CN101716179B - Anti-hepatitis B pharmaceutical composition, preparation method and applications thereof - Google Patents
Anti-hepatitis B pharmaceutical composition, preparation method and applications thereof Download PDFInfo
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- CN101716179B CN101716179B CN200810233413A CN200810233413A CN101716179B CN 101716179 B CN101716179 B CN 101716179B CN 200810233413 A CN200810233413 A CN 200810233413A CN 200810233413 A CN200810233413 A CN 200810233413A CN 101716179 B CN101716179 B CN 101716179B
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Abstract
The invention discloses a pharmaceutical composition for the treatment of hepatitis B, which contains the effective amount of compounds 11, 23, 24, 25-tetra-oxide-acetyl alisol B in the formula (I) or excipient, and the invention further discloses a preparation method and applications thereof in medicines, in particular the application in preparing the medicine of anti-hepatitis B inhibitor and the medicine for the treatment of hepatitis B.
Description
Technical field: the invention belongs to technical field of pharmaceuticals, specifically, relate to a kind of pharmaceutical composition of treating hepatitis B, its preparation method, and the application of this pharmaceutical composition in preparation resistance of hepatitis B inhibitor medicaments and anti-hepatitis B medicine.
Background technology: according to World Health Organization (WHO), 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, hepatocarcinoma 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 RMB.The control HBV infection that is applied in of HBV vaccine immunity, various antiviral drugs 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, hepatocarcinoma.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 hepatocyte through receptor, sloughs adventitia behind the intrusion endochylema, forms core granule.Core granule moves to liver cell nuclear, and HBV DNA core granule shells and goes out, and in nucleus, forms cccDNA.CccDNA is the template of hepatitis B replication, is that hepatocyte 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 surfaceantigens; 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 granule with HBcAg, and then is assembled into complete HBV granule with HBsAg, discharges to the extracellular.Superfluous HBsAg is released into blood sometimes alone, forms microspheric form granule or cast granule.
It is active that some Chinese herbal medicine of research report have anti-HBV, can suppress the secretion of external HBsAg and HBeAg like Cacumen Securinegae Suffruticosae, Herba Hedyotidis Diffusae 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 inhibitory action in various degree to HBV DNA.Baicalin, kurarinone have the vitro inhibition effect to HBsAg and HBeAg.
The bifendate of China's development is a kind of effective ingredient with effect of reducing enzyme levels and treatment hepatitis of in synthetic schisandrin C process, finding.Glycyrrhizin preparations potenxin glycyrrhizin injection has effects such as mitigation symptoms, antiinflammatory and transaminase lowering to Patients with Viral Hepatitis.The regeneration product diammonium glycyrrhizinate of potenxin is the diammonium glycyrrhizinate levo-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), adefovir ester (adefovir dipivoxiil), Entecavir (enticavir), Sebivo (tibivudine).During these medicines are tested, HBV virus there is inhibitory action in external or body.Its mechanism of action is to become the triphosphoric acid chemical compound in the medicine entering cell, through the competition of substrate, to the polymerase or the reverse transcription 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 toleration 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 inoculation, is used for 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 immunomodulating.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 one 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 demand; But the chemical sproof problem of Antihepatitis medicament ubiquity of clinical practice now; Successfully develop the drug resistance that can solve medicine, the medicine of the resistance of hepatitis B of new generation that clinical efficiency height and toxic and side effects are less will have the very strong market competitiveness and market prospect.
So far, do not have 11,23,24 in the prior art, 25-four-oxygen-alisol acetyl A (I) does not have its pharmaceutical composition to be applied in the report in preparation or the treatment hepatitis B medicament as the report of the pharmaceutical composition of effective ingredient yet.
Summary of the invention: the object of the present invention is to provide to be used to treat hepatitis B pharmaceutical composition; Wherein contain 11 of treatment hepatitis B effective dose; 23,24,25-four-oxygen-alisol acetyl A (I) and pharmaceutical carrier or excipient; This preparation of drug combination method is provided, and this chemical 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:
Anti-hepatitis B pharmaceutical composition contains 11,23,24 shown in the formula (I), 25-four-oxygen-alisol acetyl A and pharmaceutically suitable carrier or excipient.
The present invention's preparation contains 11,23,24; The method of the medicine of 25-four-oxygen-alisol acetyl A (I) is in Alisol A, catalytic amount 4-dimethylamino naphthyridine, pyridine mixed liquor, to add suitable carboxylic acid anhydrides, and stirring at room reaction 4～24h is in an amount of frozen water of reactant liquor impouring; Ethyl acetate extraction, decompression and solvent recovery gets bullion; Through silica gel column chromatography, use petroleum ether: the acetone eluting gets Alisol A derivative (I), adds pharmaceutically suitable carrier and/or excipient and gets final product.
Also provide shown in the formula (I) 11,23,24, the 25-four-oxygen-application of alisol acetyl A in medicine.Particularly in preparation resistance of hepatitis B inhibitor medicaments with the treatment hepatitis B medicament in application.
In addition, pharmaceutical composition of the present invention can be used in preparation resistance of hepatitis B inhibitor medicaments equally and prepare in the treatment hepatitis B medicament.
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 materia medica, to nontoxic and inert pharmaceutically suitable carrier of humans and animals or excipient.
Described pharmaceutical carrier or excipient are one or more solids, semisolid and liquid diluent, filler and pharmaceutical preparation adjuvant.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.
The specific embodiment: in order to understand essence of the present invention better, will the present invention 11,23,24 be described with Test Example of the present invention below, the pharmacological action result of 25-four-oxygen-alisol acetyl A (I), but do not limit the present invention with this Test Example.
Test Example 1:
11,23,24,25-four-oxygen-alisol acetyl A (I) is to the drug toxicity of Hep G2.2.15 cell with to HBsAg, the excretory inhibitory action of HBeAg
1 material and method
1.1 material: 11,23,24,25-four-oxygen-alisol acetyl A (I); Lamivudine (lamivudine) (GlaxoSmithKline PLC pharmacy (Suzhou) company limited, the accurate word H20030581 of traditional Chinese medicines); Hep G2.2.15 cell (drawing air hospital) from Guangzhou; High sugared DMEM (GIBICO); G418 (GIBICO); Hyclone (Tianjin blood grinds institute); L-glutaminate (AMRESCO); Penicillin, streptomycin (Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group).
1.2Hep the G2.2.15 cell is cultivated with high sugared DMEM liquid, culture fluid adds 10% hyclone, 0.03%L-glutamine, 100mg/L G418,10
5The blue or green enzyme of IU/L is plain, 100mg/L streptomycin, 5%NaCO
3Transfer pH to 6.8-7.0.
1.3 instrument: ELIASA Bio-RAD680 (U.S.); CO
2Incubator Thermo Forma3310 (U.S.); Inverted biological microscope XD-101 type (Nanjing) etc.
1.4 experimentation with trypsin with Hep G2.2.15 cell dissociation, with having added the 0.03%L-glutamine, 100mg/L G418, the blue or green enzyme of 100IU is plain, the high sugared DMEM liquid of 100IU streptomycin 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% hyclone; The pastille culture fluid of 380 μ g/mL; Every kind of medicine is established four drug level, and each concentration is established three holes, four times of dilutions; Establish the blank groups of cells of a cell matched 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<sub >50</sub>) 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, Phytochemistry1994,36,119-127).Concrete grammar is: remove to add in the cell hole of supernatant 0.4mg/mL MTT, 0.1mL/ hole, 37 ℃ of 5%CO to suction<sub >2</sub>Cultivate 4h, remove supernatant, every hole adds the 0.1mL dimethyl sulfoxide, hatches 10min, is measuring the absorbance of solution under 490nm on the ELIASA.The destruction percentage rate η of medicine pair cell<sub >Destroy</sub>=(A<sub >The cell matched group</sub>-A<sub >Supply the test agent group</sub>)/(A<sub >The cell matched group</sub>-A<sub >Blank control group</sub>) * 100,50% toxic concentration (CC<sub >50</sub>) drug level when being control wells 50% for the experimental port survivaling cell.CC<sub >50</sub>=Antilg [(C<sub >50</sub>-<the percent of 50% destructive rate)/(>The percent of 50% destructive rate-<the percent of 50% destructive rate) * and C+lg B], A: destructive rate is greater than 50% drug level; B: destructive rate is less than 50% drug level; C=lg A-lg B.
1.6 the mensuration of medicine pair cell half-inhibition concentration adopts ELISA (ELISA) to measure.Medicine is to the inhibition percentage rate η of HBsAg, HBeAg
Inhibitory=(A
The cell matched group-A
Supply the test agent group)/A
The cell matched group-A
Blank control group) * 100,50% inhibition concentration (IC
50) for HBsAg or HbeAg are 50% o'clock drug level with suppression ratio, the same CC of computational methods
50
2, result: (SI is for estimating the parameter of clinical drug application prospect, SI=CC with selection index for final result
50/ IC
50) estimate SI > wherein; 2 is nontoxic effective, 1<sI<2 is poisonous effective, SI<1 is poisonous invalid.Concrete outcome is seen table 1, table 2 and table 3:
3, conclusion: the experimental result demonstration, 11,23,24,25-four-oxygen-alisol acetyl A (I) has certain inhibitory action external to Hep G2.2.15 emiocytosis HBsAg and HBeAg.
Table 111,23,24,25-four-oxygen-alisol acetyl A (I) is to the toxic action of Hep G2.2.15 cell
Table 2.11,23,24,25-four-oxygen-alisol acetyl A (I) is to HepG2.2.15 cell HBsAg, the excretory inhibitory action of HBeAg
Table 3.11,23,24,25-four-oxygen-alisol acetyl A (I) is to the inhibition effect of Hep G2.2.15 cell HBsAg, HBeAg
Below come further to illustrate method for preparing of the present invention and medicine through embodiment and form.But do not limit content of the present invention with this.
Embodiment 1:11,23,24, the method for preparing of 25-four-oxygen-alisol acetyl A (formula I compound):
In the 10mL round-bottomed flask, add 98mg Alisol A, 2mL pyridine, 5.0mg4-dimethylamino pyridine, stir, in mixed liquor, drip the 3mL acetic anhydride, stirring at room reaction 24h; In an amount of frozen water of reactant liquor impouring, ethyl acetate extraction, decompression and solvent recovery gets bullion; Through silica gel column chromatography, use petroleum ether: acetone=6:1 eluting gets chemical compound 11,23; 24,25-four-oxygen-alisol acetyl A (I) adds pharmaceutically suitable carrier and/or excipient and gets final product.
Mass spectrum (MS) is measured with VG Auto Spec-3000 type mass spectrograph, adopts the FAB-MS technology; Nuclear magnetic resoance 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.
11,23,24, the structured data of 25-four-oxygen-alisol acetyl A (I):
Structural formula: shown in right figure.
Spectral data:
1H?NMR(CDCl
3，400MHz)δ5.14(1H，d，J＝2.8Hz，H-24)，5.00-5.04(1H，m，H-11)，4.90-4.97(1H，m，H-23)，2.14(3H，s，OCOCH
3)，2.03(3H，s，OCOCH
3)，2.01(3H，s，OCOCH
3)，1.95(3H，s，OCOCH
3)；
13C?NMR(CDCl
3，100MHz)δ219.9(s，C-3)，170.2(s，O
COCH
3)，170.1(s，O
COCH
3)，169.9(s，O
COCH
3)，169.5(s，O
COCH
3)，136.9(s，C-13)，135.6(s，C-17)，82.2(s，C-25)，76.9(d，C-24)，73.1(d，C-11)，69.2(d，C-23)，56.9(s，C-14)，48.3(d，C-5)，?46.95(s，C-4)，46.90(d，C-9)，40.7(s，C-8)，38.1(t，C-22)，36.6(s，C-10)，34.2(t，C-7)，33.4(t，C-2)，31.1(t，C-1)，30.5(t，C-15)，29.5(q，C-28)，29.3(t，C-12)，29.2(t，C-16)，28.1(d，C-20)，25.4(q，C-19)，24.0(q，C-30)，23.3(q，C-26)，22.44(q，C-18)，26.36(q，C-27)，22.3(q，OCO
CH
3)，21.7(q，OCO
CH
3)，21.1(q，OCO
CH
3)，20.7(q，OCO
CH
3)，20.2(q，C-21)，19.9(t，C-6)，19.8(q，C-29)；ESI-MS：m/z681[M+Na]
+.
Embodiment 2:
Method by embodiment 1 makes 11,23,24 earlier, and 25-four-oxygen-alisol acetyl A after a spot of DMSO dissolving, adds the injection water by routine, fine straining, and injection is processed in the embedding sterilization.
Embodiment 3:
Method by embodiment 1 makes pool 11,23,24 earlier; 25-four-oxygen-alisol acetyl A after a spot of DMSO dissolving, is dissolved in it in sterile water for injection; Stirring makes dissolving, filters aseptic again fine straining with aseptic suction funnel; Be sub-packed in the ampoule, aseptic sealing by fusing gets injectable powder behind the frozen drying.
Embodiment 4:
With separate obtain 11,23,24,25-four-oxygen-alisol acetyl A is that the ratio of 9:1 adds excipient in itself and excipient weight ratio, processes powder.
Embodiment 5:
Method by embodiment 1 makes 11,23,24 earlier, and 25-four-oxygen-alisol acetyl A is the ratio adding excipient of 5:1 in itself and excipient weight ratio, pelletizing press sheet.
Embodiment 6:
Method by embodiment 1 makes 11,23,24 earlier, and 25-four-oxygen-alisol acetyl A is processed oral liquid by conventional oral liquid method for making.
Embodiment 7:
Method by embodiment 1 makes 11,23,24 earlier, and 25-four-oxygen-alisol acetyl A is the ratio adding excipient of 5:1 in itself and excipient weight ratio, processes capsule.
Embodiment 8:
Method by embodiment 1 makes 11,23,24 earlier, and 25-four-oxygen-alisol acetyl A is the ratio adding excipient of 3:1 in itself and excipient weight ratio, processes capsule.
Claims (1)
1. 11,23,24 shown in the formula (I), the application of 25-four-oxygen-alisol acetyl A in preparation treatment hepatitis B medicament,
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| CN200810233413A CN101716179B (en) | 2008-10-09 | 2008-10-09 | Anti-hepatitis B pharmaceutical composition, preparation method and applications thereof |
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|---|---|---|---|
| CN200810233413A CN101716179B (en) | 2008-10-09 | 2008-10-09 | Anti-hepatitis B pharmaceutical composition, preparation method and applications thereof |
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| CN101716179A CN101716179A (en) | 2010-06-02 |
| CN101716179B true CN101716179B (en) | 2012-09-05 |
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