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(+/-) Uncarilins A and B, and pharmaceutical composition and application thereof

A composition and drug technology, applied in the field of medicine, can solve the problems of no compound pharmaceutical composition, no compound, etc.

Active Publication Date: 2017-08-18
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, there are no (-)‐uncarilin A (1a), (+)‐uncarilin A (1b), (-)‐uncarilin B (2a) and (+)‐uncarilin B (2b) reports in the prior art, and no compounds 1a / 1b or / and 2a / 2b as the report of the pharmaceutical composition of active ingredient, also do not have compound 1a / 1b or / and 2a / 2b pharmaceutical composition as melatonin receptor agonist, and treatment or improvement and melatonin Application report of hormone receptor-related central nervous system diseases

Method used

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  • (+/-) Uncarilins A and B, and pharmaceutical composition and application thereof
  • (+/-) Uncarilins A and B, and pharmaceutical composition and application thereof
  • (+/-) Uncarilins A and B, and pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of Compounds 1a / 1b and 2a / 2b:

[0026] Take the dried hooked stems and branches of Uncaria uncaria, crush them, extract twice with 90% ethanol under reflux, each time for 3 hours, combine the ethanol extracts, recover the ethanol under reduced pressure to obtain the extract. The extract was dissolved and adsorbed on silica gel with 80% ethanol, placed at room temperature to evaporate the solvent, ground and sieved, and subjected to silica gel column chromatography, followed by gradient elution with chloroform and chloroform-methanol (9:1). The fraction eluted with chloroform-methanol (9:1) was further subjected to silica gel column chromatography and eluted isocratically with petroleum ether-acetone (1:1) to obtain 4 components A-D. Component C was prepared by MCI CHP-20Pgel column under medium pressure, and eluted with acetonitrile-water gradient from 20:80 to 80:20 to obtain 5 fractions C-1-C-5. C‐2 was purified by sephadexLH‐20 column chromatography, elu...

Embodiment 2

[0028] Structural identification of compounds 1a / 1b and 2a / 2b:

[0029] Optical rotation was measured by Jascommodel 1020 polarimeter (Horiba, Tokyo, Japan); infrared spectrum (IR) was measured by KBr pellet method, and was measured by Bio-Rad FTS-135 infrared spectrometer (Hercules, California, USA); ultraviolet spectrum was measured by UV- 2401PC type ultraviolet spectrometer (Shimadzu, Kyoto, Japan) was measured; ECD spectrum was measured by Applied Photophysics circular dichroism spectrometer (Agilent, Santa Clara, United States); nuclear magnetic resonance spectrum (1D and 2D NMR) was measured by AVANCE III‐600 superconductor Nuclear magnetic resonance (Bruker, Bremerhaven, Germany) was used to measure deuterated methanol as solvent and TMS (tetramethylsilane) as internal standard; high-resolution mass spectrometry (HRMS) was performed with LCMS‐IT‐TOF mass spectrometer (Shimadzu, Kyoto, Japan). Japan) determination; TLC silica gel and column chromatography silica gel (20...

Embodiment 3

[0056] Compounds 1a / 1b and 2a / 2b on MT 1 and MT 2 Agonistic activity of the receptor.

[0057] 1 Materials and methods

[0058] 1.1 Materials:

[0059] MT 1 and MT 2 The cell lines used for activity screening correspond to human kidney epithelial cells HEK293‐MT 1 and HEK293‐MT 2 ; Cell culture medium (Dulbecco's Modified Eagle Medium, DMEM) containing 10% fetal bovine serum; Wash-free calcium flow kit.

[0060] 1.2 Instrument: CO 2 Constant temperature incubator Thermo Forma 3310 (USA); Inverted biological microscope XD‐101 (Nanjing); Flexstation 3 Benchtop Multi‐Mode Microplate Reader (MolecularDevices, Sunnyvale, California, USA).

[0061] 1.3 Experimental process

[0062] Spread the matrix BD Matrigel on the 96-well black-walled transparent bottom plate, and after 1 hour in a 37°C constant temperature incubator, draw the supernatant and divide it into 4×10 4 / well density, the corresponding cells were seeded in a 96-well black-walled transparent bottom plate, and...

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Abstract

The invention provides four isoechinulin dimers (-)-uncarilins A(1a), (+)-uncarilins A(1b), (-)-uncarilin B(2a) and (+)-uncarilins B(2b) as shown in a structural formula (I), a pharmaceutical composition formed by a therapeutically effective amount of compound 1a / 1b or 2a / 2b and a pharmaceutically acceptable carrier or excipient, a preparation method of the compound 1a / 1b or 2a / 2b and the pharmaceutical composition thereof, a melatonin receptor agonist and an application of the isoechinulin dimmers in treatment or improvement of central nervous system diseases related to a melatonin receptor.

Description

Technical field: [0001] The invention belongs to the technical field of medicines. Specifically, four isoechinulin dimers (-)-uncarilin A (1a), (+)-uncarilin A (1b), (-)-uncarilin B (2a) and (+)-uncarilin B (2b) were involved, to Compound 1a / 1b or / and 2a / 2b are active ingredients, used as melatonin receptor agonists, and for treating or improving central nervous system diseases related to melatonin receptors. Background technique: [0002] Melatonin (melatonin, MT) is an indole hormone secreted by the pineal gland. Its secretion has obvious circadian and seasonal rhythms. It plays a role in the body by activating specific melatonin receptors. Physiological activities such as aging and improving the body's immunity, in addition to regulating depression, anxiety and pain. Melatonin receptors including MT 1 , MT 2 and MT 3 Three subtypes, of which MT 1 and MT 2 The two subtypes belong to G protein-coupled receptors, with a total of 7 transmembrane segments, which have hi...

Claims

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Application Information

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IPC IPC(8): C07D487/10A61K31/499A61P25/00
CPCC07D487/10
Inventor 陈纪军耿长安黄晓燕马云保李天泽张雪梅
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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