CN105030804A - Application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug - Google Patents
Application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug Download PDFInfo
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Abstract
The invention belongs to the technical field of preparation of cardiotonic drugs, and discloses an application of Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing a cardiotonic drug. The Bufalin-3beta-N-methoxyl-N-beta-D-heteroside in preparing cardiotonic drug has the structure as shown in the formula I (the formula I is in the description). The researches made in the invention shows that Bufalin-3beta-N-methoxyl-N-beta-D-heteroside has obvious activity in inhibiting Na<+>/K<+>-ATP enzyme, higher cardiotonic activity than that of positive medicine digoxin, and higher selectivity index for alpha2 subtype than that of positive medicine digoxin. The Bufalin-3beta-N-methoxyl-N-beta-D-heteroside is high in safety, strong in cardiotonic effect and good officinal prospect, and the preparation technology is simple, low in cost and high in yield.
Description
Technical field
The invention belongs to cardiac drug preparing technical field, particularly Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides is preparing the application in cardiac drug.
Background technology
Along with the quickening of worldwide aged tendency of population process, the common incidence of cardiovascular disease such as hypertension, coronary heart disease rises year by year, and thus the prevalence of heart failure also raises gradually.According to statistics, the patients with heart failure of annual China about ten thousand.Na
+/ K
+-ATP enzyme is the action target of cardenolide.Cardenolide is by suppressing Na
+/ K
+-ATP enzyme, makes Na in cell
+concentration rises, and starts Na
+-Ca
+exchange, make Ca in cell
+concentration rises, thus plays cardiotonic.Conventional cardenolide class medicine has digoxin, Digitoxin, Allocor, strophanthin K and Adoniside etc., is A type cardenolide.Wherein the application of digoxin is more than 200 years.These medicines are used for the treatment of heart failure and some arrhythmia clinically, as (Gheorghiade, the M. such as atrial fibrillation and tachycardia; Adams, K.F.; Colucci, W.S.Digoxininthemanagementofcardiovasculardisorders.Circ ulation, 2004,109,2959-2964.).But the security window of A type cardenolide class medicine is young, general treatment amount close to 60% of toxic dose, (Chan, K.E. therefore the poisoning case of A type cardenolide happens occasionally; Lazarus, J.M.; Hakim, R.M.DigoxinassociateswithmortalityinESRD.J.Am.Soc.Nephro l, 2010,21,1550-1555.).Its poisoning symptom relates to multiple system, cardiac response be cardenolide the most seriously, the most dangerous untoward reaction, about there is the case of 40% that various types of arrhythmia occurs, also with gastrointestinal reaction and reaction of central nervous system, as headache, insomnia and visual disorder (TheDigitalisInvestigationGroup.Theeffectofdigoxinonmorta lityandmorbidityinpatientswithheartfailure.NewEngl.J.Med, 1997,336,525-533; Hallberg, P.;
j.; Lindahl, B.; Stenestrand, U.; Melhus, H.; RIKS-HIAgroup.Digoxinandmortalityinatrialfibrillation:ap rospectivecohortstudy.Eur.J.Clin.Pharmacol, 2007,63,1201-1202.).Although existing multiple A type cardenolide class medicinal application is in clinical, its security window is young, therefore is badly in need of novel alternative cardiac drug.
Early-stage Study is known, and the Toadpoison Medicine (bufalin) in Chinese medicine Venenum Bufonis has good Na
+/ K
+-ATP enzyme inhibit activities and cardiac activity (Tian, H.Y., Luo, S.L., Liu, J.S., Wang, L., Wang, Y., Zhang, D.M., Zhang, X.Q., JiangR.W.; YeW.C.C23SteroidsfromtheVenomofBufobufogargarizans.J.Nat .Prod, 2013,76 (10), 1842-1847.), but its poorly water-soluble, and it is to Na
+/ K
+the inhibitory action of-ATP enzyme α 1 and α 2 hypotype is suitable.Modern study is thought, Na
+/ K
+-ATP enzyme α 1 hypotype is extensively present in each tissue in human body, and α 2 hypotype is present in myocardial cell, and therefore, higher to the selectivity of α 2 hypotype, the safety of its cardiotonic is better.In addition, a kind of bufadienolide biotransformation compound of existing patent report 3-table-Toadpoison Medicine 3-O-β-D-Glucose glycosides has antitumor action (Chinese invention patent number: 200610023793.4), this compound is oxygen glycosides (aglycon is connected by oxygen atom with sugar), glycosyl is in 3 α positions, also mention this compounds in patent and may have heart tonifying, shock, antivirus action, but without concrete Data support.
In order to overcome the shortcoming of above-mentioned prior art with not enough, present invention applicant has synthesized Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) and Toadpoison Medicine-3 α-N-methoxyl group-N-β-D-Glucose glycosides (2).These two compounds are nitrogen glycosides (aglycon is connected by nitrogen-atoms with sugar).The glycosyl of compound 1 is positioned at 3 β positions, and the glycosyl of compound 2 is positioned at 3 α positions.Antitumor activity evaluation result shows, the inhibit activities of this kind of compound on tumor cell is strong, and to Normocellular inhibitory action weak (Chinese invention patent number: CN103288911B).Present invention applicant furthers investigate discovery further, and compound 1 also has significant Na
+/ K
+-ATP enzyme inhibit activities, its activity is far better than the compound 2 that glycosyl is positioned at 3 α positions, and the selectivity of compound 1 pair of α 2 hypotype is high, and selectivity index is 4.0, higher than positive drug digoxin.Cardiac activity evaluation shows, the activity of compound 1 is all significantly better than compound 2.
Summary of the invention
In order to overcome the shortcoming of above-mentioned prior art with not enough, primary and foremost purpose of the present invention is to provide Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides preparing the application in cardiac drug.
Object of the present invention is realized by following proposal:
Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides is preparing the application in cardiac drug.
Described Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides has structure shown in formula ():
Described Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (hereinafter referred compound 1) is nitrogen glycosides structure, and wherein, aglycon part is Toadpoison Medicine, and glycosyl part is β-D-Glucose (D-Glu), and nitrogen-atoms has methoxy substitution.
Described medicine contains at least one in Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides, its pharmaceutical salts and its solvate.
Described medicine contains one or more pharmaceutically acceptable carrier or excipient.
Described excipient can comprise diluent, wetting agent, lubricant, filler, antiseptic etc.Wherein diluent can be lactose, starch, dextrin, microcrystalline Cellulose, micropowder silica gel etc., and wetting agent can be the ethanol of water and 50 ~ 85% variable concentrations.
Described medicine can adopt the conventional method of this area to be prepared into various dosage form, and the form of administration beyond dosage form and injection etc. as oral administrations such as capsule, pill, tablet, oral liquid, granule, tinctures are oral, as injection etc.
The synthetic method of the present invention's above-mentioned Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides is: with pyridinium chlorochromate hydrochlorate, Toadpoison Medicine is oxidized to keto-acid derivant, after carrying out nucleophilic addition with methoxamine hydrochloride again, slough a part water and generate oxime formula intermediate, the aglycon generating α and β two kinds of configurations is reacted again with tert-butylamine base monoborane hydrochlorate complex, finally the aglycon of α and beta configuration and D-Glucose are reacted and generate Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides and Toadpoison Medicine-3 α-N-methoxyl group-N-β-D-Glucose glycosides, see CN103288911B.
The present invention, relative to prior art, has following advantage and beneficial effect:
(1) the present invention has excavated new medical application to Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides, has opened up a new application.
(2) Toadpoison Medicine-3 β-N-methoxyl group-N-of the present invention β-D-Glucose glycosides safety is high, and cardiotonic is strong, imply that good prospect in medicine.
(3) preparation technology of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides of the present invention is simple, and cost is low, and productive rate is high.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1) and Toadpoison Medicine-3 α-N-methoxyl group-N-β-D-Glucose glycosides (compound 2).
Fig. 2 is that Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides is on the impact of Brachydanio rerio cardiac shape.
Fig. 3 is the cardiotonic design sketch of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides.
Detailed description of the invention
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Experimental example 1: the synthesis of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides
(1) reaction substrate Toadpoison Medicine C3 position hydroxyl is through oxidants chlorine chromic acid pyridine hydrochloride (PCC) oxidation, and generate the Bufalone that C3 position becomes ketone, this step is reacted in room temperature, yield higher (productive rate 90%); (2) the latter and methoxamine hydrochloride are through affine addition-elimination reaction, generate the Toadpoison Medicine derivant 2a/b that C3 position is connected with the imine structure of methoxyl group, Bufaloneoximes, and reaction is comparatively thorough, yield higher (productive rate 90%); (3) oxime formula mixture Bufaloneoximes reduces through reducing agent tert-butylamine monoborane hydrochlorate, generate C3 position configuration different isomeric compound 3 α and 3 β, reaction is carried out under ice cooling, 4, yield about 60%, wherein, intermediate mol ratio is about 3 α: 3 β=2:1, and two isomers are separated by silicagel column; (4) glycosylation is carried out in the isomer of 3 β, 3 α configurations and glucose, thus synthesis C3 position is connected with the nitrogen glycosides type Toadpoison Medicine glycation product of glucosyl group, i.e. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1, productive rate is 40%) and Toadpoison Medicine-3 α-N-methoxyl group-N-β-D-Glucose glycosides (compound 2, productive rate is 48%).Concrete operations are see CN103288911B.Structural formula is shown in Fig. 1.
The spectral data of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1): ESI-MSm/z:578.4 [M+H]
+, 600.5 [M+Na]
+, 1177.2 [2M+Na]
+.
1HNMR(Pyridine-d5，400MHz)δ8.25(1H，dd，J＝9.6，2.4Hz)，7.48(1H，d，J＝2.4Hz)，6.35(1H，d，J＝9.6Hz)，4.72(1H，d，J＝8.6Hz)，4.46(m，1H)，4.28(m，1H)，4.22(m，1H)，3.88(m，1H)，4.55，4.35(m，2H)，3.94(s，3H)，3.83(m，1H)，2.50(m，1H)，2.18，1.87(m，2H)，2.16，1.45(m，2H)，1.79，1.33(m，2H)，1.69，1.51(m，2H)，1.28，1.09(m，2H)，2.19(m，1H)，1.87(m，1H)，1.73(m，1H)，1.75(m，1H)，1.42(m，1H)，0.89(s，3H)，0.81(s，3H)。
13CNMR(Pyridine-d5，100MHz)δ162.1，149.2，147.5，123.8，115.1，90.9，84.3，80.5，80.2，71.7，71.6，63.6，62.9，57.1，51.4，48.8，42.2，40.8，37.0，36.5，35.8，32.8，31.0，29.5，29.4，27.2，23.9，23.7，22.1，21.6，17.1。
According to mass spectrum, nuclear magnetic resonance information, identify that product is Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides, its chemical formula is C
31h
47nO
9.
The spectral data of Toadpoison Medicine-3 α-N-methoxyl group-N-beta-D-glucoside (compound 2):
1hNMR (Pyridine-d
5, 300MHz) δ 8.33 (dd, 1H, J=9.7, 2.5Hz), 7.56 (d, 1H, J=2.5Hz), 6.44 (d, 1H, J=9.7Hz), 4.90 (d, 1H, J=8.7Hz), 4.57 (m, 1H), 4.39 (m, 1H), 4.31 (m, 1H), 3.98 (m, 1H), 4.63, 4.47 (m, 2H), 4.06 (s, 3H), 2.27, 1.93 (m, 2H), 1.90, 1.60 (m, 2H), 3.66 (m, 1H), 2.58 (m, 1H), 2.07 (m, 2H), 2.26 (m, 2H), 1.02 (m, 2H), 0.97 (s, 3H), 0.89 (s, 3H).
13CNMR(Pyridine-d
5，75MHz)δ162.1，149.2，147.5，123.9，115.1，91.4，84.2，80.5，80.3，71.7，71.3，63.8，62.9，62.2，51.3，48.7，42.3，42.0，40.7，36.5，35.9，35.3，32.9，32.1，29.4，27.8，25.2，23.6，22.4，21.5，17.1。ESI-MSm/zC
31H
47NO
9：578.4[M+H]
+，600.3[M+Na]
+，1177.3[2M+Na]
+，HRMS(ESI)m/zC
31H
47NO
9Na([M+Na]
+)600.3145，cacl.600.3148。
According to mass spectrum, nuclear magnetic resonance information, identify that product is Toadpoison Medicine-3 α-N-methoxyl group-N-beta-D-glucoside, its chemical formula is C
31h
47nO
9.
Embodiment 2: the Na of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1) and Toadpoison Medicine-3 α-N-methoxyl group-N-beta-D-glucoside (compound 2)
+/ K
+-ATP enzyme inhibit activities.
Method of testing is see document (Zhang, R.R.; Tian, H.Y.; Tan, Y.F.; Chung, T.Y.; Sun, X.H.; Xia, X.; Ye, W.C., Middleton, M.A.; NatalyaF.; EsmannM.; Tzen, J.T.C.; Jiang, R.W.Structures, chemotaxonomicsignificance, cytotoxicandNa+, K+-ATPaseinhibitoryactivitiesofnewcardenolidesfromAsclep iascurassavica.Org.Biomol.Chem.2014,12 (44), 8919-8929.), carry out activity rating to compound 1 and 2, concrete steps are as follows:
(1) join in 96 orifice plates by active testing solution, every hole 100 μ L, containing 100mMNaCl, 20mMKCl, 1mMMgCl
2, 1mMEGTA, 20mMTris-HCl, pH7.4, and 0.2 μ gofpurifiedNa
+/ K
+-ATP enzyme α 1 or α 2 hypotype.
(2), after adding the compound 1 and 2 of variable concentrations, 96 orifice plate 37 DEG C is hatched 15min.
(3) add 2mMATP-Mg and start enzymatic reaction, and hatch 15min at 37 DEG C.
(4) in every hole, add ice-cold BIOMOLGreen reagent 100 μ L, and room temperature places 20 minutes, the absorbance of test 620nm.
The amount of the phosphoric acid discharged can be calculated according to absorbance, thus calculate the inhibit activities of compound 1 and 2 pairs of enzymes.This experiment records Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1) to Na
+/ K
+the IC of-ATP enzyme α 1
50it is 0.20 ± 0.03 μM, to the IC of α 2 hypotype
50being 0.05 ± 0.01 μM, is 4.0 to the selectivity index of α 2 hypotype; Toadpoison Medicine-3 α-N-methoxyl group-N-beta-D-glucoside (2) is to the IC of α 2 hypotype
50all be greater than 20 μMs, and the IC of positive drug digoxin (digoxin) under the same terms
50to the IC of α 1, α 2 hypotype
50for being respectively 0.31 ± 0.04 μM and 0.18 ± 0.03 μM, be 1.72 to the selectivity index of α 2 hypotype.Visible, compound 1 couple of Na
+/ K
+the inhibit activities of-ATP enzyme is better than compound 2 and positive drug digoxin, and compound 1 is significantly better than positive drug digoxin to the selectivity index of α 2 hypotype.
Embodiment 3: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1) cardiotonic to Brachydanio rerio
The present invention adopts heart with the zebra fish model of green fluorescence (being convenient to observe) to study its cardiotonic (Huang, C.C.; Monte, A.; Cook, J.M.; Kabir, M.S.; Peterson, K.P.ZebrafishHeartFailureModelsfortheEvaluationofChemica lProbesandDrugs.AssayDrugDev.Technol.2013,11 (9-10), 561-572.).
Adopt Tg (cmlc2:GFP) transgenic zebrafish (University of Macao), its germ cell is obtained by female milter copulation in early morning.Germ cell being divided into four groups (administration group, positive controls, negative control group, Vehicle controls groups) is then put in culture fluid by each group of germ cell, 28 DEG C of hatchings.After 24h, in culture fluid, add doxorubicin (0.3 μM), and continue cultivation 24 hours, modeling), observe the cardiac shape of Brachydanio rerio with digitized fluorescence inverted microscope and measure heart rate to determine that Heart Failure Model successfully constructs.Then, the compound 1 of variable concentrations is added in administration group culture fluid, digoxin (0.5 μM) is added in positive drug control group, the DMSO of 0.1% is added in Vehicle controls group, and continue cultivation after 48 hours, the restitution of each compound to damaged heart form is observed with digitized fluorescence inverted microscope, and according to method (Moore, the F.B.G. of bibliographical information; HoseyM.; Bagatto, B.Cardiovascularsysteminlarvalzebrafishrespondstodevelop mentalhypoxiainafamilyspecificmanner.FrontiersinZoology, 2006,3,4.) measure the cardiac activity that the cardiac functions such as stroke volume (strokevolume), cardiac output (cardiacoutput) carry out assessing compound, the results are shown in Figure 2, administration group echo is " 1 ".
Result shows, after doxorubicin modeling, the often rich output of Brachydanio rerio is reduced to 66.7% of matched group, and cardiac output is reduced to 67.9% of matched group, shows modeling success.Be 0.125,0.25,0.5 when adding concentration, after Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides of 1.0,2.0 μMs, often rich output significantly increases, relative to model group, recruitment is respectively 11.1%, and 55.6%, 88.9%, 105.5% and 122.2% (same, the cardiac output of Brachydanio rerio also significantly increases, recruitment is respectively 21.1%, 47.3%, 78.9%, 100.0% and 115.8%.Under the same conditions, the often rich output of positive drug digoxin (0.5 μM) and kinemic recruitment are respectively 66.7% and 68.4%.Visible, the cardiotonic of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides of the present invention has dose dependent, further, under same concentrations (0.5 μM), the cardiotonic of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides is better than digoxin.
Embodiment 4: the cardiac toxicity of the Brachydanio rerio of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (compound 1)
Adopt AB system Brachydanio rerio (wild type, University of Macao), its germ cell is obtained by female milter copulation in early morning.Germ cell is divided into four groups (matched group, model group, administration group and positive drug groups), then each group of germ cell is put in culture fluid, 28 DEG C of hatchings.After 24h, in administration group culture fluid, add compound 1 sample (0.3 μM), in model group culture fluid, add doxorubicin (0.3 μM), in positive drug group culture fluid, add digoxin (0.3 μM), and continue to cultivate 48h.Zebrafish embryo is fixed with 3% methylcellulose and uses 3-benzocaine mesylate (0.16mg/mL) to anaesthetize.Finally, by SZX10 stereomicroscope observation and the cardiac shape comparing four groups of Brachydanio rerio, the results are shown in Figure 3.
Result shows: similar to matched group, and compound 1 does not cause the change of Brachydanio rerio cardiac shape, and the cardiac contour of digoxin and doxorubicin group all shows as compensatory expands.Therefore the cardiac toxicity of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) of the present invention is significantly lower than positive drug digoxin (digoxin) and doxorubicin (doxorubicin, antineoplastic agent, its major side effects is cardiac toxicity, Liu Beijing. cardiotoxicity of medicine reaction and pharmacovigilance. pharmacoepidemiology magazine, 2011,20,205-208.).
Experimental example 5: the acute toxicity testing of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1)
(1) oral administration
Get the Kunming mouse (purchased from Guangdong Province's animal center) of body weight 18 ~ 22g, Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) prepared by embodiment 1 is made into aqueous solution (suspendible) gavage 50.0mg/kg, continuous one week, have no dead mouse.
(2) intraperitoneal injection
Test method: the Kunming mouse (purchased from Guangdong Province's animal center) getting body weight 18 ~ 22g, random packet, often organizes 12, the compound 1 of lumbar injection various dose, according to mouse survival situation, calculates half lethal dose LD50.
Table 1 Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is to the Acute Toxicity of mice
Median lethal dose(LD 50) is calculated as follows:
Result shows (see table 1), and compound 1, under the dosage of 15mg/kg, does not observe the death of mice, and its half lethal dose is 30mg/kg, and Toadpoison Medicine is under the dosage of 10mg/kg, has observed the death of mice.
Embodiment 6: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is preparing the application of cardiac drug
Get Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 50g, starch 190g mix homogeneously, make soft material with 70% ethanol, granulate, dry.Add 10g magnesium stearate mix homogeneously, tabletting, make 2000, film coating, every sheet is containing Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides 25mg.
Embodiment 7: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is preparing the total application of cardiac drug
The preparation of slow releasing tablet
By Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 25g, with recipe quantity 85% dissolve with ethanol solution, add adjuvant lactose 120g, hydroxypropyl emthylcellulose (HPMC) 110g, pregelatinized Starch 60g, mix homogeneously; Add 85% alcoholic solution and be mixed and made into soft material, granulate, dry after crossing (18 ~ 35) mesh sieve, dry granule is crossed (18 ~ 35) eye mesh screen granulate; Take magnesium stearate 10g, add in dry granule, mix homogeneously, shallow arc stamping (1000), obtain the plain sheet of Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) slow releasing tablet, every sheet is containing Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides 25mg.
Embodiment 8: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is preparing the total application of cardiac drug
The preparation of oral cavity disintegration tablet
Get Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 200g, microcrystalline Cellulose 600g, polyvinylpolypyrrolidone 300g, mannitol 160g, magnesium stearate 170g, aspartame 160g, citric acid 10g, mix homogeneously, cross 80 mesh sieves, adopting direct compression process to prepare sheet is heavily the oral cavity disintegration tablet (8000) of 0.20g, and every sheet is containing Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides 25mg.
Embodiment 9: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is preparing the total application of cardiac drug
The preparation of capsule
Get Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 50g, lactose 200g, starch 130g, magnesium stearate 20g, add 65% ethanol and make soft material, dry, sieve, granulate, incapsulate, make 2000.Every capsules is containing Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 25mg.
Embodiment 10: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is preparing the total application of cardiac drug
The preparation of injection
Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 100g, propylene glycol 5000g, grinding, add the dilution of appropriate water for injection again, mixing, then adds sodium chloride in right amount, adds water for injection again to 100L after dissolving, adjust pH 7.0-7.4, filter, embedding, sterilizing, obtain 10,000 injection injections, often prop up containing Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 10mg.
Embodiment 11: Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) is preparing the total application of cardiac drug
The preparation of liposome nano granule
Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 100g, soybean lecithin 50g, is dissolved in 2500mL ethanol, separately gets stearic acid 20g and soybean lecithin fat 50g is dissolved in 2500mL cyclohexane extraction, mixing and stirring.The rotary evaporation that reduces pressure in 37 DEG C of waters bath with thermostatic control removing organic solvent, makes medicine and adjuvant form even lipid membrane in flask walls, places and spend the night, eliminate organic solvent in vacuum desiccator; Another taking polyethylene glycol monostearate 375g, stirring and dissolving is in 17.5L water, and add in above-mentioned thin film, ultrasonic 30min, is dissolved to 25L, obtains light yellow transparent solution.This solution lyophilization can be obtained lyophilized powder.With ball mill grinding 24 hours, the nanoparticle of obtained uniform particle sizes, mixing subpackage.Every bag containing Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides (1) 10mg.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (8)
1. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides is preparing the application in cardiac drug.
2. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 1 is preparing the application in cardiac drug, it is characterized in that described Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides has structure shown in formula ():
3. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 1 is preparing the application in cardiac drug, it is characterized in that: described medicine contains at least one in Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides, its pharmaceutical salts and its solvate.
4. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 1 is preparing the application in cardiac drug, it is characterized in that: described medicine contains one or more pharmaceutically acceptable carrier or excipient.
5. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 4 is preparing the application in cardiac drug, it is characterized in that: described excipient comprises diluent, wetting agent, lubricant, filler and at least one of the preservatives.
6. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 5 is preparing the application in cardiac drug, it is characterized in that: described diluent is at least one in lactose, starch, dextrin, microcrystalline Cellulose and micropowder silica gel.
7. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 5 is preparing the application in cardiac drug, it is characterized in that: described wetting agent is the ethanol of water and 50 ~ 85% variable concentrations.
8. Toadpoison Medicine-3 β-N-methoxyl group-N-β-D-Glucose glycosides according to claim 1 is preparing the application in cardiac drug, it is characterized in that: described medicine adopts conventional method to be prepared into various dosage form, comprise capsule, pill, tablet, oral liquid, granule, the dosage form of tincture and injection.
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| CN201510413764.8A CN105030804B (en) | 2015-07-14 | 2015-07-14 | - 3 β-N- methoxyl groups-N- β of Bufalin-application of the D-Glucose glycosides in preparing cardiac drug |
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| CN201510413764.8A CN105030804B (en) | 2015-07-14 | 2015-07-14 | - 3 β-N- methoxyl groups-N- β of Bufalin-application of the D-Glucose glycosides in preparing cardiac drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777844A (en) * | 2016-03-16 | 2016-07-20 | 暨南大学 | Bufalin riboside having selective inhibition action to Na+/K+-ATPase alpha2 subtype and application of bufalin riboside |
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| CN101016326A (en) * | 2006-02-08 | 2007-08-15 | 赵军 | Toad sterene compounds and application thereof in pharmaceutical preparation |
| CN103288911A (en) * | 2013-06-04 | 2013-09-11 | 暨南大学 | Bufalin glycosylation derivative and preparation method and application thereof in preparation of anti-tumour medicaments |
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| CN101016326A (en) * | 2006-02-08 | 2007-08-15 | 赵军 | Toad sterene compounds and application thereof in pharmaceutical preparation |
| CN103288911A (en) * | 2013-06-04 | 2013-09-11 | 暨南大学 | Bufalin glycosylation derivative and preparation method and application thereof in preparation of anti-tumour medicaments |
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| CN105777844A (en) * | 2016-03-16 | 2016-07-20 | 暨南大学 | Bufalin riboside having selective inhibition action to Na+/K+-ATPase alpha2 subtype and application of bufalin riboside |
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