstituted 1H-indole derivative and its synthesis and application. Background technique [0002] Cancer is the second leading cause of death after cardiovascular disease, accounting for nearly one in six deaths globally. In recent years, the morbidity and mortality of cancer are still rising. In 2015, there were about 4.292 million new cases of malignant tumors and 2.814 million deaths in my country, accounting for nearly 22% of new cases and 27% of deaths in the world. [0003] At present, the commonly used drugs for clinical treatment of malignant tumors mainly include traditional cytotoxic drugs, such as doxorubicin, 5-fluorouracil, cyclophosphamide, etc., and targeted drugs, such as sorafenib, gefitinib, crizotinib, etc. Ni and so on. Although these drugs have good clinical efficacy in the treatment of various tumors, the clinical use of cytotoxic drugs has been limited due to the shortcomings of hi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/4155A61P35/00
CPCC07D403/12
Inventor 杨羚羚晏婕苏荟琳王周玉钱珊王丽姣
Owner XIHUA UNIV
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