CN108084232B - A kind of glucokinase activators and its preparing the application in hypoglycemic medicine - Google Patents
A kind of glucokinase activators and its preparing the application in hypoglycemic medicine Download PDFInfo
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- CN108084232B CN108084232B CN201711457867.XA CN201711457867A CN108084232B CN 108084232 B CN108084232 B CN 108084232B CN 201711457867 A CN201711457867 A CN 201711457867A CN 108084232 B CN108084232 B CN 108084232B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
- C07H1/08—Separation; Purification from natural products
Abstract
The present invention relates to a kind of glucokinase activators and its preparing the application in hypoglycemic medicine, and in particular to the compound or its pharmaceutically acceptable salt of a kind of Formulas I for being isolated from radix rehmanniae recen, Formula II structure, it is characterised in that the Formulas I, Formula II structure are as follows:
Description
Technical field
The invention belongs to active ingredient of Chinese herbs to extract field, and in particular to a kind of glucokinase activators and its prepare
Application in hypoglycemic medicine.
Background technique
Glutinous rehmannia is the fresh or dried root of scrophulariaceae rehmannia glutinosa plant (Rehmannia glutinosa Libosch.),
Top grade is listed in Shennong's Herbal.It is divided on medicinal material according to concocting method: fresh rehmannia root, dried rehamnnia root and Rehmannia glutinosa, simultaneously
Its pharmacological property and effect also have biggish difference, and classify according to " China's book on Chinese herbal medicine " effect: fresh rehmannia root is heat-clearing drug；Rehmannia glutinosa is then
For tonic.Chemical component mainly has oligosaccharide, polysaccharide, iridoid glycoside, amino acid etc. in glutinous rehmannia, they are that glutinous rehmannia pharmacology is made
Material base.The present invention isolated two new glucoside compounds from radix rehmanniae recen, show stronger grape
Sugared kinase activation effect, and there is certain hypoglycemic effect.
Summary of the invention
The present invention provides the compound or its pharmaceutically acceptable salt of a kind of Formulas I for being isolated from radix rehmanniae recen, Formula II structure,
It is characterized in that the Formulas I, Formula II structure are as follows:
Another embodiment of the present invention provides the preparation method of above-mentioned Formulas I and Formula II compound, it is characterised in that including
Following steps:
(1) radix rehmanniae recen is taken, after being crushed to 20-80 mesh, obtains crude extract through SCF-CO 2；
(2) after the ethyl alcohol dissolution of 2-3 times of quality of the crude extract for obtaining step (1), by macroporous resin adsorption, body is used
Fraction is the ethanol elution of 50-70%, 3-5 times of column volume eluent is collected, after reduced pressure, then through Sephadex LH-20
Gel filtration chromatography, eluant, eluent are the CHCl that volume ratio is 1:13/ MeOH mixed solvent collects 2-3 times of column volume eluent, decompression
It after concentration, is prepared through high-efficient liquid phase chromatogram HPLC, successively obtains Formulas I, Formula II compound.
Supercritical CO described in step (1)2Extraction, extracting pressure 20-30MPa, extraction temperature are 45-50 DEG C, CO2
Flow is 50-55L/h, and extraction time 3-5h, separation reactor I temperature is 35-40 DEG C, pressure 7-10MPa, separation reactor I I temperature
It is 30-35 DEG C, pressure 5-6MPa.
The model of step (2) described macroreticular resin is selected from one of AB-8, D101, HZ818, HPD100.
The chromatographic condition of step (2) high-efficient liquid phase chromatogram HPLC preparation are as follows: chromatographic column be Agilent C18,9.4 ×
250mm, 7 μm, flow velocity 2mL/min, mobile phase MeOH: H2O=55: 45.
Another embodiment of the present invention provides above-mentioned Formulas I, Formula II compound or its pharmaceutically acceptable salt and is preparing
Application in hypoglycemic drug.
Another embodiment of the present invention provides above-mentioned Formulas I, Formula II compound or its pharmaceutically acceptable salt and is preparing
Application in hypoglycemic drug lead compound.
Another embodiment of the present invention provides above-mentioned Formulas I, Formula II compound or its pharmaceutically acceptable salt and is preparing
Application in hypoglycemic drug candidate.
Another embodiment of the present invention provides above-mentioned Formulas I, Formula II compound or its pharmaceutically acceptable salt and is preparing
The application in drug for preventing and/or treating the disease mediated by glucokinase.
Specific embodiment
For the ease of a further understanding of the present invention, examples provided below has done more detailed description to it.But
It is that these embodiments are only not supposed to be a limitation to the present invention or implementation principle for better understanding invention, reality of the invention
The mode of applying is not limited to the following contents.
Embodiment 1
(1) radix rehmanniae recen 1.0kg is taken, after being crushed to 20-80 mesh, through supercritical CO2Extract to obtain crude extract 45g；Wherein, it extracts
Pressure is 20MPa, and extraction temperature is 50 DEG C, CO2Flow is 50L/h, and extraction time 5h, separation reactor I temperature is 35-40 DEG C,
Pressure is 10MPa, and separation reactor I I temperature is 30-35 DEG C, pressure 6MPa.
(2) after the ethyl alcohol dissolution of 2 times of quality of the crude extract for obtaining step (1), by AB-8 type macroporous resin adsorption,
The ethanol elution for being 50% with volume fraction, collects 5 times of column volume eluents, after reduced pressure, then through Sephadex LH-20
Gel filtration chromatography, eluant, eluent are the CHCl that volume ratio is 1:13/ MeOH mixed solvent collects 2 times of column volume eluents, depressurizes dense
After contracting, prepare through high-efficient liquid phase chromatogram HPLC (chromatographic column is Agilent C18,9.4 × 250mm, 7 μm, flow velocity 2mL/min,
Mobile phase is MeOH: H2O=55: 45) Formulas I (19mg), Formula II compound (36mg) are successively obtained,.Structural identification data:
Compound of formula I:ESI-MS (m/z): 723.2 [M+H]+Formula II compound:
ESI-MS (m/z): 765.2 [M+H]+；
1 Formulas I of table, Formula II compound NMR data (1H/13C NMR 400/100MHz,CD3OD)
Embodiment 2
(1) radix rehmanniae recen 1.5kg is taken, after being crushed to 20-80 mesh, through supercritical CO2Extract to obtain crude extract 73g；Wherein, it extracts
Pressure is 30MPa, and extraction temperature is 45 DEG C, CO2Flow is 55L/h, and extraction time 3h, separation reactor I temperature is 35-40 DEG C,
Pressure is 7MPa, and separation reactor I I temperature is 30-35 DEG C, pressure 5MPa.
(2) after the ethyl alcohol dissolution of 3 times of quality of the crude extract for obtaining step (1), by D101 type macroporous resin adsorption,
The ethanol elution for being 70% with volume fraction, collects 3 times of column volume eluents, after reduced pressure, then through Sephadex LH-20
Gel filtration chromatography, eluant, eluent are the CHCl that volume ratio is 1:13/ MeOH mixed solvent collects 3 times of column volume eluents, depressurizes dense
After contracting, prepare through high-efficient liquid phase chromatogram HPLC (chromatographic column is Agilent C18,9.4 × 250mm, 7 μm, flow velocity 2mL/min,
Mobile phase is MeOH: H2O=55: 45) Formulas I (33mg), Formula II compound (59mg) are successively obtained,.Structural identification data and reality
It is consistent to apply example 1.
Embodiment 3
Testing in vitro formula I, glucokinase (GK) the activation effect of Formula II compound and EC50
According to the method recorded in patent CN102482267A (WO2011/013141), formula I, Formula II are tested
Close glucokinase (GK) the activation effect and EC of object50, the results show that Formulas I and Formula II compound are in DMSO under 1 μM of concentration
In GK activity be respectively 281.5% and 292.2%, EC50Respectively less than 0.1 μM.
Embodiment 4
The hypoglycemic effect of internal test formula I, Formula II compound
According to Chinese patent, (application number: the method recorded in 201410759327.7) tests formula I, Formula II
Object is closed to the hypoglycemic effect of diabetic mouse model, the results showed that after administration 2 hours, (dosage is for Formulas I, Formula II compound
Model mice blood glucose can 250mg/kg) be set to decline 63%.
Claims (4)
1. the compound or its pharmaceutically acceptable salt of a kind of Formulas I for being isolated from radix rehmanniae recen, Formula II structure, it is characterised in that institute
It is as follows to state Formulas I, Formula II structure:
2. Formulas I described in claim 1, Formula II compound or its pharmaceutically acceptable salt are preparing answering in hypoglycemic drug
With.
3. Formulas I described in claim 1, Formula II compound or its pharmaceutically acceptable salt are in preparing hypoglycemic drug candidate
Application.
4. Formulas I described in claim 1, Formula II compound or its pharmaceutically acceptable salt are in preparation for preventing and/or controlling
Treat the application in the drug of the disease mediated by glucokinase.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201711457867.XA CN108084232B (en) | 2017-12-27 | 2017-12-27 | A kind of glucokinase activators and its preparing the application in hypoglycemic medicine |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711457867.XA CN108084232B (en) | 2017-12-27 | 2017-12-27 | A kind of glucokinase activators and its preparing the application in hypoglycemic medicine |
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| CN108084232A CN108084232A (en) | 2018-05-29 |
| CN108084232B true CN108084232B (en) | 2019-10-01 |
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Citations (5)
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| CN101040851A (en) * | 2006-03-20 | 2007-09-26 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The use of dicaffeoylguinic acid ramification and the analog in the treatment of diabetes and the corresponding disease |
| CN102058712A (en) * | 2009-11-13 | 2011-05-18 | 上海玉森新药开发有限公司 | Rehmannia stem and leaf extract and preparation method and application thereof |
| CN102827215A (en) * | 2012-09-18 | 2012-12-19 | 南京泽朗医药科技有限公司 | Method for preparing jionoside A1 from purple rehmannia |
| CN103006878A (en) * | 2011-09-20 | 2013-04-03 | 玄振玉 | Fresh rehmannia root total glycoside extract, preparation method and application thereof |
| CN104666585A (en) * | 2015-03-16 | 2015-06-03 | 河南中医学院 | Application of radix rehmanniae leaf extract in preparation of blood glucose-reducing medicines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100475243C (en) * | 2007-07-18 | 2009-04-08 | 张玲 | Hypoglycemic, antilipenic and hemopathy-treating glutinous rehmannia extract and preparing method thereof |
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2017
- 2017-12-27 CN CN201711457867.XA patent/CN108084232B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101040851A (en) * | 2006-03-20 | 2007-09-26 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | The use of dicaffeoylguinic acid ramification and the analog in the treatment of diabetes and the corresponding disease |
| CN102058712A (en) * | 2009-11-13 | 2011-05-18 | 上海玉森新药开发有限公司 | Rehmannia stem and leaf extract and preparation method and application thereof |
| CN103006878A (en) * | 2011-09-20 | 2013-04-03 | 玄振玉 | Fresh rehmannia root total glycoside extract, preparation method and application thereof |
| CN102827215A (en) * | 2012-09-18 | 2012-12-19 | 南京泽朗医药科技有限公司 | Method for preparing jionoside A1 from purple rehmannia |
| CN104666585A (en) * | 2015-03-16 | 2015-06-03 | 河南中医学院 | Application of radix rehmanniae leaf extract in preparation of blood glucose-reducing medicines |
Non-Patent Citations (4)
| Title |
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| Chemical Constituents of Smilax china L. Stems and Their Inhibitory Activities against Glycation,Aldose Reductase, α-Glucosidase, and Lipase;Hee Eun Lee et al.;《Molecules》;20170311(第22期);第1-18页 * |
| Synthesis and antiproliferative activity of helonioside A, 3,4,6-tri-O-feruloylsucrose,lapathoside C and their analogs;Parthasarathi Panda et al.;《European Journal of Medicinal Chemistry》;20121027;第58卷;第418-430页 * |
| UPLC/ESI-Q-TOF MS法分析鲜地黄、生地黄、熟地黄的化学成分;张波泳 等;《中成药》;20160531;第38卷(第5期);第1104-1108页 * |
| 地黄化学成分与药理研究进展;李更生 等;《国外医学中医中药分册》;20041231;第26卷(第2期);第74-78,104页 * |
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