CN101255184B - Hepatitis B resistant compound, medicament composition and use in medicament preparation - Google Patents
Hepatitis B resistant compound, medicament composition and use in medicament preparation Download PDFInfo
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- CN101255184B CN101255184B CN2008100582914A CN200810058291A CN101255184B CN 101255184 B CN101255184 B CN 101255184B CN 2008100582914 A CN2008100582914 A CN 2008100582914A CN 200810058291 A CN200810058291 A CN 200810058291A CN 101255184 B CN101255184 B CN 101255184B
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Abstract
The invention provides a compound represented by formula I, wherein the compound is 11, 12, 13- triacetyl-25- dehydration-13beta, 12beta, 13betaepoxy alisol when X represents beta-epoxy bond; and the compound is 11, 12, 13- triacetyl-25- dehydration alisol when X represents c-c single bond, drug compositions for curing hepatitis b with compound I and pharmaceutically acceptable carrier, a preparation method of the pharmaceutical compound, the applications for preparing anti hepatitis b suppressing agent medicant and curing hepatitis b medicant, wherein X represents a beta-epoxy bond or a c-c single bond.
Description
Technical field:
The invention belongs to medical compounds and technical field of pharmaceuticals, particularly, relate to compound 11; 12,13-triacetyl-25-alisol and 11,12 that dewaters; 13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols, and with the pharmaceutical composition of these two kinds of compounds treatment hepatitis B that is activeconstituents; Its preparation method, and the application in preparation resistance of hepatitis B inhibitor medicaments and anti-hepatitis B medicine.
Background technology:
According to the World Health Organization, the whole world has 2,000,000,000 people of surpassing to be hepatitis b virus carrier, and wherein about 300,000,000 people are chronic lifelong infection intercurrent disease.The patient of these chronic hepatitiss is prone to change into chronic hepatitis, be liver cirrhosis, liver cancer main diseases because of.It is a serious public health problem that hepatitis B virus (HBV) infects, and the expense of treatment chronic hepatitis is quite expensive, estimate every year due to illness virus hepatitis cause direct economic loss 30,000,000,000～50,000,000,000 Renminbi.The control HBV infection that is applied in of HBV vaccine immunity, various antiviral has in recent years obtained certain effect; But also cause the HBV variant to occur simultaneously; The negative chronic viral hepatitis B of HBeAg (CHBV) increases, and HBV is prone to bounce-back after the drug withdrawal, and expense is high.In order to control HBV effectively, need the dissimilar clinical treatment medicine of development.
(hepatitis B virus HBV) belongs to DNA and has a liking for hepatovirus section hepatitis B virus, mainly is to propagate through blood products, mother and baby and approach such as property contacts, and is prone to change into chronic hepatitis, is the main diseases therefore that causes liver cirrhosis, liver cancer.The reproduction process of hepatitis B virus related to for 5 steps: combine, invade, transcribe, translation, gene replication and packing.At first virion is attached to liver cell through acceptor, sloughs adventitia behind the intrusion endochylema, forms core particle.Core particle moves to liver cell nuclear, and HBV DNA core particle shells and goes out, and in nucleus, forms cccDNA.CccDNA is the template of hepatitis B replication, is that liver cell continues infected key substance for a long time.CccDNA has 2 kinds of functions, and the various members of the synthetic virion of the first are like HBsAg (hepatitis B virus surface antigens; Surface antigen constitutes adventitia), HBcAg (hepatitis virus c antigens; CAg constitutes inner membrance), HBeAg (hepatitis B virus e antigens; E antigen is secreted in the blood); It two is synthetic HBV DNA of future generation.Most of new synthetic HBV DNA is used for the packing of reovirion, and part then gets into liver cell nuclear again, becomes another source of cccDNA.The new synthetic HBV DNA of part at first is assembled into core particle with HBcAg, and then is assembled into complete HBV particle with HBsAg, discharges to the extracellular.Superfluous HBsAg is released into blood sometimes alone, forms microspheric form particle or cast particle.
It is active that some herbal medicine of research report have anti-HBV, can suppress the secretion of external HBsAg and HBeAg like Common Leafflower Herb, Spreading Hedyotis Herb etc., has anti-HBV effect, and their untoward reaction is less relatively, can take for a long time.The extract of some of them plant has restraining effect in various degree to HBV DNA.Baicaline, kurarinone have the vitro inhibition effect to HBsAg and HBeAg.
The Biphenylylmethylcarbinol of China's development is a kind of effective constituent with effect of reducing enzyme levels and treatment hepatitis of in synthetic Wuweizisu C process, finding.Glycyrrhizin preparations potenxin glycyrrhizin injection liquid has effects such as mitigation symptoms, anti-inflammatory and transaminase lowering to Patients with Viral Hepatitis.The regeneration product Glycyrrhizic acid,diammonium salt of potenxin is the diammonium glycyrrhizinate levorotatory compound, and curative effect is better than potenxin.Their main transaminase lowering.
Present internationally recognized curative effect anti-hepatic-B virus medicine preferably is mainly nucleoside medicine such as lamivudine (lamivudine), Adifuwei ester (adefovir dipivoxiil), Entecavir (enticavir), Telbivudine (tibivudine).During these medicines are tested, HBV virus there is restraining effect in external or body.Its mechanism of action is to become the triphosphoric acid compound in the medicine entering cell, through the competition of substrate, to the polysaccharase or the ThermoScript II inhibition of virus, finally suppresses synthetic, the viral propagation of viral DNA.Because of the short-term use only has temporary transient effect, be fit to long-term prescription.But through after the long periods of treatment, variation and tolerance possibly appear in virus, and after the drug withdrawal, the virus bounce-back is high.
Be spreading of control hepatitis B, medical circle also works out effective hepatitis B vaccine, and the public is carried out immunization, is mainly used in prevention, has obtained good effect.But it is then invalid to infecting HBV.
The medicine of treating the chronic hepatitis B employing in addition is alpha-interferon (IFN), and its effect mainly is immunomodulatory.But interferon treatment in chronic hepatitis B has its restraining factors: one of which, it never obtains real success, only if the substantive immunoreation to HBV has appearred in patient before treatment.Its two, before the conversion of interferon-induced HBeAg serum, hepatitis active unexpected is crossed property and is increased the weight of, and shows as ALT and raises, and can cause patient with liver cirrhosis generation liver failure, occurs dead once in a while.
In sum; Antihepatitis medicament has the very large market requirement; But the chemical sproof problem of Antihepatitis medicament ubiquity of clinical application now; Successfully develop the resistance that can solve medicine, the medicine of the resistance of hepatitis B of new generation that clinical efficiency height and toxic side effect are less will have the very strong market competitiveness and market outlook.
So far, do not have the report of formula (I) compound in the prior art, do not have its report yet, do not have these two compounds or its pharmaceutical composition to be applied in the report in preparation or the treatment hepatitis B medicament yet as the pharmaceutical composition of effective constituent.
Summary of the invention: the object of the present invention is to provide compound 11,12,13-triacetyl-25-alisol and 11 that dewaters; 12; 13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols, and these two kinds of compounds are used to treat the pharmaceutical composition of hepatitis B as activeconstituents; This preparation of drug combination method is provided, and this compound or its pharmaceutical composition are in preparation resistance of hepatitis B inhibitor medicaments and the application in preparation treatment hepatitis B medicament.
In order to realize above-mentioned purpose of the present invention, the invention provides following technical scheme:
Formula (I) compound 11,12,13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols and compound 11,12, the 13-triacetyl-25-alisol that dewaters
Wherein, when X was the beta epoxide key, compound was 11,12,13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols; When X was carbon-carbon single bond, compound was 11,12,13-triacetyl-25-alisol that dewaters.
The pharmaceutical composition of treatment hepatitis B wherein contains formula (I) compound and pharmaceutically acceptable carrier.
The preparation method of formula (I) compound comprises that the alisol A that obtains with separation and purification in the rhizoma alismatis is a reaction raw materials, and stirring at room reaction 12h in acetic anhydride/pyridine system is in an amount of frozen water of reaction solution impouring; Ethyl acetate extraction, ethyl acetate layer are used 5% hydrochloric acid, saturated sodium bicarbonate respectively; Anhydrous sodium sulfate drying is used in the saturated common salt water washing then, reclaim under reduced pressure ETHYLE ACETATE; Get 11,12,13-triacetyl alisol; 11,12,13-triacetyl alisol and La Weisong reagent are at reflux in toluene 6h, and removal of solvent under reduced pressure gets bullion, through silica gel column chromatography, uses sherwood oil: acetone (6: 1) wash-out gets compound 11,12,13-triacetyl-25-alisol that dewaters; In round-bottomed flask, add alisol A, metachloroperbenzoic acid and methylene dichloride in addition, stirring at room reaction 2h is in an amount of frozen water of reaction solution impouring; Ethyl acetate extraction; Ethyl acetate layer is used anhydrous sodium sulfate drying, reclaim under reduced pressure ETHYLE ACETATE then with Sulfothiorine and the washing of saturated sodium bicarbonate (1: 1) mixed solution; Get 13 β, 17 beta epoxide alisols; 13 β, 17 beta epoxide alisols are stirring at room reaction 12h in acetic anhydride/pyridine system, in an amount of frozen water of reaction solution impouring, and ethyl acetate extraction; Ethyl acetate layer is used 5% hydrochloric acid respectively, saturated sodium bicarbonate, saturated common salt water washing; Use anhydrous sodium sulfate drying then, reclaim under reduced pressure ETHYLE ACETATE gets 11; 12,13-triacetyl-13 β, 17 beta epoxide alisols; 11,12,13-triacetyl-13 β, 17 beta epoxide alisols and La Weisong reagent are at reflux in toluene 6h; Removal of solvent under reduced pressure gets bullion, and through silica gel column chromatography, with 5: 1 sherwood oil: the acetone wash-out gets compound 11; 12,13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols.
Formula (I) compound 11,12, the 13-triacetyl-25-alisol or 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, the application of 17 beta epoxide alisols in preparation resistance of hepatitis B inhibitor medicaments.
Formula (I) compound 11,12, the 13-triacetyl-25-alisol or 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, the application of 17 beta epoxide alisols in the preparation anti-hepatitis B medicine.
When The compounds of this invention is used as medicine, can directly use, perhaps use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1-99%, is preferably the The compounds of this invention of 0.5-90%, and all the other are acceptable on the pharmacology, nontoxic and inert pharmaceutically acceptable carrier and/or vehicle to humans and animals.
Described pharmaceutical carrier or vehicle are one or more solids, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent.Pharmaceutical composition of the present invention is used with the form of per weight dose.Medicine of the present invention can be through injection (quiet notes, intramuscular injection) and oral two kinds of form administrations.
Embodiment:
In order to understand essence of the present invention better; To The compounds of this invention 11,12 be described with Test Example of the present invention below, 13-triacetyl-25-alisol and 11 that dewaters; 12; 13-triacetyl-25--13 β that dewater, the pharmacological action result of 17 beta epoxide alisols, but do not limit the present invention with this Test Example.
Test Example 1: compound 11,12, the 13-triacetyl-25-alisol and 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols are to the drug toxicity of Hep G2.2.15 cell with to HBsAg, HBeAg excretory restraining effect
1 material and method
1.1 material: compound 11,12, the 13-triacetyl-25-alisol, 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols; Lamivudine (lamivudine) (GlaxoSmithKline PLC pharmacy (Suzhou) ltd, the accurate word H20030581 of traditional Chinese medicines); Hep G2.2.15 cell (drawing air hospital) from Guangzhou; High sugared DMEM (GIBICO); G418 (GIBICO); Foetal calf serum (Tianjin blood grinds institute); L-glutaminate (AMRESCO); Penicillium mould, Streptomycin sulphate (Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group).
1.2Hep the G2.2.15 cell is cultivated with high sugared DMEM liquid, nutrient solution adds 10% foetal calf serum, 0.03%L-Stimulina, 100mg/L G418,10
5The blue or green enzyme of IU/L is plain, 100mg/L Streptomycin sulphate, 5%NaCO
3Transfer pH to 6.8-7.0.
1.3 instrument: ELIASA Bio-RAD 680 (U.S.); CO
2Incubator Thermo Forma3310 (U.S.); Inverted biologic microscope XD-101 type (Nanjing) etc.
1.4 experimentation with trypsinase with Hep G2.2.15 cell dissociation, with having added the 0.03%L-Stimulina, 100mg/L G418, the blue or green enzyme of 100IU is plain, the high sugared DMEM liquid of 100IU Streptomycin sulphate is processed single cell suspension, every hole is by 3 * 10
5* 0.1mL
-1Divide kind in 96 orifice plates, the 0.1mL/ hole is used instead behind the 24h and is contained 2% foetal calf serum; The pastille nutrient solution of 380 μ g/mL; Every kind of medicine is established four drug levels, and each concentration is established three holes, four times of dilutions; Establish the blank groups of cells of a cell control group and a hole that three holes do not add medicine simultaneously, and do the positive drug contrast with lamivudine; Collect supernatant behind the 7d, measure the secretion situation of HBsAg and HBeAg with the ELISA method.Measure the toxicity of medicine pair cell simultaneously with mtt assay.
1.5 medicine pair cell half toxic concentration (CC
50) the mtt assay detection of drugs set up according to Mosmann of mensuration cytotoxicity (Y.Nakajima, Y.Saton, M.Katsumata, K.Tsujiyama, Y.Ida, and J.Shoji, Phytochemistry 1994,36,119-127).Concrete grammar is: in the cell hole of supernatant is removed in suction, add 0.4mg/mLMTT, 0.1mL/ hole, 37 ℃ of 5%CO
2Cultivate 4h, remove supernatant, every hole adds the 0.1mL DMSO 99.8MIN., hatches 10min, is measuring the absorbance of solution under 490nm on the ELIASA.The destruction percentage η of medicine pair cell
Destroy=(A
The cell control group-A
Supply the test agent group)/(A
The cell control group-A
Blank control group) * 100,50% toxic concentration (CC
50) drug level when being control wells 50% for the experimental port survivaling cell.CC
50=Anti 1g [(C
50The percentage ratio of-＜50% destructive rate)/and (percentage ratio of the percentage ratio of＞50% destructive rate-＜50% destructive rate) * C+1g B], A: destructive rate is greater than 50% drug level; B: destructive rate is less than 50% drug level; C=1g A-1g B.
1.6 the mensuration of medicine pair cell half-inhibition concentration adopts ELISA (ELISA) to measure.Medicine is to the inhibition percentage η of HBsAg, HBeAg
Inhibitory=(A
The cell control group-A
Supply the test agent group)/A
The cell control group-A
Blank control group) * 100,50% inhibition concentration (IC
50) for HBsAg or HbeAg are 50% o'clock drug level with inhibiting rate, the same CC of method of calculation
50
2. result: (SI is a parameter of estimating the clinical drug application prospect to net result, SI=CC with selectivity index
50/ IC
50) estimate, wherein SI＞2 are nontoxic effective, and 1＜SI＜2 are poisonous effective, and SI＜1 is poisonous invalid.Concrete outcome is seen table 1, table 2 and table 3:
Table 1 compound (I) and (II) to the toxic action of Hep G2.2.15 cell
Table 2. compound (I) and (II) to Hep G2.2.15 cell HBsAg, HBeAg excretory restraining effect
Table 3. compound (I) and (II) to the inhibition effect of Hep G2.2.15 cell HBsAg, HBeAg
3. conclusion: experimental result shows, compound 11,12, the 13-triacetyl-25-alisol and 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, and 17 beta epoxide alisols have certain restraining effect external to HepG2.2.15 emiocytosis HBsAg and HBeAg.
Below come further to illustrate preparation method of the present invention and medicine through embodiment and form.
Embodiment 1:11,12,13-triacetyl-25-alisol and 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, the preparation of 17 beta epoxide alisols:
(1) 11,12, the preparation method of 13-triacetyl-25-dehydration alisol:
In the 10mL round-bottomed flask, add 98mg alisol A, 1.0ml acetic anhydride, 1.5ml pyridine stirring at room reaction 12h, in the reaction solution impouring 30ml frozen water, ethyl acetate extraction (3 * 50ml); Ethyl acetate layer is used 5% hydrochloric acid respectively, saturated sodium bicarbonate, saturated common salt water washing; Use anhydrous sodium sulfate drying then, reclaim under reduced pressure ETHYLE ACETATE gets 11; 12,13-triacetyl alisol; 11,12,13-triacetyl alisol and La Weisong reagent are at reflux in toluene 6h; Removal of solvent under reduced pressure gets bullion, and through silica gel column chromatography, with 6: 1 sherwood oil: the acetone wash-out gets compound 11; 12,13-triacetyl-25-alisol that dewaters, two step total recoverys: 65%;
Mass spectrum (MS) is measured with VG Auto Spec-3000 type mass spectrograph, adopts the FAB-MS technology; Nuclear magnetic resonance spectrum (
1H NMR with
13C NMR) measures mark in TMS does with Bruker AM-400 NMR spectrometer with superconducting magnet; The 200-300 order silica gel that Haiyang Chemical Plant, Qingdao produces is as the column chromatography material.
11,12,13-triacetyl-25-dehydration alisol structured data:
Molecular formula: C
36H
54O
7
Molecular weight: 598
Proterties: white solid powder
1H?NMR(CDCl
3，400MHz)δ5.02(1H，d，J＝5.6Hz，H-24)，4.95，4.93(1H?each，both?br?s，H-26)，4.84-4.91(2H，m，H-11，23)，2.04，2.01，1.96(3H?each，all?s，3×OCOC
H 3)，1.72(3H，s，C-27)；
13C?NMR(CDCl
3，100MHz)δ219.9(s，C-3)，170.1(s，O
COCH
3)，169.9(s，O
COCH
3)，169.8(s，O
COCH
3)，140.5(s，C-25)，137.0(s，C-13)，135.4(s，C-17)，114.6(t，C-26)，78.1(d，C-24)，73.0(d，C-11)，70.4(d，C-23)，56.8(s，C-14)，48.2(d，C-5)，46.9(s，C-4)，46.8(d，C-9)，40.8(s，C-8)，36.5(s，C-10)，35.6(t，C-22)，34.1(t，C-7)，33.4(t，C-2)，31.0(t，C-1)，30.4(t，C-15)，29.5(q，C-28)，29.2(t，C-12)，29.0(t，C-16)，28.1(d，C-20)，25.4(q，C-19)，24.0(q，C-30)，22.5(q，C-18)，21.7(q，OCO
CH
3)，20.9(q，OCO
CH
3)，20.8(q，OCO
CH
3)，20.2(q，C-21)，19.9(t，C-6)，19.7(q，C-29)，19.0(q，C-27)；positive?FAB-MS：m/z?599[M+1]
+。
(2) 11,12,13-triacetyl-25--13 β that dewater, the preparation method of 17 beta epoxide alisols:
In round-bottomed flask, add 98mg alisol A, 34mg metachloroperbenzoic acid and 3ml methylene dichloride, stirring at room reaction 2h is in an amount of frozen water of reaction solution impouring; Ethyl acetate extraction (3 * 30ml); Ethyl acetate layer is used anhydrous sodium sulfate drying, reclaim under reduced pressure ETHYLE ACETATE then with Sulfothiorine and the washing of saturated sodium bicarbonate (1: 1) mixed solution; Get 13 β, 17 beta epoxide alisols; 13 β, 17 beta epoxide alisols are stirring at room reaction 12h in acetic anhydride/pyridine system, in an amount of frozen water of reaction solution impouring, and ethyl acetate extraction; Ethyl acetate layer is used 5% hydrochloric acid respectively, saturated sodium bicarbonate, saturated common salt water washing; Use anhydrous sodium sulfate drying then, reclaim under reduced pressure ETHYLE ACETATE gets 11; 12,13-triacetyl-13 β, 17 beta epoxide alisols; 11,12,13-triacetyl-13 β; 17 beta epoxide alisols and La Weisong reagent are at reflux in toluene 6h, and removal of solvent under reduced pressure gets bullion, through silica gel column chromatography; Sherwood oil with 5: 1: the acetone wash-out gets compound 11,12,13-triacetyl-25--13 β that dewater; 17 beta epoxide alisols, three step total recoverys: 72%;
11,12,13-triacetyl-25--13 β that dewater, the structured data of 17 beta epoxide alisols:
Molecular formula: C
36H
54O
8
Molecular weight: 614
Proterties: white solid powder
1H?NMR(CDCl
3，400MHz)δ5.24-5.29(1H，m，H-11)，5.14(1H，d，J＝4.4，H-24)，5.08-5.13(1H，m，H-23)，4.96，4.94(1H?each，both?s，H-26)，2.09，2.04，2.02(3H?each，all?s，3×OCOC
H 3)，1.77(3H，s，C-27)；
13C?NMR(CDCl
3，100MHz)δ219.4(s，C-3)，169.9(s，2×O
COCH
3)，169.8(s，O
COCH
3)，140.4(s，C-25)，113.8(t，C-26)，77.4(s，C-17)，76.7(d，C-24)，71.5(s，C-13)，71.1(d，C-11)，70.8(d，C-23)，49.8(s，C-14)，48.4(d，C-5)，46.8(s，C-4)，46.3(d，C-9)，40.4(s，C-8)，36.5(s，C-10)，35.2(t，C-22).，34.6(t，C-7)，33.2(t，C-2)，32.0(d，C-20)，31.0(t，C-1)，30.6(t，C-15)，30.0(t，C-12)，29.5(q，C-28)，26.4(t，C-16)，25.6(q，C-19)，24.5(q，C-30)，21.6(q，OCO
CH
3)，20.9(q，OCO
CH
3)，20.8(q，OCO
CH
3)，19.9(t，C-6)，19.6(q，C-29)，19.4(q，C-18)，19.1(q，C-21)，16.6(q，C-27)；positive?ESI-MS：m/z637[M+Na]
+.
Embodiment 2:
Method by embodiment 1 makes 11,12 earlier, and 13-triacetyl-25-alisol that dewaters after a spot of DMSO dissolving, adds the injection water by routine, smart filter, and injection liquid is processed in the embedding sterilization.
Method by embodiment 1 makes 11,12 earlier, 13-triacetyl-25--13 β that dewater, and 17 beta epoxide alisols after a spot of DMSO dissolving, add the injection water by routine, smart filter, injection liquid is processed in the embedding sterilization.
Embodiment 3:
Method by embodiment 1 makes 11,12 earlier, and 13-triacetyl-25-alisol that dewaters is after a spot of DMSO dissolving; It is dissolved in the sterile water for injection, stirs and make dissolving, filter with aseptic suction funnel; Aseptic more smart filter is sub-packed in the ampoule, and aseptic sealing by fusing gets powder injection behind the frozen drying.
Method by embodiment 1 makes 11,12 earlier, 13-triacetyl-25--13 β that dewater; 17 beta epoxide alisols after a spot of DMSO dissolving, are dissolved in it in sterile water for injection; Stirring makes dissolving, filters with aseptic suction funnel, aseptic more smart filter; Be sub-packed in the ampoule, aseptic sealing by fusing gets powder injection behind the frozen drying
Embodiment 4:
With separate obtain 11,12,13-triacetyl-25-alisol that dewaters is that 9: 1 ratio adds vehicle in itself and vehicle weight ratio, processes pulvis.
With separate obtain 11,12,13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols are that 9: 1 ratio adds vehicle in itself and vehicle weight ratio, process pulvis.
Embodiment 5:
Method by embodiment 1 makes 11,12 earlier, and 13-triacetyl-25-alisol that dewaters is that 5: 1 ratio adds vehicle, pelletizing press sheet in itself and vehicle weight ratio.
Method by embodiment 1 makes 11,12 earlier, 13-triacetyl-25--13 β that dewater, and 17 beta epoxide alisols are that 5: 1 ratio adds vehicle, pelletizing press sheet in itself and vehicle weight ratio.
Embodiment 6:
Method by embodiment 1 makes 11,12 earlier, and 13-triacetyl-25-alisol that dewaters is processed oral liquid by conventional oral liquid method for making.
Method by embodiment 1 makes 11,12 earlier, 13-triacetyl-25--13 β that dewater, and 17 beta epoxide alisols are processed oral liquid by conventional oral liquid method for making.
Embodiment 7:
Method by embodiment 1 makes 11,12 earlier, and 13-triacetyl-25-alisol that dewaters is that 5: 1 ratio adds vehicle in itself and vehicle weight ratio, processes capsule.
Method by embodiment 1 makes 11,12 earlier, 13-triacetyl-25--13 β that dewater, and 17 beta epoxide alisols are that 5: 1 ratio adds vehicle in itself and vehicle weight ratio, process capsule.
Embodiment 8:
Method by embodiment 1 makes 11,12 earlier, and 13-triacetyl-25-alisol that dewaters is that 3: 1 ratio adds vehicle in itself and vehicle weight ratio, processes capsule.
Method by embodiment 1 makes 11,12 earlier, 13-triacetyl-25--13 β that dewater, and 17 beta epoxide alisols are that 3: 1 ratio adds vehicle in itself and vehicle weight ratio, process capsule.
Claims (4)
1. the compound 11,12 shown in the following structural formula, 13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols, X is the beta epoxide key in the formula,
2. the pharmaceutical composition of treatment hepatitis B wherein contains formula (I) compound and pharmaceutically acceptable carrier,
Wherein, when X was the beta epoxide key, compound was 11,12,13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols; When X was carbon-carbon single bond, compound was 11,12,13-triacetyl-25-alisol that dewaters.
3. the compound 11,12 of claim 1,13-triacetyl-25--13 β that dewater, the preparation method of 17 beta epoxide alisols; Comprise that the alisol A that obtains with separation and purification in the rhizoma alismatis is a reaction raw materials, stirring at room reaction 12h in acetic anhydride/pyridine system is in an amount of frozen water of reaction solution impouring; Ethyl acetate extraction, ethyl acetate layer are used 5% hydrochloric acid, saturated sodium bicarbonate respectively; Anhydrous sodium sulfate drying is used in the saturated common salt water washing then, reclaim under reduced pressure ETHYLE ACETATE; Get 11,12,13-triacetyl alisol; 11,12,13-triacetyl alisol and La Weisong reagent are at reflux in toluene 6h, and removal of solvent under reduced pressure gets bullion, and through silica gel column chromatography, with 6: 1 sherwood oil: the acetone wash-out gets compound 11,12,13-triacetyl-25-alisol that dewaters; In round-bottomed flask, add alisol A, metachloroperbenzoic acid and methylene dichloride in addition, stirring at room reaction 2h is in an amount of frozen water of reaction solution impouring; Ethyl acetate extraction; Ethyl acetate layer washs with 1: 1 Sulfothiorine and saturated sodium bicarbonate mixed solution, uses anhydrous sodium sulfate drying then, reclaim under reduced pressure ETHYLE ACETATE; Get 13 β, 17 beta epoxide alisols; 13 β, 17 beta epoxide alisols are stirring at room reaction 12h in acetic anhydride/pyridine system, in an amount of frozen water of reaction solution impouring, and ethyl acetate extraction; Ethyl acetate layer is used 5% hydrochloric acid respectively, saturated sodium bicarbonate, saturated common salt water washing; Use anhydrous sodium sulfate drying then, reclaim under reduced pressure ETHYLE ACETATE gets 11; 12,13-triacetyl-13 β, 17 beta epoxide alisols; 11,12,13-triacetyl-13 β, 17 beta epoxide alisols and La Weisong reagent are at reflux in toluene 6h; Removal of solvent under reduced pressure gets bullion, and through silica gel column chromatography, with 5: 1 sherwood oil: the acetone wash-out gets compound 11; 12,13-triacetyl-25--13 β that dewater, 17 beta epoxide alisols.
4. formula (I) compound 11,12,13-triacetyl-25-alisol or 11,12 that dewaters, 13-triacetyl-25--13 β that dewater, the application of 17 beta epoxide alisols in the preparation anti-hepatitis B medicine.
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| CN2008100582914A CN101255184B (en) | 2008-04-17 | 2008-04-17 | Hepatitis B resistant compound, medicament composition and use in medicament preparation |
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| CN2008100582914A CN101255184B (en) | 2008-04-17 | 2008-04-17 | Hepatitis B resistant compound, medicament composition and use in medicament preparation |
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| CN1775217A (en) * | 2005-05-27 | 2006-05-24 | 中国科学院昆明植物研究所 | Medicinal composition for treating Heptitis B |
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| Title |
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| Yoshikawa, Masayuki et al..Crude drugs from aquatic plants. I. On the constituents of Alismatis.《Chemical & Pharmaceutical Bulletin》.1993,第41卷(第11期),1948-54. * |
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