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Preparation of substituted indole lactam derivative and application of substituted indole lactam derivative as antimalarial agent

A technology for products and compounds, applied in the field of biomedicine, can solve the problems of inability to obtain analogs effectively, long steps, and difficult synthesis.

Inactive Publication Date: 2012-07-18
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the novelty of this structure, due to the multi-substitution and ring structure on the indole ring, the synthesis is difficult and the steps are long (20 steps of chemical reactions are required), so the yield is very low (Eur.J.Org.Chem.2007, 237-240 , J.Am.Chem.Soc.2008, 130, 16854-16855), so analogs cannot be obtained effectively, so as to conduct more in-depth research on the relationship between structure and activity and the mechanism of action

Method used

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  • Preparation of substituted indole lactam derivative and application of substituted indole lactam derivative as antimalarial agent
  • Preparation of substituted indole lactam derivative and application of substituted indole lactam derivative as antimalarial agent
  • Preparation of substituted indole lactam derivative and application of substituted indole lactam derivative as antimalarial agent

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Compound 1: In tetrahydrofuran (3 mL) solvent, add the corresponding bromide (642 mg, 3.0 mmol), sodium trichloroacetate (835 mg, 4.5 mmol) and tetrabutylammonium bromide (96 mg, 0.3 mmol). The mixture was reacted at 60°C for 24 hours. Then the mixture was added with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to obtain the corresponding compound 1 (713 mg, 60%).

[0035] 1 H NMR(400MHz, CDCl 3 )d 6.69-6.88(m, 6H), 5.98(s, 2H), 5.94(s, 2H), 5.17(s, 2H), 3.62(s, 2H);

[0036] 13 C NMR(100MHz, CDCl 3 )d165.5, 148.1, 147.9, 147.4, 147.3, 127.9, 126.6, 124.7, 122.8, 111.3, 109.2, 108.3, 107.9, 101.3, 101.1, 84.0, 69.3, 50.2;

[0037] HRMS(ESI)m / z calcd for C 18 H 14 Cl 2 NaO 6 (M+Na) + 419.0060; found 419.0067.

Embodiment 2

[0039]

[0040] Compound 2: Dissolve compound 1 (486mg, 1.0mmol) in H 2 O / THF (1 / 3, 12 mL), then NaOH (120 mg, 3.0 mmol) was added. The mixture was reacted at room temperature for 3 hours. Then spin off part of the solvent, add 50ml of water to the remaining mixture; then wash twice with dichloromethane, discard the dichloride layer, the resulting aqueous layer is acidified with 1M hydrochloric acid solution to make the solution pH less than 5, and then add ethyl acetate After extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was removed by rotating to obtain the desired product 2 (249 mg, 95%). Can be used directly without further purification.

[0041] 1 H NMR(400MHz, acetone-d 6 )d 6.91 (d, J = 1.6 Hz, 1H), 6.88 (dd, J = 8.0, 1.6 Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.99 (s, 2H), 3.69 (s , 2H);

[0042] 13 C NMR(100MHz, acetone-d 6 )d167.9, 149.1, 149.0, 129.2, 126.5, 113.0, 109.4, 102.9, 86.8, 51.4;

[0043] HRM...

Embodiment 3

[0045]

[0046] Compound 3: Compound 2 (157mg, 0.6mmol) was dissolved in treated DMF / CH 2 Cl 2 (1 / 5, 6mL) solution, then add HOBt (88mg, 0.65mmol), HBTU (246mg, 0.65mmol), 5-hydroxytryptamine hydrochloride (106mg, 0.5mmol) and DIPEA in ice bath conditions (134μL / 0.75mmol). The reaction solution was gradually warmed to room temperature, and then stirred at room temperature for 24 hours. Part of the solvent was spun off under reduced pressure, then diluted acidic water was added, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by column chromatography to obtain the desired compound 3 (185 mg, 88%).

[0047] 1 H NMR(400MHz, acetone-d 6 )d 9.74 (br s, 1H), 7.93 (br s, 1H), 7.65 (s, 1H), 7.19 (d, J=8.8Hz, 1H), 7.01 (d, J=2.4Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.89 (d, J = 1.6 Hz, 1H), 6.84 (dd, J = 8.0, 1.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.71 (dd, J=8.8, 2.4 Hz, 1H), 5.97 (s, 2H), 3.69 (s, 2H), 3.52 (m, 2H), 2.86 ...

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Abstract

The invention designs an efficient synthesis method for preparing a compound shown as a general formula (I) and an application of a derivative of the compound to the research and development of an antimalarial active medicament. The method comprises the following steps of: dissolving a reactant into an appropriate solvent; and reacting under the irradiation condition of a high-voltage mercury lamp (ultraviolet lamp). In the method disclosed by the invention, a series of poly-substituted indole lactam compounds taking 3,4,5-trisubstituted indole as a basic framework are efficiently synthesized with a one-pot method under an illumination condition, so that the defects of complex steps, difficulty in operating and low total yield existing in synthesis of the type of compounds under the condition of the prior art are overcome. Derivatives containing different substituted functional groups are obtained only through a four-step reaction, and the type of compounds has potential antimalarial activity, so that necessary material bases are provided for the researches of active screening, acting mechanisms and structure-activity relationships of a large quantity of analogues, and the type of compound can possibly become a new type of antimalarial candidate medicament. The general formula (I) is shown in the specifications.

Description

Technical field [0001] The invention relates to a preparation method of a multi-substituted indololactam derivative characterized by 3,4,5-tri-substituted indole and its use as an antimalarial agent in the research and development. The invention belongs to the field of biomedicine. Background technique [0002] Malaria is a global acute parasitic disease that is caused by Plasmodium and is transmitted by Anopheles mosquitoes. There are 4 species of Plasmodium that infect humans, namely Plasmodium falciparum, Plasmodium vivax, Plasmodium vivax and Plasmodium ovale. Among them, Plasmodium falciparum is the main pathogen of malaria in sub-Saharan Africa, and it is also the Plasmodium causing the highest mortality in patients. The life history of Plasmodium is very complicated. The spore stage of Plasmodium enters the human body through mosquito bites, first invades the liver, and matures into schizonts in the liver cells. As the liver cells burst, the released merozoites enter the...

Claims

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Application Information

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IPC IPC(8): C07D491/16C07D487/04A61K31/407A61P33/06
CPCY02A50/30
Inventor 覃华贾彦兴
Owner PEKING UNIV
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