CN1381463A - Magnesium isoglycyrrhetate and its preparing process and usage - Google Patents
Magnesium isoglycyrrhetate and its preparing process and usage Download PDFInfo
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- CN1381463A CN1381463A CN 02111693 CN02111693A CN1381463A CN 1381463 A CN1381463 A CN 1381463A CN 02111693 CN02111693 CN 02111693 CN 02111693 A CN02111693 A CN 02111693A CN 1381463 A CN1381463 A CN 1381463A
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- Prior art keywords
- magnesium
- acid
- isoglycyrrhetate
- isoglycyrrhiza
- potenlini
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- 239000011777 magnesium Substances 0.000 title claims abstract description 37
- 229910052749 magnesium Inorganic materials 0.000 title claims abstract description 37
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims description 5
- 230000008569 process Effects 0.000 title description 2
- 239000002253 acid Substances 0.000 claims abstract description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims description 26
- 150000004702 methyl esters Chemical class 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000012535 impurity Substances 0.000 claims description 6
- 238000006317 isomerization reaction Methods 0.000 claims description 5
- 208000019423 liver disease Diseases 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- OGWLTJRQYVEDMR-UHFFFAOYSA-F tetramagnesium;tetracarbonate Chemical compound [Mg+2].[Mg+2].[Mg+2].[Mg+2].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O OGWLTJRQYVEDMR-UHFFFAOYSA-F 0.000 claims description 4
- 229930182470 glycoside Natural products 0.000 claims description 3
- 159000000003 magnesium salts Chemical class 0.000 claims description 3
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 claims description 3
- -1 pyrans glycosides Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 150000002680 magnesium Chemical class 0.000 claims description 2
- 239000012452 mother liquor Substances 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 abstract 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 abstract 1
- 239000001095 magnesium carbonate Substances 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 230000003472 neutralizing effect Effects 0.000 abstract 1
- 206010067125 Liver injury Diseases 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 102000003929 Transaminases Human genes 0.000 description 7
- 108090000340 Transaminases Proteins 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 6
- 231100000012 chronic liver injury Toxicity 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 231100000572 poisoning Toxicity 0.000 description 5
- 230000000607 poisoning effect Effects 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000009466 transformation Effects 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 102000009027 Albumins Human genes 0.000 description 4
- 108010088751 Albumins Proteins 0.000 description 4
- 101710092506 Aspartate aminotransferase Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 101710101107 Probable aspartate aminotransferase Proteins 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000002574 poison Substances 0.000 description 4
- 231100000614 poison Toxicity 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 231100000234 hepatic damage Toxicity 0.000 description 3
- 206010019692 hepatic necrosis Diseases 0.000 description 3
- 230000007866 hepatic necrosis Effects 0.000 description 3
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 3
- 210000005229 liver cell Anatomy 0.000 description 3
- 230000008818 liver damage Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 2
- SQVRNKJHWKZAKO-PFQGKNLYSA-N N-acetyl-beta-neuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-PFQGKNLYSA-N 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 231100000439 acute liver injury Toxicity 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000004761 fibrosis Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 108010074605 gamma-Globulins Proteins 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010019668 Hepatic fibrosis Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000334 hepatotoxic Toxicity 0.000 description 1
- 230000003082 hepatotoxic effect Effects 0.000 description 1
- 230000005745 host immune response Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
A novel compound, magnesium isoglycyrrhetate, whose chemical formula is 18 alpha, 20 beta-carboxyl-11-oxide-n-oleanane-12-ene-3 beta-yl-2-O-beta-D-glycopyranose aldehydic acid-alpha-D-glycopyranoside magnesium aldehydate, is prepared through putting the isomerized product into methanol, adding small amount of dewatering agent, quickly educing out methyl isoglycyrrhetate, filtering, hydrolyzing in alkali solution, adding acif ro neutralizing, extracting by n-butanol to obtain the refined isoglycyrrhinic acid, and adding alkaline magnesium carbonate. It can be used for treating hepatism.
Description
The present invention relates to a kind of a kind of new compound magnesium isoglycyrrhetate and production method and purposes that can be applicable to liver disease.
Magnesium isoglycyrrhetate is the magnesium salts of pentacyclic triterpenoid, and chemistry is by name: 18 α, and 20 β-carboxyl-11-oxidation-positive volatile oil-12-alkene-3 beta-yls-2-o-β-D-glucopyanosyl aldehydic acid base-α-D-grape pyrans glycosides aldehydic acid magnesium, chemical structure is:
Magnesium isoglycyrrhetate can obtain by the Isoglycyrrhiza acid after chemical reaction, contain the Isoglycyrrhiza acid of trace in natural high-quality Radix Glycyrrhizae rhizome, but content is atomic, should not directly extract making.
Isoglycyrrhiza acid can obtain by the Potenlini isomerization reaction, because the physico-chemical property of Isoglycyrrhiza acid and natural Potenlini exactly likes, preparation technology in the past often exists a large amount of impurity (pigment, tannin, flavones and Potenlini homologue) and natural Potenlini, be difficult for removing, bring very big difficulty for the single Isoglycyrrhiza acid of preparation.Adopting rational technology, remove impurity effectively, and improve the transformation efficiency of natural Potenlini, is the key of preparation Isoglycyrrhiza acid.
Generally be by the alkali isomerization reaction natural Potenlini occurred conformation to be transformed to form Isoglycyrrhiza acid in the prior art, transformation efficiency is 60～70%, extract with hexanol again, recrystallizing methanol, resulting product is the mixture of Potenlini steric isomer, in mixture, except that containing unconverted natural Potenlini, still have the degradation production in the base catalyzed reactions.Carry out base catalyzed reactions repeatedly and can obtain the higher Isoglycyrrhiza acid of purity, transformation efficiency is about 90%, but product yield is very low.Because this technology can not obtain single Isoglycyrrhiza acid, has used a large amount of hexanols, methyl alcohol in the technology again, complex process exists three-waste pollution, and problems such as cost costliness have been brought many difficulties to suitability for industrialized production.
The objective of the invention is for a kind of new compound Isoglycyrrhiza acid salt being provided and solving the deficiencies in the prior art in the production link that above-mentioned need use and a kind of transformation efficiency that improves natural Potenlini is provided, obtain that more economical practicality, technology are simple, the production method of high-quality magnesium isoglycyrrhetate and be used for liver disease.
In order to achieve the above object, a kind of magnesium isoglycyrrhetate provided by the invention is the magnesium salts of pentacyclic triterpenoid, chemistry is by name: 18 α, 20 β-carboxyl-11-oxidation-positive volatile oil-12-alkene-3 beta-yls-2-o-β-D-glucopyanosyl aldehydic acid base-α-D-grape pyrans glycosides aldehydic acid magnesium, chemical structure is:
Its production method is easily to form the characteristic that methyl esters is separated out according to Isoglycyrrhiza acid in methyl alcohol, and the alkali isomerization reactor product is dropped in the methyl alcohol, adds a small amount of dewatering agent, and the Isoglycyrrhiza acid methyl esters is separated out very soon, filters, and promptly obtains high purity Isoglycyrrhiza acid methyl esters.Natural Potenlini and impurity can not separated out in mother liquor, thereby Isoglycyrrhiza acid is almost completely separated with impurity with unconverted Potenlini.According to the character of Isoglycyrrhiza acid methyl esters facile hydrolysis, hydrolysis in alkali lye adds the acid neutralization again, makes the Isoglycyrrhiza acid elaboration with the method for n-butanol extraction, adds the magnesium basic carbonate formation magnesium isoglycyrrhetate of calculated amount at last.
This magnesium isoglycyrrhetate can be used for liver disease.
Magnesium isoglycyrrhetate provided by the invention, prove through a large amount of pharmacology, Biochemical Research, it causes in the model of liver injury at the different hepatotoxic agents of animal, can obviously stop the animal serum transaminase to raise, alleviate hepatocellular degeneration, necrosis and inflammatory cell infiltration, and promoting the liver cell regeneration effect, the anti-liver injury effect of magnesium isoglycyrrhetate obviously is better than natural Potenlini.
Make magnesium isoglycyrrhetate with present method, the transformation efficiency that technology is simple, improved natural Potenlini has reduced production cost, has improved quality product and yield, and it has very active operation significance to the treatment of human hepatopathy.
The present invention is further described by the following embodiment: example 1:
Weighing sodium hydroxide 640g drops in the retort, add water 4200ml and be dissolved into high alkali liquid (4mol/L), add monoammonium glycyrrhizinate 840g (1mol) stirring and dissolving, normal pressure reflux 8 hours, reaction solution is chilled to room temperature, adds hydrochloric acid and transfers pH2～3, sedimentation and filtration, be washed to pH4～5, drying gets Potenlini stereoisomer mixture 672g.
Get " mixture " 672g (0.82mol), add methyl alcohol 5L, under stirring at room, carefully add acetyl chloride 250ml (3.2mol), continue to stir 30 minutes, room temperature is placed and is spent the night, and filters, and dries, and is the Isoglycyrrhiza acid methyl esters, and yield is 55%.
Get Isoglycyrrhiza acid methyl esters 370g, hydro-oxidation potassium solution (3mol/L) 900ml.Reflux is to solution becomes clear (about 3 hours), puts coldly, adds dilute sulphuric acid to pH3.0, uses n-butanol extraction.After propyl carbinol reclaimed, residue added 90% Glacial acetic acid thermosol, and room temperature is placed, and filtered, and must make with extra care Isoglycyrrhiza acid 315g after the drying, and yield is 85%.
To make with extra care Isoglycyrrhiza acid and be dissolved in 70% Virahol, and add the magnesium basic carbonate of calculated amount, boiling water bath is back to no CO
2Produce, a small amount of insolubles of cold slightly back elimination, filtrate placement is spent the night, and filters, and washes crystallization with Virahol, drains, and dries productive rate: 295g (94%).
(50%C
2H
5OH, 1%) E
1cm119.1 (50%C
2H
5OH, 1%) determination of elemental analysis value (%) calculated value (%) C 54.84 54.88H 7.73 7.62Mg 2.637 2.640
Example 2:
Take by weighing the Potenlini stereoisomer mixture 412g (0.5mol) that the alkali isomerization reaction obtains, add methyl alcohol 1.0L, chloroform 2.0L, vitriol oil 16ml (0.3mol), reflux 4 hours, tell organic layer after cold, wash with water to pH4～5, add anhydrous sodium sulfate drying and spend the night, distillation, get resistates 173g, yield is 42%.
Get above resistates, hydro-oxidation potassium solution (3mol/L) 500ml.Reflux is clear to solution becomes, puts coldly, adds dilute sulphuric acid to pH3.0, uses n-butanol extraction.Reclaim propyl carbinol, residue adds 90% Glacial acetic acid thermosol, and room temperature is placed, and filters, and drying must be made with extra care Isoglycyrrhiza acid 151g, and yield is 87%.
Get refining Isoglycyrrhiza acid and be dissolved in 70% Virahol, add the magnesium basic carbonate of calculated amount, boiling water bath is back to no CO
2Produce, a small amount of insolubles of cold slightly back elimination, filtrate placement is spent the night, and filters, and washes crystallization with Virahol, drains, and dries productive rate: 140g (93%).
(50%C
2H
5OH, 1%) E
1cm120.5 (50%C
2H
5OH, 1%) determination of elemental analysis value (%) calculated value (%) C 54.80 54.88H 7.74 7.62Mg 2.657 2.640
Below be pharmacodynamics of the present invention and toxicity test
Table 1 causes the validity of rat acute liver injury to D-Gal for magnesium isoglycyrrhetate.Test shows that dosage is mouse iv LD
501/23 (table 6) can suppress obviously that serum transaminase increases and hepatic necrosis, be dosage and rely on, and be better than the natural Potenlini of same dose.
Table 2, table 3 cause the therapeutic action of rat chronic liver injury to tetracol phenixin for magnesium isoglycyrrhetate.Test shows that dosage is mouse iv LD
501/39 (table 6) can obviously suppress the progress of chronic hepatic injury, and serum transaminase is reduced, and albumin increases, and suppresses the level of serum sialic acid, hyaluronic acid and hepatic tissue oxyproline, and is the dosage dependence.Can illustrate that from histology fibrosis (S) this product has provide protection to chronic hepatic injury, the hepatic fibrosis that chronic hepatic injury is taken place has restraining effect, and these effects obviously are better than the natural Potenlini of same dose.
Table 4, table 5 bring out the therapeutic action of black mouse immune liver damage to D-Gal (Gal) the full adjuvant of coupling Fu Shi (FCA) for magnesium isoglycyrrhetate.Test shows that this product dosage is iv LD
501/11 (table 6) can obviously reduce black mortality of mice, suppress that serum transaminase increases, gamma globulin level and blood plasma nitric oxide concentration, and can improve the liver cell metabolic disturbance, promote albumin synthetic, and be dosage and rely on.The test prompting, this product has good efficacy to the chronic hepatitis that host immune response forms, and also is better than the natural Potenlini of same dose.
Table 1, magnesium isoglycyrrhetate cause the therapeutic action test group dosage animal serum transaminase hepatic tissue of rat acute liver injury to D-Gal
(mg/kg) count AlaAT (IU/L) AspAT (IU/L) hepatic necrosis number
The Δ Δ
(only) x ± s x ± s x ± s
-Normal control PSS
Δ10 85 ± 19 287 ± 44 0 poison contrasts PSS
Δ10 6931 ± 913 8003 ± 1,379 84 ± 42 magnesium isoglycyrrhetates 25 10 4320 ± 1036
* *5521 ± 1943
* *55 ± 20
*
50 10 3273±1347
***?3267±1369
***44±16
***
100 10 2104 ± 1080
* *2804 ± 1416
* *40 ± 15
* *Natural Potenlini
Δ Δ Δ50 10 4507 ± 1019
* *5257 ± 1477
* *69 ± 17
* Δ: physiological saline
The Δ Δ: the average hepatic necrosis number of each high power field, each high power field normal liver cell number is 300
Δ Δ Δ: monoammonium glycyrrhizinate
*P＞0.05;
*P＜0.05;
* *Compare with the poisoning control group P＜0.01.AlaAT: gpt; AspAT: glutamic-oxal(o)acetic transaminase
Table 2 magnesium isoglycyrrhetate causes the therapeutic action test group dosage number of animals seroenzyme serum protein of rat chronic liver injury to tetracol phenixin
(mg/kg) (only) AlaAT (IU/L) AspAT (IU/L) albumin (g/L)
X ± s x ± s x ± s normal control PSS
Δ10 82 ± 19 299 ± 34 45 ± 4.9 models contrast PSS
Δ10 5002 ± 1,801 8603 ± 2,153 28 ± 1.3 magnesium isoglycyrrhetates 15 10 3100 ± 1501
*6053 ± 2410
*32 ± 1.1
* *
30 10 2847±1380
*** 4390±1867
*** 34±2.7
***
60 10 1536 ± 829
* *3505 ± 1778
* *36 ± 2.1
* *Natural Potenlini 60 10 2893 ± 1299
* *5171 ± 1826
* *32 ± 1.5
* * Δ: physiological saline
*P＜0.05;
* *Compare with the poisoning control group P＜0.01
Table 3 magnesium isoglycyrrhetate causes the therapeutic action test group dosage number of animals serum liver tissue of rat hepatocirrhosis to tetracol phenixin
(mg/kg) (only) NANA HA Hyp S
(μ mol/L) be (μ mol/g) (average issue) (ng/ml)
X ± s x ± s x ± s normal control PSS
Δ10 14.90 ± 3.4 696 ± 157 1.95 ± 0.89 0 poison contrasts PSS
Δ10 58.78 ± 6.7 1482 ± 74 11.68 ± 2.22 4.0 magnesium isoglycyrrhetates 15 10 47.02 ± 7.0
*1315 ± 141
*6.16 ± 1.72
* *3.4
* *
30 10 41.08±6.8
***?1101±275
***?6.58±2.10
***?3.1
***
60 10 31.57 ± 2.3
* *1057 ± 263
* *3.59 ± 0.93
* *2.8
* *Natural Potenlini 60 10 43.53 ± 4.7
*1306 ± 100
*4.76 ± 1.78
* *3.6
* Δ: physiological saline
*P＜0.05;
* *NANA is compared with the poisoning control group in P＜0.01: sialic acid; HA: hyaluronic acid; Hyp: oxyproline; S: fibrosis
Table 4 magnesium isoglycyrrhetate brings out the therapeutic action test group dosage number of animals serum transaminase serum protein of black mouse immune liver damage to Gal/FCA
(mg/kg) (only) AlaAT (IU/L) AspAT (IU/L) albumin (g/dl) gamma globulin (g/dl)
-X ± s
-X ± s
-X ± s
-X ± s normal control PSS
Δ10 62.6 ± 14 111.7 ± 13 4.19 ± 0.9 0.35 ± 0.04 poison contrasts PSS
Δ10 122.1 ± 48 256.4 ± 96 2.69 ± 0.9 0.73 ± 0.12 magnesium isoglycyrrhetates 50 10 86.4 ± 19
*150.2 ± 54
* *3.96 ± 0.8
* *0.53 ± 0.11
* *
100 10 77.8±15
** 148.2±51
***?4.08±0.8
***?0.49±0.10
***
150 10 72.7 ± 21
* *124.5 ± 37
* *4.02 ± 1.0
* *0.41 ± 0.08
* *Natural Potenlini 100 10 79.2 ± 19
*150.5 ± 70
*3.97 ± 0.8
* *0.54 ± 0.11
* * Δ: physiological saline
*P＜0.05;
* *Compare with the poisoning control group P＜0.01
Table 5 magnesium isoglycyrrhetate brings out heavy (mg) mortality ratio (%) of therapeutic action test group dosage number of animals blood plasma NO (mol/L) spleen of black mouse immune liver damage to Gal/FCA
(mg/kg) (only) x ± s x ± s normal control PSS
Δ10 12.4 ± 3 75 ± 11 0 poison contrasts PSS
Δ10 36.1 ± 11 179 ± 23 66.7 (20/30) magnesium isoglycyrrhetates 50 10 26.5 ± 5
*132 ± 21
*40.0 (12/30)
*
100 10 21.4±4
*** 117±17
*** 23.3(7/30)
***
150 10 19.5 ± 6
* *90 ± 21
* *10.0 (3/30)
* *Natural Potenlini 100 10 24.7+5
*122+18
* *367 (11/30)
*Δ: physiological saline NO: nitrogen protoxide
*P＜0.05;
* *Compare with the poisoning control group P＜0.01
The acute toxicity medicine animals administer approach LD of table 6 magnesium isoglycyrrhetate
50(mg/kg) 95% fiducial limit magnesium isoglycyrrhetate ICR mouse iv, 586.5 521.4～651.6 natural Potenlini ICR mouse iv 540.0
Claims (3)
1, a kind of new compound magnesium isoglycyrrhetate, it is characterized in that it is the magnesium salts of pentacyclic triterpenoid, chemistry is by name: 18 α, and 20 β-carboxyl-11-oxidation-positive volatile oil-12-alkene-3 beta-yls-2-o-β-D-glucopyanosyl aldehydic acid base-α-D-grape pyrans glycosides aldehydic acid magnesium, chemical structure is:
2, a kind of production method of new compound magnesium isoglycyrrhetate, it is characterized in that in methyl alcohol, easily forming the characteristic that methyl esters is separated out according to Isoglycyrrhiza acid, the alkali isomerization reactor product is dropped in the methyl alcohol, add a small amount of dewatering agent, the Isoglycyrrhiza acid methyl esters is separated out very soon, filter, promptly obtain high purity Isoglycyrrhiza acid methyl esters.Natural Potenlini and impurity can not separated out in mother liquor, thereby Isoglycyrrhiza acid is almost completely separated with impurity with unconverted Potenlini.According to the character of Isoglycyrrhiza acid methyl esters facile hydrolysis, hydrolysis in alkali lye adds the acid neutralization again, makes the Isoglycyrrhiza acid elaboration with the method for n-butanol extraction, adds the magnesium basic carbonate formation magnesium isoglycyrrhetate of calculated amount at last.
3, a kind of purposes of new compound magnesium isoglycyrrhetate is characterized in that this magnesium isoglycyrrhetate is used for the liver disease medicine.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100381124C (en) * | 2004-09-09 | 2008-04-16 | 江苏正大天晴药业股份有限公司 | Magnesium iso-glycyrrhetate gel and its preparing method and use |
| CN101062047B (en) * | 2006-04-29 | 2010-06-09 | 江苏正大天晴药业股份有限公司 | Combination including isoglycyrrhizinate and oxymatrine and the purpose thereof |
| CN102584928A (en) * | 2011-12-02 | 2012-07-18 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
| CN103242392A (en) * | 2012-02-13 | 2013-08-14 | 南京华狮化工有限公司 | Novel glycyrrhizic acid double salt, and preparation and application thereof |
| CN104861031A (en) * | 2015-03-16 | 2015-08-26 | 李玉山 | Magnesium isoglycyrrhizinate preparation method |
| CN107970248A (en) * | 2016-10-21 | 2018-05-01 | 正大天晴药业集团股份有限公司 | Isoglycyrrhiza acid is preparing the purposes in treating hypertension drug |
| CN109486895A (en) * | 2018-12-04 | 2019-03-19 | 南京工业大学 | Method for preparing isoglycyrrhizic acid by catalytic resolution |
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| WO2019196920A1 (en) * | 2018-04-13 | 2019-10-17 | 正大天晴药业集团股份有限公司 | Crystals of glycyrrhizic acid derivatives, crystalline compositions, pharmaceutical compositions and uses thereof |
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| CN100381124C (en) * | 2004-09-09 | 2008-04-16 | 江苏正大天晴药业股份有限公司 | Magnesium iso-glycyrrhetate gel and its preparing method and use |
| CN101062047B (en) * | 2006-04-29 | 2010-06-09 | 江苏正大天晴药业股份有限公司 | Combination including isoglycyrrhizinate and oxymatrine and the purpose thereof |
| CN102584928A (en) * | 2011-12-02 | 2012-07-18 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
| CN102584928B (en) * | 2011-12-02 | 2014-04-02 | 杭州市第六人民医院 | Preparation method for trans-glycyrrhizic acid |
| CN103242392A (en) * | 2012-02-13 | 2013-08-14 | 南京华狮化工有限公司 | Novel glycyrrhizic acid double salt, and preparation and application thereof |
| CN103242392B (en) * | 2012-02-13 | 2016-04-13 | 南京华狮化工有限公司 | A kind of glycyrrhizic acid double salt and preparation and application thereof |
| CN104861031A (en) * | 2015-03-16 | 2015-08-26 | 李玉山 | Magnesium isoglycyrrhizinate preparation method |
| CN107970248A (en) * | 2016-10-21 | 2018-05-01 | 正大天晴药业集团股份有限公司 | Isoglycyrrhiza acid is preparing the purposes in treating hypertension drug |
| CN109486895A (en) * | 2018-12-04 | 2019-03-19 | 南京工业大学 | Method for preparing isoglycyrrhizic acid by catalytic resolution |
| CN109486896A (en) * | 2018-12-04 | 2019-03-19 | 南京工业大学 | Method for preparing isoglycyrrhizic acid by catalytic resolution |
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