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Compound, and preparation method and application thereof

A compound and low-level technology, applied in organic chemistry, drug combination, pharmaceutical formula, etc., can solve the problems of anti-cancer effect gap, ataxia, toxicity, etc., and achieve significant anti-cancer effect and good anti-cancer effect

Active Publication Date: 2020-06-12
辽宁孚音生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] And so far the best anticancer effect of PBTs compounds is the compound 21 (as shown in formula D) reported in the literature J.Med.Chem.2009, 52, 5262-5268, its anticancer effect (for lung cancer, Prostate cancer, breast cancer, and nasopharyngeal carcinoma cells have the best IC50 at 0.08 μM) or the anticancer effect of the azaphenanthrene and indolizidine alkaloid compound (-)-Antofine (as shown in formula D) There is a certain gap in the effect. The half inhibitory concentration (IC50) of (-)-antofine to lung cancer, prostate cancer, breast cancer, and nasopharyngeal cancer cells is the worst at 0.036 μM, but it is comparable to other phenanthroindolizidines. Alkaloids also exhibit CNS toxicity (eg, disorientation and ataxia)

Method used

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  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof
  • Compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Embodiment 1: the preparation of compound MA1

[0107]

[0108] 1.1 Preparation of compound 2A:

[0109] Add ethanol (10mL), compound 1A (1g), piperazine (1.06), and paraformaldehyde (0.37g) into the reaction flask in turn, add concentrated hydrochloric acid (0.5mL) while stirring, heat to 70°C, and stir until compound 1 After the reaction is complete, most of the ethanol is concentrated under reduced pressure, the solid is precipitated, filtered with suction, the solid is washed with methyl tert-butyl ether, the solid is dissolved in water, the pH value is adjusted to ≈8 by adding saturated sodium bicarbonate, and the extracted with base ether, combined the organic layers, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2A (1.12 g), which was directly cast down. LCMS(ESI): 261.1[M+H] + .

[0110] Add methanol (10mL), compound 1A (1g), piperazine (1.06), and paraformaldehyde (0.74g) into the reaction flask in sequenc...

Embodiment 2

[0121] Embodiment 2: the preparation of compound MB1

[0122]

[0123] 2.1 Preparation of Compound 4B:

[0124] When B is Br:

[0125] Add acetonitrile (100mL), compound 3B (10g), and piperazine (3.58g) into the reaction flask in sequence, heat to 80°C, stir until compound 3B reacts completely, cool down to room temperature, add saturated brine to wash, wash with anhydrous sulfuric acid Dry over sodium and concentrate under reduced pressure to obtain compound 4B (9.5 g), which is directly cast down. LCMS(ESI): 367.1[M+H] + . .

[0126]Add N,N-dimethylformamide (100mL), compound 3B (10g), piperazine (4.77g), and potassium carbonate (3.83g) into the reaction flask in sequence, heat to 70°C, and stir until the reaction of compound 3B is complete , filtered, washed with ethyl acetate, washed with saturated brine, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure...

experiment example 1

[0183] Experimental example 1: Determination of anti-tumor activity in vitro (MTT method)

[0184] In order to measure the in vitro antitumor activity of the compounds of the present invention, the compounds prepared in the examples of the present invention were determined, and the experimental steps are:

[0185] 1. Culture normal growth tumor cells with 1×10 4 The cells / mL were inoculated into a 96-well plate (100 μL per well), and incubated at 37° C. in a 5% CO2 incubator for 24 hours.

[0186] 2. Add the test compound respectively, and cultivate for 5 days in a 5% CO2, complete humidity incubator.

[0187] 3. Discard the culture medium, add 100 μL of 0.04% MTT to each well, and incubate under the same conditions for 4 hours.

[0188] 4. Abandon the culture medium, add DMSO (150 μL per well), mix and record the light absorbance colorimetrically at a measurement wavelength of 570 nm and a reference wavelength of 450 nm, and calculate the inhibitory rate of the compound on ...

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Abstract

The invention relates to a compound, and a preparation method and an application thereof. The compound is prepared by connecting sydnone with a PBTs compound. A pharmaceutical composition containing the compound and / or the pharmacologically acceptable salt thereof has the following advantages: the anticancer effect is obvious; compared with (-)-Antofine, the compounds have better anticancer effects, have no obvious toxicity to animals, also have antiviral activity, and can be used for preparing drugs for preventing and / or treating cancers and / or resisting viruses.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a compound and its preparation method and application. Background technique [0002] Azaphenanthrene-indolizidine and azaphenanthrene-quinolizidine alkaloids are a class of pentacyclic natural products isolated from plant families such as Romoaceae, Moraceae, Acanthaceae and Lauraceae. Since the first phenanthrene and indolizidine alkaloid, sylphine ((R)-tylophorine) (as shown in formula A), was isolated in 1935, numerous phenanthrene and indolizidine biological Bases are isolated or synthesized, and they have a wide range of biological activities, such as anti-cancer (anti-tumor), anti-leukemia, anti-inflammatory, anti-viral, anti-bacterial, anti-amoeba activities, etc. Among many biological activities, its unique Anticancer activity is of most interest. But at the same time, their toxicity to the central nervous system has largely influenced the development of s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D271/04A61K31/496A61K31/5377A61P35/00A61P31/18A61P31/14A61P31/20
CPCC07D413/12C07D271/04A61P35/00A61P31/18A61P31/14A61P31/20Y02P20/55
Inventor 莫岚刘文娟于鹏飞
Owner 辽宁孚音生物科技有限公司
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