CN103524593A - Chikusetsusaponin IVa, derivatives thereof, preparation method thereof and application thereof to preparation of medicines - Google Patents
Chikusetsusaponin IVa, derivatives thereof, preparation method thereof and application thereof to preparation of medicines Download PDFInfo
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- CN103524593A CN103524593A CN201310503239.6A CN201310503239A CN103524593A CN 103524593 A CN103524593 A CN 103524593A CN 201310503239 A CN201310503239 A CN 201310503239A CN 103524593 A CN103524593 A CN 103524593A
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Abstract
The invention relates to the technical field of medicines and in particular relates to a triterpenoid saponin compound chikusetsusaponin IVa separated from panax japonicus, derivatives and a preparation method thereof, a medicine composition containing the same and new medical application thereof to preparation of medicines for treating diabetes mellitus II. Biological activity tests show that the compound and the derivatives thereof have significant insulin sensitization activity, and can be used for preparing the medicines for treating diabetes mellitus II and complications which are caused by the diabetes mellitus II.
Description
Technical field:
The invention belongs to technical field of pharmaceuticals, particularly, relate to a kind of separation obtains from panax species rhizome of Japanese Ginseng (Panax japonicus C.A.Mey.) compound Rhizoma Panacis Japonici saponin IVa (chikusetsusaponin IVa) and derivative thereof, or natural, synthetic, the semisynthetic composition that is rich in the mixture of Rhizoma Panacis Japonici saponin IVa or its any derivative, their preparation method, and show its remarkable insulin-sensitizing activity through biological activity test, thereby for the preparation of the medicine for the treatment of II-type diabetes and other complication causing thus.
Background technology:
Diabetes (diabetes mellitus) are that the relative or absolute deficiency of Regular Insulin or target cell reduce insulin sensitivity in a kind of body, or Regular Insulin itself exists structural defect and a kind of chronic disease of the carbohydrate, fat and the protein metabolism disorder that cause.Its principal feature is hyperglycemia, glycosuria.Show as clinically many drink, many foods, diuresis and lose weight (i.e. " three-many-one-little "), can make some tissues or organ generation morphological structure change and dysfunction, concurrent ketoacidosis, extremity gangrene, polyneuritis, blind and renal failure etc.Onset diabetes rate increases day by day, the common disease that become international, frequently-occurring disease.Conventionally diabetes are divided into I type and II type (non insulin dependent diabetes), and wherein 90% above patient is type ii diabetes.Key factor in type ii diabetes generation and evolution is insulin resistant.Research shows, insulin action activates its signal path, finally transfers the process of GLUT4 (GLUT4) from intracellular transport to after birth after muscle and adipocyte is the steps necessary that this tissue is carried out this function of glucose uptake.In insulin signaling pathway and GLUT4 transhipment, the impaired of membrane process is the major reason that body produces insulin resistant and type ii diabetes.Therefore, in research muscle and adipocyte, on the basis of insulin signaling pathway, research and development euglycemic agent, to improve insulin-resistant states, is the important directions of current type ii diabetes new drug research.
Rhizoma Panacis Japonici saponin IVa (chikusetsusaponin IVa, oleanolic acid3-O-β-D-glucurono-pyranosyl-28-O-β-D-glucopyranoside, CAS accession number: 51415-02-2) be olea alkanes pentacyclic triterpene glycoside.Be mainly derived from araliaceae ginseng plant.So far, existing partial monopoly relates to separation from Rhizome of Bipinnatifid Ginseng and prepares Rhizoma Panacis Japonici saponin IVa and Rhizoma Panacis Japonici saponin IVa protecting liver, lowering enzymes, treats osteoporosis, anti-inflammatory, the apoptosis that suppresses keratinocyte, can be used for the medicinal use of the aspects such as tetter that treatment is relevant to inflammation.So far, do not find Rhizoma Panacis Japonici saponin IVa or derivatives thereof tool insulin-sensitizing activity or take it as report and the patent of raw material useful in preparing drug formulations for type ii diabetes disease.
Summary of the invention:
The object of the present invention is to provide a kind of separation obtains from panax species rhizome of Japanese Ginseng (Panax japonicus C. A.Mey.) compound Rhizoma Panacis Japonici saponin IVa (chikusetsusaponin IVa) and derivative thereof, or natural, synthetic, the semisynthetic composition that is rich in the mixture of Rhizoma Panacis Japonici saponin IVa or its any derivative, their preparation method, and show its remarkable insulin-sensitizing activity through biological activity test, thereby for the preparation of medicine and the application thereof for the treatment of II-type diabetes and other complication causing thus.
Following technical proposals of the present invention is for reaching above-mentioned technical purpose:
Rhizoma Panacis Japonici saponin Iva or derivatives thereof and pharmaceutical salts thereof shown in following structural formula:
Wherein, R is alkyl or the amino of hydrogen, C1～C6.
Described Rhizoma Panacis Japonici saponin IVa or derivatives thereof, R is hydrogen, methyl, ethyl, propyl group, butyl, amyl group or hexyl.
Described Rhizoma Panacis Japonici saponin IVa or derivatives thereof, R is hydrogen or amino.
The method of described Rhizoma Panacis Japonici saponin IVa or derivatives thereof, comprises the steps:
1) get fresh rhizome of Japanese Ginseng rhizome chopping, with methyl alcohol or alcohol reflux, obtain extracting medicinal extract;
2) extraction medicinal extract is suspended in water, the suspension of water, successively with sherwood oil, ethyl acetate, n-butanol extraction, obtains sherwood oil, ethyl acetate, n-butanol layer and water extraction position;
3) n-butanol layer is through macroporous resin column column chromatography, water and aqueous alcohol solutions wash-out according to this, the concentrated total saponins that merges to obtain of alcohol eluen;
4) total saponins, through silicagel column column chromatography, with chloroform-methanol-water gradient elution, obtains I and II component;
5) the I component in step 4) is again through macroporous resin column column chromatography, and aqueous alcohol solutions wash-out, obtains III component;
6) the III component in step 5) is again through reverse phase silica gel post column chromatography, and aqueous alcohol solutions wash-out, obtains Rhizoma Panacis Japonici saponin IVa;
7) the II component in step 4) is again through macroporous resin column column chromatography, and aqueous alcohol solutions wash-out, obtains IV component;
8) the IV component in step 7) is again through reverse phase silica gel post column chromatography, and aqueous alcohol solutions wash-out, obtains Rhizoma Panacis Japonici saponin IVa methyl esters;
9) Rhizoma Panacis Japonici saponin IVa, by acylation reaction, esterification, obtains its corresponding derivative.
Described preparation method, Rhizoma Panacis Japonici saponin IVa and the CH of step 9)
2n
2react, obtain the esterification product of Rhizoma Panacis Japonici saponin IVa.
Described preparation method, Rhizoma Panacis Japonici saponin IVa and the ethanol synthesis of step 9), obtain the second esterification products of Rhizoma Panacis Japonici saponin IVa.
Described preparation method, the Rhizoma Panacis Japonici saponin IVa of step 9) and amine or ammonia react, obtain the amide product of Rhizoma Panacis Japonici saponin IVa.
Described pharmaceutical salts, refer to pharmacy acceptable salt, comprise the salt forming with organic acid or mineral acid, described organic acid is tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, citric acid, aspartic acid, benzene Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, succsinic acid, tartrate, sulfocyanic acid, p-tosylate and undecane hydrochlorate, described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
The present invention also provides a kind of hypoglycemic drug, it contains treats the above-mentioned Rhizoma Panacis Japonici saponin IVa or derivatives thereof of effective dose and one or more pharmaceutically acceptable drug excipients, or can with the other medicines of Rhizoma Panacis Japonici saponin IVa or its any derivative prescription.
And, medicine for the preparation for the treatment of II-type diabetes and other complication causing thus, it contains treats the above-mentioned Rhizoma Panacis Japonici saponin IVa or derivatives thereof of effective dose and one or more pharmaceutically acceptable drug excipients, or can with the other medicines of Rhizoma Panacis Japonici saponin IVa or its any derivative prescription.
The present invention provides the application of Rhizoma Panacis Japonici saponin Iva or derivatives thereof in the medicine of preparation treatment diabetes simultaneously.
And, the application of Rhizoma Panacis Japonici saponin Iva or derivatives thereof in the medicine of preparation treatment II-type diabetes and other complication causing thus.
With the application of Rhizoma Panacis Japonici saponin Iva or derivatives thereof in the medicine of preparation treatment hyperglycemia.
The present invention is that separation obtains compound Rhizoma Panacis Japonici saponin IVa, its derivative and prepares its derivative from panax species rhizome of Japanese Ginseng (Panax japonicus C.A.Mey.), in insulin sensitivity model (GLUT4 target spot), show remarkable sensitizing activity.
The compounds of this invention is through biological activity test, in insulin sensitivity model (GLUT4 target spot), compound acts on after 20 hours under 10uM concentration, shows remarkable sensitizing activity, can be used as euglycemic agent, be used for the treatment of II-type diabetes and other complication causing thus.
The pharmaceutical excipient of the Rhizoma Panacis Japonici saponin IVa that drug regimen of the present invention contains 1%-99% or its any derivative and 99%-1% (medicine that comprises other adapted).The preferred Rhizoma Panacis Japonici saponin IVa or derivatives thereof of 95%-99% and the pharmaceutical excipient of 5%-1% (medicine that comprises other adapted), also the Rhizoma Panacis Japonici saponin IVa of the optional 20%-80% of containing or its any derivative and 80%-20%'s or pharmaceutical excipient (medicine that comprises other adapted), or the pharmaceutical excipient of the Rhizoma Panacis Japonici saponin IVa that contains 60%-70% and 40%-30% (medicine that comprises other adapted).
The Rhizoma Panacis Japonici saponin IVa composition relating in the present invention comprises the plant milk extract that use contains Rhizoma Panacis Japonici saponin IVa, the extract of the by product of the industrial treatment of plant or its fruit, or contain the industry byproduct that is present in the Rhizoma Panacis Japonici saponin IVa plant of the greater concn in plant than original, but be not limited to this.Rhizoma Panacis Japonici saponin IVa except the above-mentioned type, also can be used its derivative, the derivative of the salt that wherein derivative in the present invention refers to accept in their pharmacy, ester, acyl ammonia.
Pharmaceutical salts described in above-mentioned any one, refer to pharmacy acceptable salt, comprise the salt forming with organic acid or mineral acid, described organic acid includes but not limited to tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, citric acid, aspartic acid, benzene Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, succsinic acid, tartrate, sulfocyanic acid, p-tosylate and undecane hydrochlorate, described mineral acid includes but not limited to hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
Press practice of pharmacy, the Rhizoma Panacis Japonici saponin IVa in the present invention or its any derivative can be prepared into various clinical pharmaceutical dosage form as insulin sensitivity enhancing agent medicine, comprise oral preparations or non-intestinal drug delivery agent.Said oral preparations is selected from and comprises any in tablet, pill, capsule, granule, microcapsule tablet, suspensoid, dripping pill, liquid oral; Said non-intestinal drug delivery agent is selected from and comprises any in the middle of injection, aerosol, suppository or subcutaneous administration formulation.
Auxiliary material in insulin sensitivity enhancing agent medicine of the present invention refers to conventional vehicle, as solvent, disintegrating agent, correctives, sanitas, tinting material, tackiness agent etc.
The medicine that other compatibility in insulin sensitivity enhancing agent medicine of the present invention is used, the Rhizoma Panacis Japonici saponin IVa referring to containing effective dose is certain medicine material, then the pharmaceutical chemicals that share of other Chinese medicine of compatibility or allowed.
Rhizoma Panacis Japonici saponin IVa of the present invention or its any derivative have euglycemic agent effect, are that the pharmacodynamic experiment by insulin sensitivity model (GLUT4 target spot) is confirmed.
Accompanying drawing explanation:
Fig. 1 is the compounds of this invention structure iron;
Fig. 2 is the pharmacodynamic experiment result of the insulin sensitivity model (GLUT4 target spot) of the compounds of this invention, insulin sensitivity, i.e. GLUT4 film Transport Rate=Cy3 fluorescence/GFP fluorescence (being expressed as Surface/Total GLUT4 or S/T GLUT4 in figure).
Embodiment:
Below in conjunction with accompanying drawing, with embodiments of the invention, further illustrate essentiality content of the present invention, but content of the present invention is not limited to this.
Embodiment 1:
The extraction of Rhizoma Panacis Japonici saponin IVa is with separated:
Fresh rhizome of Japanese Ginseng rhizome (18kg) chopping, extracts 3 times each 2 hours with industrial methanol eddy.Extracting solution concentrating under reduced pressure obtains crude extract (2.3kg);
1.8kg crude extract is dissolved in suitable quantity of water, uses successively ethyl acetate and n-butanol extraction, obtain ethyl acetate layer (25g), n-butanol layer (1.2kg) and water layer (1.6kg);
N-butanol layer (1.2kg) is through macroporous resin column macroporous resin column D101(90 * 8.5cm) column chromatography, use successively 60-100% methanol-water wash-out, the concentrated total saponins (about 600g) that merges to obtain of meoh eluate;
Total saponins, through 200 order silicagel column column chromatographies, is used CHCl
3-MeOH-H
2o (75:25:5 → 70:30:5 → 60:50:5 → 50:50:10) gradient elution, 250mL/ part, is total to obtain 10 components, thin-layer chromatography detects, and developping agent is chloroform/methanol/water (75:25:5), and wherein the 5th part of Rf value is between 0.3-0.4, concentrating under reduced pressure, is I component.The 8th part of Rf value is between 0.5-0.6, and concentrating under reduced pressure, is II component
I component (50g) is again through macroporous resin column MCI-gel CHP20P column chromatography, use successively 60-100% methanol-water wash-out, 80% methanol-water wash-out part, thin-layer chromatography detects, developping agent is chloroform/methanol/water (75:25:5), Rf value, between 0.3-0.4, merges concentrating under reduced pressure, is III component (10g).
III component (10g) is again through reverse phase silica gel post Rp-18 column chromatography, and 70% alcohol solution wash-out, obtains compound Rhizoma Panacis Japonici saponin IVa(5.75g of the present invention);
II component (30g) is again through macroporous resin column MCI-gel CHP20P column chromatography, use successively 60-100% methanol-water wash-out, 85% methanol-water wash-out part, thin-layer chromatography detects, developping agent is chloroform/methanol/water (75:25:5), Rf value, between 0.5-0.6, merges concentrating under reduced pressure, is IV component (200mg).
IV component (200mg) is again through reverse phase silica gel post Rp-18 column chromatography, and 60% alcohol solution wash-out, obtains compound Rhizoma Panacis Japonici saponin IVa methyl esters of the present invention (10mg).
Chickusetsusaponin IVa
ESI-MS (bearing) m/z:793[M-H]-
1HNMR(pyridine-d
5,400M):δ
H0.79(3H,s,Me-25),0.86(3H,s,Me-29),0.90(3H,s,Me-24),0.96(3H,s,Me-30),1.07(3H,s,Me-26),1.26(3H,s,Me-23),1.27(3H,s,Me-27),4.80(1H,d,J=7.2Hz,GlcH-1'),6.42(1H,d,J=7.6Hz,Glc?H-1''),5.42(1H,br.s,H-12);
13CNMR(pyridine-d
5,100M):δ
C38.7(C-1),26.4(C-2),89.4(C-3),39.7(C-4),55.9(C-5),18.6(C-6),33.3(C-7),40.0(C-8),48.1(C-9),37.0(C-10),23.7(C-11),123.0(C-12),144.2(C-13),41.9(C-14),28.4(C-15),23.7(C-16),47.2(C-17),42.2(C-18),46.3(C-19),31.0(C-20),34.0(C-21),32.6(C-22),28.4(C-23),17.1(C-24),15.6(C-25),17.5(C-26),26.1(C-27),176.6(C-28),33.6(C-29),23.7(C-30)。106.0(C-1'),82.7(C-2'),78.2(C-3'),72.8(C-4'),78.0(C-5'),170.0(C-6'),95.7(C-1''),74.1(C-2''),78.3(C-3''),71.2(C-4''),79.2(C-5''),62.4(C-6'')。
Chickusetsusaponin IVa methyl esters
ESI-MS (bearing) m/z:807[M-H]-
1H?NMR(pyridine-d
5,100M):δ
H0.76(3H,s,Me-25),0.87(3H,s,Me-29),0.90(3H,s,Me-24),0.96(3H,s,Me-30),1.08(3H,s,Me-26),1.25(3H,s,Me-23),1.29(3H,s,Me-27),3.75(3H,s,OMe),4.98(1H,d,J=7.6Hz,Glc?H-1'),6.32(1H,d,J=7.6Hz,Glc?H-1''),5.41(1H,br.s,H-12);
13C-NMR(pyridine-d5,400M):δ
C38.7(C-1),26.6(C-2),89.2(C-3),39.6(C-4),55.8(C-5),18.5(C-6),33.3(C-7),40.0(C-8),48.2(C-9),37.2(C-10),23.7(C-11),123.0(C-12),144.2(C-13),42.0(C-14),28.3(C-15),23.6(C-16),47.1(C-17),41.9(C-18),46.3(C-19),30.9(C-20),34.1(C-21),32.6(C-22),28.2(C-23),17.0(C-24),15.7(C-25),17.6(C-26),26.1(C-27),176.5(C-28),33.1(C-29),23.7(C-30),107.3(C-1'),75.1(C-2'),77.5(C-3'),73.2(C-4'),79.3(C-5'),170.9(C-6')95.8(C-1''),74.1(C-2''),78.9(C-3''),71.2(C-4''),79.2(C-5''),62.4(C-6'')。
Embodiment 2:
The preparation of Rhizoma Panacis Japonici saponin IVa derivative:
The preparation of 1, the preparation of Rhizoma Panacis Japonici saponin IVa methyl esters (R is methyl)
Rhizoma Panacis Japonici saponin IVa sample 10mg, in 20mL round-bottomed flask, adds and is dissolved with 3mg CH
2n
2diethyl ether solution 4mL, room temperature reaction 12 hours, ether and CH are removed in decompression
2n
2, obtain Rhizoma Panacis Japonici saponin IVa methyl esters (R=CH
3).
2, the preparation of Rhizoma Panacis Japonici saponin IVa amidated thing (R is amido)
Rhizoma Panacis Japonici saponin IVa sample 10mg, in 20mL round-bottomed flask, adds anhydrous pyridine and ammonia, room temperature reaction 18 hours, and anhydrous pyridine is removed in decompression, obtains Rhizoma Panacis Japonici saponin IVa acyl ammonia (R=NH
3).
Embodiment 3:
The experiment of Rhizoma Panacis Japonici saponin IVa insulin-sensitizing activity
1, detect principle:
Different insulin stimulating concentration and the expression amount of GLUT4 on after birth are linear, so detect the expression amount of GLUT4 on cytolemma, are the index that detects insulin sensitivity.
By gene engineering method, at the N-of GLUT4 end extracellular fragment and place, C-end end, add respectively HA and GFP label (HA-GLUT4-GFP).GLUT4 expression amount on cytolemma is realized by immunofluorescence dyeing HA label; Total GLUT4 expression amount of cell completes by quantizing GFP.
2, experimental technique:
2.1. built the adipocyte of expressing HA-GLUT4-GFP:
Plasmid HA-GLUT4-GFP is built to the permanent 3T3-L1 of expression cell strain by retrovirus packaging system, after cytodifferentiation lipoblast, be inoculated into 96 orifice plates, overnight incubation.
2.2. compound is hatched:
Cell inoculation was spent the night with 10uM compound preincubate respectively after 6 hours.
2.3. insulin stimulating:
Control cells respectively with 0,1 or the Regular Insulin of 100nM hatch 30 minutes.The cell that compound treatment is crossed is used 1nM insulin stimulating 30 minutes.
2.4. immunofluorescent staining:
4% paraformaldehyde fixed cell 8 minutes, uses primary antibodie (anti-HA) and two anti-(Cy3-conjugatedgoat anti-mouse IgG) to cell dyeing afterwards.
2.5. under fluorescent microscope, gather image:
Utilize full-automatic NIKON Ti-E fluorescent microscope to gather GFP positive cell in the fluorescence intensity of GFP passage and Cy3 passage.
2.6. analytical data:
With Metamorph Offline software, the image gathering is carried out to data analysis mapping.Insulin sensitivity, i.e. GLUT4 film Transport Rate=Cy3 fluorescence/GFP fluorescence.
Table 1 the compounds of this invention insulin sensitivity result
The results are shown in table 1 and Fig. 1.Result shows, in this insulin sensitivity model (GLUT4 target spot), under 10uM concentration, act on after 20 hours, Rhizoma Panacis Japonici saponin IVa methyl esters, Rhizoma Panacis Japonici saponin IVa acyl ammonia show certain insulin-sensitizing activity, and Rhizoma Panacis Japonici saponin IVa shows remarkable sensitizing activity.
Example of formulations 1:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), inject routinely water, essence filter, injection liquid is made in embedding sterilizing.
Example of formulations 2:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), be dissolved in sterile water for injection, stirring makes molten, with aseptic suction funnel, filters, more aseptic essence filter, be sub-packed in 2 ampoules, after frozen drying, aseptic sealing by fusing obtains powder injection.
Example of formulations 3:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) salt of making, the ratio that is 9:1 with vehicle weight ratio adds vehicle, makes pulvis.
Example of formulations 4:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) salt of making, the ratio that is 1:5-1:10 in itself and vehicle weight ratio adds vehicle, pelletizing press sheet.
Example of formulations 5:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and the salt that utilizes organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.) to make, oral liquid method for making is made oral liquid routinely.
Example of formulations 6:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), the ratio that is 5:1 in itself and vehicle weight ratio adds vehicle, makes capsule or granule or electuary.
Example of formulations 7:
By the method for embodiment 1-2, first make above-claimed cpd of the present invention, and utilize organic acid (tartrate, citric acid, formic acid, oxalic acid etc.) or the salt made of mineral acid (hydrochloric acid, sulfuric acid, phosphoric acid etc.), the ratio that is 3:1 in itself and vehicle weight ratio adds vehicle, makes capsule or granule or electuary.
Claims (13)
1. Rhizoma Panacis Japonici saponin Iva or derivatives thereof and the pharmaceutical salts thereof shown in following structural formula:
Wherein, R is alkyl or the amino of hydrogen, C1～C6.
2. Rhizoma Panacis Japonici saponin IVa or derivatives thereof according to claim 1, is characterized in that, R is hydrogen, methyl, ethyl, propyl group, butyl, amyl group or hexyl.
3. Rhizoma Panacis Japonici saponin IVa or derivatives thereof according to claim 1 and 2, is characterized in that, R is hydrogen or amino.
4. the method for preparation Rhizoma Panacis Japonici saponin IVa or derivatives thereof claimed in claim 1, comprises the steps:
1) get fresh rhizome of Japanese Ginseng rhizome chopping, with methyl alcohol or alcohol reflux, obtain extracting medicinal extract;
2) extraction medicinal extract is suspended in water, the suspension of water, successively with sherwood oil, ethyl acetate, n-butanol extraction, obtains sherwood oil, ethyl acetate, n-butanol layer and water extraction position;
3) n-butanol layer is through macroporous resin column column chromatography, water and aqueous alcohol solutions wash-out according to this, the concentrated total saponins that merges to obtain of alcohol eluen;
4) total saponins, through silicagel column column chromatography, with chloroform-methanol-water gradient elution, obtains I and II component;
5) the I component in step 4) is again through macroporous resin column column chromatography, and aqueous alcohol solutions wash-out, obtains III component;
6) the III component in step 5) is again through reverse phase silica gel post column chromatography, and aqueous alcohol solutions wash-out, obtains Rhizoma Panacis Japonici saponin IVa;
7) the II component in step 4) is again through macroporous resin column column chromatography, and aqueous alcohol solutions wash-out, obtains IV component;
8) the IV component in step 7) is again through reverse phase silica gel post column chromatography, and aqueous alcohol solutions wash-out, obtains Rhizoma Panacis Japonici saponin IVa methyl esters;
9) Rhizoma Panacis Japonici saponin IVa, by acylation reaction, esterification, obtains its corresponding derivative.
5. preparation method according to claim 4, is characterized in that, Rhizoma Panacis Japonici saponin IVa and the CH of step 9)
2n
2react, obtain the esterification product of Rhizoma Panacis Japonici saponin IVa.
6. preparation method according to claim 4, is characterized in that, Rhizoma Panacis Japonici saponin IVa and the ethanol synthesis of step 9) obtain the second esterification products of Rhizoma Panacis Japonici saponin IVa.
7. preparation method according to claim 4, is characterized in that, the Rhizoma Panacis Japonici saponin IVa of step 9) and amine or ammonia react obtain the amide product of Rhizoma Panacis Japonici saponin IVa.
8. pharmaceutical salts as claimed in claim 1, refer to pharmacy acceptable salt, comprise the salt forming with organic acid or mineral acid, described organic acid is tartrate, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, toxilic acid, succsinic acid, hexanodioic acid, alginic acid, citric acid, aspartic acid, benzene Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, pentamethylene propionic acid, dodecyl sulphate, ethyl sulfonic acid, glucoheptonic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, fumaric acid, 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, methylsulfonic acid, nicotinic acid, 2-naphthene sulfonic acid, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), propionic acid, succsinic acid, tartrate, sulfocyanic acid, p-tosylate and undecane hydrochlorate, described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid or phosphoric acid.
9. hypoglycemic drug, it is characterized in that containing and treat the Rhizoma Panacis Japonici saponin IVa or derivatives thereof claimed in claim 1 of effective dose and one or more pharmaceutically acceptable drug excipients, or can with the other medicines of Rhizoma Panacis Japonici saponin IVa or its any derivative prescription.
10. for the preparation of the medicine for the treatment of II-type diabetes and other complication causing thus, it is characterized in that containing and treat the Rhizoma Panacis Japonici saponin IVa or derivatives thereof claimed in claim 1 of effective dose and one or more pharmaceutically acceptable drug excipients, or can with the other medicines of Rhizoma Panacis Japonici saponin IVa or its any derivative prescription.
The application of 11. Rhizoma Panacis Japonici saponin Iva or derivatives thereofs claimed in claim 1 in the medicine of preparation treatment diabetes.
The application of 12. Rhizoma Panacis Japonici saponin Iva or derivatives thereofs claimed in claim 1 in the medicine of preparation treatment II-type diabetes and other complication causing thus.
The application of 13. Rhizoma Panacis Japonici saponin Iva or derivatives thereofs claimed in claim 1 in the medicine of preparation treatment hyperglycemia.
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| CN111235124A (en) * | 2020-01-19 | 2020-06-05 | 云南农业大学 | Rhizoma Panacis Majoris glycosyltransferase UGTPjm2 and application thereof in preparation of panax japonicus saponin IVa |
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| CN111235124A (en) * | 2020-01-19 | 2020-06-05 | 云南农业大学 | Rhizoma Panacis Majoris glycosyltransferase UGTPjm2 and application thereof in preparation of panax japonicus saponin IVa |
| CN111235124B (en) * | 2020-01-19 | 2023-04-07 | 云南农业大学 | Rhizoma panacis majoris glycosyltransferase UGTPjm2 and application thereof in preparation of panax japonicus saponin IVa |
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Application publication date: 20140122 |