CN101829096B - Application of ring E iodine substituted silybin in preparing medicaments for treating viral hepatitis B - Google Patents

Abstract

The invention relates to application of ring E iodine substituted silybin in preparing medicaments for treating viral hepatitis B, in particular to application of a compound of a formula (1) and a pharmaceutically acceptable salt thereof in preparing medicaments for clearing away hepatitis B surface antigens (HBsAg) and hepatitis e antigens (HBeAg) and suppressing the HBV (Hepatitis B Virus) DNA replication. The compound has definite activity of suppressing the HBsAg and the HBeAg, and in the presence of a concentration of 100 micrograms/milliliter, the intensities of the compound for clearing away the HBsAg and the HBeAg are respectively 20.0 percent and 29.0 percent which exceed that of a positive control medicament (10,000 units/milliliter of alpha-interferon) by 24 percent and 72 percent. Meanwhile, in the presence of the concentration, the suppression ratio of the compound on the HBV DNA is 32.6 percent which is close to that of the alpha-interferon. Accordingly, the flavone lignan or the pharmaceutically acceptable salt thereof are indicated to be capable of being used for preparing non-nucleoside medicaments for clearing away the HBsAg and the HBeAg, suppressing the HBV DNA replication and treating HBV infection diseases.

Description

E ring iodine substituted silybin is used to prepare the purposes of treatment viral hepatitis B medicine

Technical field

The present invention relates to medical technical field; Particularly, the present invention relates to a kind of E ring substituted silybin ester of iodine or its officinal salt and be used to prepare the purposes that reduces HBsAg HBsAg and hepatitis B virus e antigen HBeAg, inhibition HBV dna replication dna, treats hepatitis b virus infected disease medicament.This flavanolignan has definite inhibition HBsAg and HBeAg is active; Its intensity of removing HBsAg and HBeAg is respectively 20.0% and 29.0% under 100 mcg/ml concentration, surpasses positive control medicine (alpha-interferons of 10000 units per ml) 24% and 72% respectively; Simultaneously, it demonstrates about 32.6% suppression ratio to HBV DNA when this concentration, near alpha-interferon.Above pharmacodynamic result shows that this flavanolignan or its officinal salt can expect to be used to prepare and removes the purposes that HBsAg and HBeAg, inhibition HBVDNA duplicated, treated hepatitis b virus infected disease non-nucleoside medicine.

Background technology

Hepatitis B (hepatitis B) is the infectious disease that is caused by hepatitis b virus hbv.HBV is a member of Hepadnaviridae hepadnaviridae, and it is shaped as the spheroidal particle of diameter 42 nanometers.HBV is peculiar virus, and less being infectious in other animal has only in human body or primate chimpanzee body and just can duplicate.This virus is propagated through hepatitis B virus carriers and hepatitis B patients'blood, saliva, seminal fluid, vaginal secretions, has chronic carrier state.Hepatitis B is widely current in China, and because of it is divided in vertical transmission, horizontal transmission, the family propagation, iatrogenic infection and multiple mode such as spread through sex intercourse, high to the crowd infection rate, infection rate reaches more than 35% in certain areas.According to interrelated data, hepatitis detects male patient and has reached 1.89 hundred million, and the number (carrier) nearly 400,000,000 of should not going to a doctor is one of the most serious infectious disease of current harm people ' s health.Hepatitis B clinical manifestation variation is prone to develop into chronic hepatitis B (CHB) and liver cirrhosis, and few patients can change primary hepatocarcinoma into.

Hepatitis B surface antigen (HBsAg) is the coat protein of hepatitis B virus, and the HBsAg positive is a goldstandard of judging that HBV infects.HBsAg is positive but do not have the hepatitis symptom person of appearance and become HBV virus carrier.The HBsAg titre is big more, and it is just big more that it merges the active probability that raises of HBcAg HBeAg, the HBV DNA positive and DNA polymerase, thereby infectiousness is strong more.Therefore, suppress the secretion of HBsAg and duplicate be in the research and development anti-hepatic-B virus medicine important target with detect target.Report: hepatitis B HBsAg such as the refined cloud of the Wu of Beijing Ditan Hospital remove and there is certain dependency in hepatitis B closed loop covalency DNA (cccDNA), and removing HBsAg is the significantly reduced sign of cccDNA level.2002, deliver the researcher of result of study at " New England Journal of Medicine " and think: for CHB patient, remove as before liver cirrhosis, obtaining HBsAg, then its liver cirrhosis and hepatocarcinoma incidence rate will reduce by 60 times.All HBsAg serum is removed as one of treatment terminal point determining standard in the guide of the AASLD of U.S. hepatopathy research association, the Asia-Pacific liver APASL of research association and the EASL of EASL.

According to European liver EASD in 2008 annual meeting: Polyethylene Glycol Intederon Alpha-2a treatment CHB patient 48 week drug withdrawals afterwards; Followed up a case by regular visits to 1,2,3,4 year; Its HBsAg clearance rate is respectively 3%, 6%, 8% and 11%; And with the lamivudine person HBsAg clearance rate was merely 0%, 0%, 0% and 3% in 1,2,3,4 year after drug withdrawal separately, thereby this interferon is considered to treat the negative CHB patient's optimal treatment of HBeAg and selects.Have important social and economic benefit it is thus clear that find the medicine that efficiently to remove HBsAg.

Hepatitis B virus e antigen HBeAg is the structural protein of hepatitis B viruses (HBV) kernel, when hepatitis B virus is bred, produces in a large number.Hepatitis B viruses (HBV) has in all known dna viruses minimum genome (only 3.2kb), its gene five kinds of albumen (S, C, E, P, X) of mainly encoding.C albumen is viral core protein, and the E albumen proteic part that is C becomes hepatitis B virus e antigen (HBeAg), and it is to have encoded but unassembled albumen in the virion can be secreted in the blood samples of patients when virus replication and go.Clinically, usually serum HBeAg is treated as hbv replication, infectiousness, the degree that is in a bad way and to it and reply the important symbol thing of estimating.This antigen and HBV DNA are closely related, are to express the very practical blood serum designated object of virus replication clinically.In its body of blood serum designated object HBeAg positive patient explanation hbv replication is arranged, so higher infectiousness is arranged.It is strong more that patient HBeAg expresses this patient's infectiousness of high more explanation.In like manner, suppress the secretion of HBeAg and duplicate also be in the research and development anti-hepatic-B virus medicine important target with detect target.HBeAg removes in the explanation body has lasting HBV to suppress, and ALT is normal, and the tissue inflammation necrosis alleviates, and the liver cirrhosis odds reduces.Therefore, serum HBeAg is believed to reflect more stable therapeutic effect, and HBeAg serum clear flag patient's immune system and begun to play a role.2002, deliver the researcher of result of study at " New England Journal of Medicine " and think: for CHB patient, remove as before liver cirrhosis, obtaining HBeAg, then its liver cirrhosis and hepatocarcinoma incidence rate will reduce by 10 times.All HBeAg serum is removed as one of treatment terminal point determining standard in the guide of the AASLD of U.S. hepatopathy research association, the Asia-Pacific liver APASL of research association and the EASL of EASL.So, can suppress, reduce HBeAg expression or active medicine and also promptly belong to treatment hepatitis B virus infection active drug.

At present, the medication to hepatitis B patient mainly is divided into several big type of the liver protecting and ALT lowering, antiviral, anti-hepatic fibrosis and adjusting immunity etc.Antiviral is a basic method, and the liver protecting and ALT lowering is an auxiliary treatment, takes stopgap measures and rarely seen effecting a permanent cure more.The research that still is the antiviral treatment aspect that made progress in the last few years.Yet; Can only reach for viral hepatitis B therapeutic scheme clinically at present and suppress hbv replication and secondary infection; Main medicine is still nucleoside medicine such as lamivudine (3-TC), Entecavir, adefovirdipivoxil (ADV), Sebivo etc., is in the interim emtricitabine of clinical trial, tenofovir, clevuding etc. in addition.In China, lamivudine has become the medical insurance medication, is applied to large quantities of HBV patients.Nucleoside medicine part advantage is: bioavailability is high, and is oral safer.Yet, though their disease controlling, fetch long prices first effectively; Second life-time service all drug resistance can occur, and the bounce-back in various degree that occurs HBV DNA, ALT and liver histological after the drug withdrawal; The 3rd, the comparatively tangible well-known ill effect that the life-time service nucleoside medicine occurs, for example kidney injury, baby's teratogenesis etc.Headache is the most: virus is drug-fast cure rate to occur greatly reducing; Because nucleoside medicine is reversible to virus replication, thus to most of patient if desire to reach greatest treatment efficacy, the course of treatment must be more than 1 year; So its drug resistance occurs thereupon, does not just reach the effect of expection.Nucleoside medicine be difficult in addition remove cccDNA, treatment after 1 year HBsAg be difficult to weak points such as cloudy commentaries on classics.

The biological engineering class antiviral drugs that interferon (α, beta-interferon) and recombinant interferon class etc. derive from the HL becomes research and treatment CHB focus medicine in the recent period, and it has antiviral and immunomodulating dual function.Thereby it both can suppress virus replication through antivirus action and alleviate the liver cell inflammatory reaction, reduces hepatocellular damage, plays and improves patients clinical symptom and liver physiological function thereby delay PD; Again can the enhance immunity effect, through the effect of natural killer cell in the intensive aspect and helper T lymphocyte, especially can promote killer T cell to go to kill and wound by virus infected cell, therefore play antivirus action indirectly.The HBsAg serology conversion that interferon therapy CHB patient obtains is more more lasting than lamivudine, and " digestive tract " magazine the next item up research in 2003 shows: 3 years relapse rates of interferon therapy group HBsAg significantly are lower than the lamivudine group; And long-acting interferon can use weekly once, and is comparatively convenient.Therefore, interferon day by day becomes one of choice drug that is used to treat chronic viral hepatitis B virus clinically, but that its side effect and untoward reaction are reported is more, and total effective rate is not high, costs an arm and a leg, and patient economy burden is big, thereby causes and be difficult to clinically be widely used; And do not use the decompensated cirrhosis patient is suitable.

Along with the research of hepatopathy, developed the analysis of standardized HBV DNA in recent years, advanced understanding greatly the hepatitis B patient state of an illness.The quantitative analysis of HBV DNA can be predicted the seriousness and the prognosis thereof of hepatitis B, because HBV DNA lasting masculin (promptly continuing viremia) makes the hepatitis B disease progression easily and increases the weight of; High hepatitis B virus (HBV DNA) content promotes the formation of liver cirrhosis easily; The lasting existence of HBV DNA is that the high risk factor, particularly viral level of hepatocarcinoma (HCC) generation is higher, the course of disease is long, older or merge other liver patient; The HBV DNA that continues high concentration exists, and the mortality rate that can cause losing compensatory liver cirrhosis and constitutional liver serious symptom obviously increases.Simultaneously must recognize that the relation of HBV dna level and liver histological is extremely close: bibliographical information is through antiviral therapy, and the improvement of hepatic fibrosis and elimination are obviously; Recent international hepatopathy meeting report is imitated by force and hang down chemical sproof antiviral therapy, along with the reduction of HBV DNA with turn out cloudy, reverse in various degree can occur and observe liver cirrhosis, and therefore the opinion liver cirrhosis also should carry out antiviral therapy now.

Therefore, the application of HBV DNA index in antiviral therapy also plays a part very important: the level of HBV DNA is the important indicator whether the decision chronic hepatitis B needs antiviral therapy; Make the HBeAg positive or negative difference treatment standard and the requirement of HBeAg respectively according to the different situations of HBV DNA; In antiviral therapy, according to the therapeutic response of HBVDNA, judge whether that virusology replys in early days and then determine the strategy of long-term prescription to reply with the virusology that obtains persistence, reach and continue the purpose that virus suppresses; According to the virological situation of replying of HBVDNA, create serological switching foundation of HBeAg and condition, to reach its good middle therapeutic goal; Continue the inhibition situation according to HBV DNA and strive for that virus continues feminine gender, to strive for reaching the final therapeutic goal of antiviral; Continue to be suppressed fully according to HBV DNA, also demonstrated improvement in various degree and the disappearance of cccDNA; In antiviral therapy, assess and prevent the risk of caused virus variation of antiviral drugs and drug resistance generation with the variation of HBV DNA; In case when virus variation or drug resistance took place, the variation of HBV DNA was unique signal at first and diagnosis basis, also be treatment drug resistance and the guidance and the foundation that change therapeutic strategy.In sum, the inhibition degree of HBV DNA there is new important meaning in the further diagnosis of hepatitis B and treatment,, assessment hepatitis B prognosis and drug resistance danger is all had bigger directive function the observation of curative effect.

Can be known by above-mentioned factor: the basic link of another one that the inhibition hepatitis B virus is bred in vivo is to suppress duplicating of HBV DNA.The reduction of HBV dna level or be lower than detection level be the check antiviral drugs other one JINYAOSHI.So, Asia-Pacific liver EASD and European liver EASD all with the HBV DNA detection less than as one of hepatitis B virus patient treatment terminal point.Also tested compounds is regarded as one of the test event that to accomplish in China's new drug development guide for the inhibition strength of HBV DNA.Why lamivudine can become first-selected nucleoside medicine is because it has the activity of the inhibition HBV dna replication dna of strong effect.Therefore can suppress the novelty medicine that chemical compound that the HBV dna replication dna can suppress HBsAg and/or HBeAg again will more promise to be the treatment hepatitis B patient.

Mandatory declaration be: the antiviral drugs of using at present is the inhibitor of virus replication just in fact, directly kill virus and break virus body, otherwise will damage host cell.These antiviral drugs (being mostly nucleoside medicine) also exist above-mentioned toxic and side effects big, be prone to cause and be prone to shortcoming such as knock-on after viral gene sudden change, the drug withdrawal.Therefore the development of new antiviral drugs is the task of top priority in current medicament research and development field, and it all has extremely important social meaning and economic implications for treatment China a large amount of hepatitis B patient and virus carrier, the control source of infection etc.So; New non-nucleoside hepatitis B virus inhibitor and this type of lead compound that can reduce HBsAg, HBeAg or inhibition HBV dna replication dna of discovery has very big guiding significance from the natural drug of national folk life-time service, and vast development prospect is arranged.

Based on this purpose; The inventor once accomplished the patent and the article of multinomial anti-hepatitis virus natural product and structure of modification derivant thereof in the past; Having found that multiple inhibition HBsAg HBsAg or hepatitis B virus e antigen HBeAg are active, suppressed the chemical compound of HBV dna replication dna, is feasible [referring to " medical usage of one type of mapping eucalyptus globulus alkanol type sesquiterpene for inhibiting hepatitis virus " (Zhao Yu, Liu Guangming, Yu Rongmin, Li Haibo etc. thereby explanation filters out the novelty medicine that can reduce HBsAg or HBeAg, control hepatitis B virus infection from natural product and synthesis of derivatives thereof; ZL 200610053827.4); " medical usages of 2 beta-hydroxy Ilicis Purpureae acid for inhibiting hepatitis B virus " (Lee school Kun, Zhao Yu, Huang Kexin, Li Haibo etc.; ZL200610053749.8); " 2 α, the medical usage of 3 beta-dihydroxies-5,11 (13)-diene eucalyptus globulus alkane-12-acid for inhibiting hepatitis B virus " (Zhao Yu, Zhang Li and, Dong Sun Han, Li Haibo etc.; ZL200610053601.4); The purposes and the pharmaceutical composition thereof of hepatitis B virus " the eremophilane lactone suppress " (Zhao Yu, Li Haibo, Yang Leixiang, girth are new etc.; ZL 03153691.3); " a kind of Eremophilone lactones acid natural product and application thereof " (Zhao Yu, girth are new, Shi Shuyun, Wang Xiaoyu etc.; ZL 200610053575.5); " a kind of eudesmane type sesquiterpenes acid and uses thereof " (Zhao Yu, Liu Guangming, Li Haibo, Wu Xiumei etc.; ZL 200610053579.3); " purposes of laggera plant abstract in inhibiting herpes simplex virus and hepatitis B virus " (Zhao Yu, girth are new, Yu Rongmin, Bai Hua; CN 1989989A); " medical usage of 1 β-oxo-5,11 (13)-diene eucalyptus globulus alkane-12-acid for inhibiting hepatitis B virus " (Zhao Yu, Lee school Kun, Huang Kexin, Li Haibo etc.; CN 1927197A); " medical usage of 1 beta-hydroxy Ilicis Purpureae acid for inhibiting hepatitis B virus " (Zhao Yu, Lee school Kun, Huang Kexin, Wu Xiumei etc.; CN 1935131A); " medical usage of acid of mapping eremophilane and inhibition hepatitis B surface antigen thereof " (Huang Kexin, Lee school Kun, Wang Xiaoyu, Zhao Yu etc.; CN 101239054); " 1-oxygen-substituted benzene formyl quinic acid chemical compound and inhibition hepatitis B virus purposes thereof " (Lee school Kun, Hu Lihong, Wu Xiumei, Zhao Yu etc.; CN101293836); The inhibition HBsAg that the inventor has delivered, HBeAg and HBV DNA isoreactivity article are referring to " In Vitro Antiviral Activity of Three EnantiomericSesquiterpene Lactones from Senecio Species Against Hepatitis B Virus "; Haibo Li (Li Haibo); Changxin Zhou (girth is new), Xiumei Wu (Wu Xiumei), YuZhao* (Zhao Yu) etc.; Antiviral Chemistry&Chemotherapy; 2005,16,277-282; " Evaluation of Antiviral Activity of Compounds Isolated fromRanunculus sieboldii Miq.and Ranunculus sceleratus L ", Haibo Li (Li Haibo), Changxin Zhou (girth is new); Xiumei Wu (Wu Xiumei); Yu Zhao* (Zhao Yu) etc., Planta Medica, 2005; 71 (12), 1128-1133; " Application ofhigh-speed counter-current chromatography for the isolation of antiviraleremophilenolides from Ligularia atroviolacea ", Shi, Shu-Yun (Shi Shuyun); Hai-Bo (Li Haibo), Zhao, Yu (Zhao Yu) etc.; Biomedical Chromatography; 2008,22 (9), 985-991; " Purification and identification of antiviralcomponents from Laggera pterodonta by high-speed counter-currentchromatography "; Shuyun Shi (Shi Shuyun); Yu Zhao (Zhao Yu) etc., Journalof Chromatography B, 2007; 859,119-124].Undoubtedly; Continuation is sought from natural product and structure of modification derivant thereof, and can to remove lead compound that HBsAg or HBeAg, inhibition HBVDNA duplicate be unusual being necessary property and urgent, also therefore classified as one of great special project of new drug development by the Ministry of Science and Technology.

In above-mentioned treatment CHB medicine, also have one type to be type of protecting the liver medicine, its clinical a large amount of uses be typically the silymarin in the seed that is present in the feverfew Herba Silybi mariani.Herba Silybi mariani is extensive use clinically, its commodity Legalon by name on market ^TMGrand or the Flavobion of sharp liver ^TM, its representative compound surely belongs to flavanolignan's silibinin.Flavone lignin compound belongs to weedtree quality class, is one type of natural product of and a part flavone be combined into plain by a part phenylpropyl alcohol.Silibinin content is maximum in the Herba Silybi mariani, and activity is also the highest.This medicine effect mainly contain following some: (one) free radical resisting is active: silymarin has protective effect for the hepatic injury that is caused by carbon tetrachloride, galactosamine, alcohols and other hepatotoxin.People such as nineteen ninety Lotteron have reported in the Mouse Liver microsome; Silymarin can reduce external lipid peroxidation that is caused by the carbon tetrachloride metabolism and the peroxidation that is caused separately by reduced coenzyme, and these show that all silymarin is the chain interruption antioxidant or is free radical scavenger.(2) protection liver plasma membrane: keep flowability of cell membranes through the anti peroxidation of lipid reaction, the protection liver plasma membrane.Can also block combining of special receptor on mycotoxin phalloidine and α-amanitin etc. and the hepatocyte, suppress it, interrupt its liver sausage circulation, thereby the enhance hepatocyte film be for the resistance of multiple damage factor hepatocellular attack and transmembrane transport.(3) promote hepatocellular reparation and regeneration: silibinin can combine with ER after getting into cell; And make it to activate; Activated receptors can enhance hepatocyte nuclear RNA polymerase 1 activity, rna transcription is strengthened, promote enzyme and proteinic synthetic; And promote the synthetic of DNA indirectly, help hepatocellular reparation and regeneration.(4) antitumor action: various active oxygens can form 8-hydroxyl guanine by the oxidation guanine, cause DNA damage, and then cause tumor, and silibinin has also shown the effect of prevention and treatment tumor as an effective free radical resisting material.This medical instrument of the clinical trial certificate of three more than ten years has definite curative effect and hypotoxicity (to consult Flora, K. etc., Am.J.Gastroenterol, 1998,93,139-143; Saller, R. etc., Drugs, 2001,61 (14), 2035-2063;

R. etc.; Curr.Med.Chem.2007; 14,315-338; Z. etc.; Phytother.Res.2003; 17,524-530;

R. etc.; Bioorg.Med.Chem.2004; 12,5677-5687; Varga, Z. etc.; Phytothe.Res.2001,15,608-612.Singh, R.P. etc., Curr.CancerDrug Tar.2004,4,1-11).Therefore; The flavone lignin chemical compound that with the silibinin is representative has caused increasing concern; In the period of 2006-2009, prepare and a plurality of serial silibinin analog derivative reported also has obvious antioxidation activity (Yang Leixiang, Zhao Yu etc., " Design, synthesis andexamination of neuron protective properties of alkenylated and amidateddehydro-silybin derivatives " like the inventor; Journal of Medicinal Chemistry; 2009,52 (23), 7732-7752; Wang Feng; Zhao Yu etc.; " Preparation of C-23esterified silybinderivatives and evaluation of their lipid peroxidation inhibitory and DNAprotective properties ", Bioorganic&Medicinal Chemistry, 2009; 17 (17), 6380-6389; Yang Leixiang, Zhao Yu etc., " Synthesis and antioxidant propertiesevaluation of novel silybin analogues "; Journal of Enzyme Inhibition andMedicinal Chemistry; 2006,21 (4), 399-404; Or the like).In the above-mentioned article of inventor report, A ring, B ring, E ring, 23 substituted flavanolignan compounds of a plurality of series that design and synthesize out through the inventor all demonstrate strong effect and catch the activity of DPPH free radical and ultra-oxygen anion free radical, antioxidant activity and protection PC12 cell activity.But obvious: above-mentioned research only concentrates on antioxidation and the cytoprotection of studying the silibinin flavonolignan.

(2006) in the recent period; Xie Jun has reported that Combined application has the interferon of antiviral and immunomodulating dual function and the silibinin phosphatide complexes of hepatoprotective is treated the result of chronic viral hepatitis B; It is more obvious with the interferon effect than independent to find that drug combination reduces ALT, AST value in patient's body, explains that the silibinin phosphatide complexes can strengthen the effect of the treatment chronic viral hepatitis B of interferon.But similarly therapeutic scheme is still flavanolignans such as silibinin as adjuvant drug, and mainly is to be used to protect liver plasma membrane but not directly to implement antivirus action with it.(left side is state-run for the state-run grade in a left side; Liu Shuling, Xu Guili, world Chinese digests magazine; 2006 14 13 phases of volume; The 1241-1246 page or leaf) summarized the active progress of the external anti-HBV of medicinal plants composition over nearly 20 years, the multiple natural product of touching upon in the literary composition does not report that wherein any flavanolignan compounds has the active relative recording of anti-HBV.Especially silibinin class natural product and derivant thereof, domestic almost nobody relates to, and only by inventor team it has been carried out structure of modification and the antioxidant activity research that forefathers do not add attention.

Though be the antioxidation curative effect that flavanolignan's chemical compound of representative has the above with the silibinin, yet that it appears in the newspapers is less relatively in the document of antiviral therapy aspect.The compounds for treating DNA of flavanolignan viroid infection especially its new purposes that is used for anti-hepatitis virus aspect (comprising inhibition hepatitis B surface antigen HBsAg or HBeAg, inhibition HBV dna replication dna) is effectively developed as yet.So from flavanolignan, seek the reactive compound in anti-hepatitis virus field; Also being about to flavanolignan's structure of modification, to make it have anti-DNA viroid activity be a brand-new field, from wherein finding to remove the lead compound challenge that forefathers did not attempt especially that HBsAg or HBeAg, inhibition HBVDNA duplicate.In order to explore this field; Our design has also prepared and silibinin structure a kind of new flavanolignan's derivant of difference to some extent; The E ring module that also is about to former silibinin transform 3-iodo-4-hydroxy-5-methyl oxygen base substitute mode as; Change whole molecular conjugation scope and conjugation intensity; Introduce halogen iodine atom and new hydrogen bond receptor or donor simultaneously, so design can generate the plain flavanone alcohol compound (also being one type of novel flavanolignan chemical compound) of one type of novel wooden that the new spatial structure is different from silibinin.In the hope of reducing flavanolignan's lead compound of HBsAg or HBeAg, inhibition HBV dna replication dna, have the novelty medicine that can remove HBsAg or HBeAg, inhibition HBV dna replication dna, treatment CHB thereby it is developed further into, accomplish the present invention in view of the above.

Summary of the invention

The purpose of this invention is to provide the E ring substituted silybin ester flavonolignan of iodine shown in the formula (1) or its officinal salt is used for preparation and removes the new purposes that HBsAg or HBeAg, inhibition HBVDNA duplicated, treated the hepatitis B medicine.

The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.

The present invention also provides the method for the substituted silybin esters flavonol of the E ring iodine lignin chemical compound shown in a kind of preparation formula (1); It is characterized in that realizing through following steps: the 3-iodo-4-hydroxy-5-methyl substituted benzaldehyde of oxygen base (I-a) obtains the 3-iodo-4-hydroxy-5-methyl substituted ethyl cinnamate of oxygen base (I-b) with the phosphorus ylide condensation in chloroformic solution; In anhydrous tetrahydro furan, it is substituted to hydroxyl cinnamyl alcohol (I-c) to obtain 3-iodo-4-hydroxy-5-methyl oxygen base with lithium aluminium hydride-alchlor in the room temperature reduction.Dihydroquercetin (II) and I-c are oxidant with the Disilver carbonate in anhydrous benzene and anhydrous propanone mixed solvent, obtain the substituted silibinin analog of E ring iodine shown in the formula (1) through oxidative coupling:

Wherein, R ₁Be the iodine atom, R ₂It is methoxyl group.

Another object of the present invention has provided a kind of pharmaceutical composition that is used to remove HBsAg or HBeAg, inhibition HBV dna replication dna, treatment hepatitis B, it is characterized by the perhaps mixture formed of its officinal salt and pharmaceutically acceptable auxiliaries of the formula as active component (1) chemical compound of treat effective dose by containing.Its pharmaceutical dosage form can be that tablet, capsule, injection, aerosol, suppository, membrane, drop pill, paster agent, subcutaneous planting bury agent, externally-applied liniment, oral liquid or ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.

The E ring substituted silibinin ester compounds of iodine of the present invention (1) is compared with natural flavone Lignanoids compounds silibinin; Characteristic with differentiation on many structures and the physico-chemical property comprises that speciality such as its hydrophobicity, armaticity, Gibbs free energy, hydrogen bond receptor, electrical, intermolecular Van der Waals force and 3D conformation, direction of extension, molecule center of gravity, conjugated degree, electrical distribution center all have obviously different with silibinin; And chemical compound (1) molecular weight ratio silibinin has increased 126 mass units.The three-dimensional conformation that above-mentioned characteristic has all determined chemical compound shown in the formula (1) and HBsAg or or the ligand-receptor that combines of the 3d space structure of HBeAg and even HBV DNA combine complex form and combination all possibly produce bigger difference; Its binding site and binding pattern, it combines free energy etc. all can produce bigger change, thereby possibly beyond thought effect arranged aspect HBsAg or HBeAg, the inhibition HBV dna replication dna removing.

We have tested the growth inhibited effect of this chemical compound to the HepG2.2.15 cell, the inhibition activity of having tested its B-mode HBsAg to HepG2.2.15 emiocytosis, HBeAg simultaneously and HBVDNA being duplicated.Result of the test is found: the synthetic substituted silybin ester of E ring iodine that obtains is (±)-2-[2 among the present invention; 3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1; 4-benzodioxane-6-]-2; 3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone has definite inhibition activity to the HBsAg and the HBeAg of HepG2.2.15 emiocytosis; Its intensity of removing HBsAg and HBeAg is respectively 20.0% and 29.0% under 100 mcg/ml concentration, surpasses positive control medicine 2 (alpha-interferons of 10000 units per ml) 24% and 72% respectively; Simultaneously, it demonstrates about 32.6% suppression ratio to HBV DNA when this concentration, near alpha-interferon.Explain all that below formula (1) chemical compound has beyond thought anti-HBV effect, thereby can expect that it can be used as the active lead compound continuation exploitation of removing HBsAg or HBeAg, inhibition HBV dna replication dna, treating hepatitis B.Through the detailed Literature Consult of the inventor, up to the present, still there is not report about this compounds for treating hepatitis B virus infection property disease and preparation anti-hepatic-B virus medicine.Flavanolignan's formula (1) chemical compound is imitated inhibition by force for HBsAg, HBeAg and HBV DNA and is all belonged to beyond thought discovery, and definite originality is arranged.

In sum; Uniqueness on our synthetic this silybin ester flavonolignan existing structure; The novelty that the research of antivirus action aspect is arranged again; And in anti-hepatitis B activity test, both found the activity of uncommon inhibition HBsAg, and found the activity of significant inhibitions HBeAg again, also find its activity of inhibition HBV dna replication dna with extremely strong effect; Be expected to become the lead compound that strong effect is removed the non-nucleoside medicine of HBsAg or HBeAg, inhibition HBV dna replication dna and treatment CHB.

Usefulness of the present invention is: the substituted silybin ester flavonolignan of the E shown in the discoverable type (1) ring iodine has and removes HBsAg or HBeAg, the effect of inhibition HBV dna replication dna, the patent medicine potentiality of control hepatitis B virus infection property disease aspect first; For exploitation becomes treatment hepatitis B original new drug, the non-nucleoside original new drug of exploitation removing HBsAg or HBeAg, inhibition HBV dna replication dna provides new material base.Have potential huge social benefit and economic benefit.The present invention's characteristics again is: the present invention's synthetic starting material convenient sources, and synthetic convenient.Its preparation method is simple, and raw material sources conveniently are easy to get, and cost is low, pollutes for a short time, is beneficial to the large-scale production under the energy-saving and emission-reduction condition.Industrialization prospect is very clear and definite.

The specific embodiment

The inventor is through chemosynthesis; And obtain this through multiple chromatography means purification and can imitate the secretion that suppresses hepatitis B HBsAg and HBeAg by force and can effectively suppress the active E of HBV dna replication dna again and encircle the substituted silybin ester flavonolignan of iodine class reactive compound, derive its chemical constitution through integration analysis such as mass spectrum and NMR spectrums again.The inventor finds; Formula (1) chemical compound does not have obvious inhibitory action to the growth of HepG2.2.15 cell; And the hepatitis B HBsAg of HepG2.2.15 emiocytosis and secretion and the duplicating of HBV DNA of HBeAg are had definite inhibitory action; Point out this chemical compound to have drug safety, effectively remove HBsAg or HBeAg, reach the characteristics that effectively suppress the HBV dna replication dna.Therefore, according to the inventor's research, the inventor design and synthetic formula (1) shown in flavanolignan's chemical compound can be used to prepare the non-nucleoside medicine of treatment hepatitis B virus infection property disease.

In order to understand essence of the present invention better; Use the preparation of formula (1) chemical compound below respectively and, its new purposes in pharmaceutical field is described to the HepG2.2.15 cell growth inhibition and to the result of the inhibitory action test of HBsAg, HBeAg and the HBV dna replication dna of HepG2.2.15 emiocytosis.Embodiment has provided partial synthesis, the structure of formula (1) chemical compound and has identified and activity data.Mandatory declaration, embodiments of the invention are to be used to explain the present invention rather than limitation of the present invention.The simple modifications that essence according to the present invention is carried out the present invention all belongs to the present invention and requires the scope protected.

Embodiment 1:Formula (1) chemical compound (±)-2-[2,3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2,3-dihydro-3,5, the preparation of 7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone

1.1 instrument and reagent:

Ultraviolet spectra is measured with Shimadzu UV-240 ultraviolet spectrophotometer; Proton nmr spectra ¹H-NMR measures (tetramethylsilane ether TMS is interior mark) by INOVA type NMR spectrometer with superconducting magnet (VARIAN INOVA-400MHz); Electrospray Mass Spectrometry ESI-MS is measured by BrukerEsquire 3000+ mass spectrograph, and column chromatography is produced by Haiyang Chemical Plant, Qingdao with silica GF254 (10-40 order) with silica gel (100-200,200-300 and 300-400 order) and thin layer chromatography; Agents useful for same is analytical pure, and thin layer preparative chromatography (PTLC) is with the aluminium foil silica gel plate of Merck company; Column chromatography adopts Sweden Amersham Pharmacia Biotech AB Company products with polydextran gel Sephadex LH-20; Reverse phase silica gel RP-18 adopts the Chromatorex product of Japanese Fuji Silysia Chemical company; MCI is a Mitsubishi chemical company product, and thin plate (TLC) detects the uviol lamp with 254nm and 365nm; Developer is with iodine vapor, 10% sulphuric acid-ethanol and phosphorus molybdenum acid solution.

1.2 the preparation of key intermediate I-c (3-iodo-4-hydroxy-5-methyl oxygen base cinnamyl alcohol):

In drying, add 0.11 gram lithium aluminium hydride (3 mM) in the reaction bulb of nitrogen protection, 0.13 gram aluminum chloride (1 mM) slowly adds 10 milliliters of anhydrous tetrahydro furans, is stirred to no gas and emits; 5 milliliters of anhydrous tetrahydrofuran solutions that will be dissolved with 0.36 gram 3-iodo-4-hydroxy-5-methyl oxygen base ethyl cinnamate (1 mM, self-control) slowly add in the reactant, in stirring at room after 1 hour with 20% hcl acidifying to pH=2; Filter; Dried over mgso is filtered, concentrate yellow oil; Get light yellow solid 0.24 gram, yield 80% through column chromatography.R _f(petroleum ether: ethyl acetate=3: 1): 0.12; Proton nmr spectra ¹H NMR (400MHz, deuterochloroform) δ: 3.85 (unimodal, 3H, OCH ₃), 4.40 (bimodal, J=5.6Hz, 2H, H-9), 6.24 (the dt peak, J=5.6,16.0Hz, 1H, H-8), 6.46 (bimodal, J=16.0Hz, 1H, H-7), 6.93 (bimodal, J=2.0Hz, 1H, H-2), 6.95 (bimodal, J=2.0Hz, 1H, H-6); Electrospray Mass Spectrometry ESI-MS m/z:305 [M-H] ⁺

1.3 the preparation of chemical compound (1)

In the reaction bulb of drying nitrogen protection, drop into 80 milligrams of dihydroquercetins (this chamber self-control, purity is greater than 98% (HPLC)), 122 milligrams of 3-iodo-4-hydroxy-5-methyl oxygen base cinnamyl alcohol and 88 milligrams of Disilver carbonates; Inject 5 milliliters of anhydrous propanones and 20 milliliters of anhydrous benzene; Insulation is 3.5 hours between 55-60 ℃, filters, and mother solution concentrates; Column chromatography (chloroform: ethyl acetate: formic acid=25: 1: 0.25) separate 80 milligrams of buff powders, yield 33%.

(±)-2-[2; 3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2,3-dihydro-3; 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone: Rf (chloroform: ethyl acetate: formic acid=25: 1: 0.25): 0.12; Proton nmr spectra ¹H NMR (400MHz, deuterated acetone) δ: 3.51 (multiplet, 1H, H-23a), 3.75 (multiplet, 1H, H-23b), 3.87 (unimodal, 3H, OCH ₃), 4.13 (multiplet, 1H, H-10), 4.62 (bimodal, J=12.0Hz, 1H; H-3), 4.99 (bimodal, J=8.0Hz, 1H, H-11), 5.08 (bimodal, J=12.0Hz; 1H, H-2), 5.95 (unimodal, 1H, H-6), 5.98 (unimodal, 1H; H-8), 6.92-7.41 (multiplet, 5H, Ar-H), 11.65 (unimodal, 1H, 5-OH); Electrospray Mass Spectrometry ESI-MS m/z:607 [M-H] ⁺

Embodiment 2:Chemical compound (1) is to the inhibitory action of the hbs antigen (HBsAg) of HepG2.2.15 emiocytosis

2.1 cell culture:

In containing 10% inactivated fetal bovine serum, 100U/ ml penicillin and 100U/ milliliter streptomycin in the DMEM culture medium of 100 mcg/ml G418, are put 37 ℃, 5%CO with the HepG2.2.15 cell culture ₂, cultivate in the incubator of 100% relative humidity.

Measure the inhibitory action of formula (1) chemical compound 2.2 adopt mtt assay to the growth of HepG2.2.15 cell:

The take the logarithm HepG2.2.15 cell of trophophase becomes 1 * 10 with culture medium with cell dilution ⁵Individual/milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres, at 37 ℃, 5%CO ₂, cultivate the chemical compound (1) that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 1000 mcg/ml; 200 mcg/ml, 40 mcg/ml and 8 mcg/ml, every hole 200 microlitres; Each concentration is established three multiple holes, places 37 ℃, 5%CO ₂, cultivate in the incubator of 100% relative humidity, to cultivate after 72 hours, every hole adds MTT reagent 10 microlitres, continues to cultivate 4 hours, discards culture medium, and every hole adds the DMSO200 microlitre, with agitator vibration 20 minutes, under the 570nm wavelength, measures the OD value with ELIASA.With the culture hole that only adds culture medium is control wells.Suppression ratio (%)=(control wells OD value-experimental group OD value)/control wells OD value * 100%.The experiment triplicate.

Measure the inhibitory action of 1 pair of hbs antigen of chemical compound (HBsAg): the HepG2.2.15 cell of the trophophase of taking the logarithm becomes 1 * 10 with culture medium with cell dilution ⁵/ milliliter is inoculated in 96 porocyte culture plates, 100 milliliters in every hole, and at 37 ℃, 5%CO ₂, cultivate the sample that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 100 mcg/ml, 20 mcg/ml and 4 mcg/ml, every hole 200 microlitres, each concentration is established three multiple holes, places 37 ℃, 5%CO ₂, cultivate in the incubator of 100% relative humidity, changed the culture medium that contains the same concentrations sample in per 4 days, with the culture medium equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.With HBsAg concentration in the ELISA kit measurement culture medium, represent with P/N; With the positive contrast 1 of lamivudine (3-TC) (test concentrations is 100 mcg/ml, 20 mcg/ml and 4 mcg/ml); With the positive contrast 2 of alpha-interferon (test concentrations is 10000 units per ml, 5000 units per ml and 1000 units per ml).

2.3 experimental result:

Experimental result is as shown in table 1; Formula (1) chemical compound (±)-2-[2; 3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2,3-dihydro-3; 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone has the effect of definite inhibition hbs antigen (HBsAg).Its growth to the HepG2.2.15 cell does not have obvious inhibitory action, is higher than lamivudine and alpha-interferon but the HBsAg of HepG2.2.15 emiocytosis was suppressed activity under the high dose the 8th day the time.

Table 1. sample in the time of the 8th day to the excretory hbs antigen suppression ratio of HepG2.2.15

2.4 presentation of results:

This embodiment presentation of results: the flavanolignan's chemical compound shown in the formula (1) has definite inhibitory action to the hbs antigen (HBsAg) of HepG2.2.15 emiocytosis; Its intensity of removing HBsAg is 20.0% under 100 mcg/ml concentration, surpasses positive control medicine 2 (alpha-interferons of 10000 units per ml) 24%; More surpass positive control 1 (lamivudine) 75%, visible this flavanolignan has very strong inhibition viral secretory surface antigen active.

It is clinically near the state of curing that HBsAg removes, and for hepatitis B patient, its HBsAg removes becomes very valuable CHB treatment terminal point.Thereby the flavanolignan's chemical compound shown in the formula (1) can be expected and developed into the non-nucleoside original new drug that reduces hbs antigen, control Type B viral hepatitis symptom.

Embodiment 3:Chemical compound (1) is to the inhibitory action of the hepatitis B e antigen (HBeAg) of HepG2.2.15 emiocytosis

3.1 cell culture: method is with embodiment 2.

Measure the inhibitory action of formula (1) chemical compound to the growth of HepG2.2.15 cell 3.2 adopt mtt assay: method is with embodiment 2.

3.3 measure the inhibitory action of chemical compound to hepatitis B e antigen (HBeAg): the HepG2.2.15 cell of the trophophase of taking the logarithm becomes 1 * 10 with culture medium with cell dilution ⁵/ milliliter is inoculated in 96 porocyte culture plates, 100 milliliters in every hole, and at 37 ℃, 5%CO ₂, cultivate the sample that adds after 24 hours with the culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 100 mcg/ml, 20 mcg/ml and 4 mcg/ml, every hole 200 microlitres, each concentration is established three multiple holes, places 37 ℃, 5%CO ₂, cultivate in the incubator of 100% relative humidity, changed the culture medium that contains the same concentrations sample in per 4 days, with the culture medium equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.With HBeAg concentration in the ELISA kit measurement culture medium, represent with P/N; With the positive contrast 1 of lamivudine (3-TC) (test concentrations is 100 mcg/ml, 20 mcg/ml and 4 mcg/ml); With the positive contrast 2 of alpha-interferon (test concentrations is 10000 units per ml, 5000 units per ml and 1000 units per ml).

3.4 experimental result: experimental result is as shown in table 2; Formula (1) chemical compound (±)-2-[2; 3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2,3-dihydro-3; 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone demonstrates the effect that suppresses hepatitis B e antigen (HBeAg) comparatively significantly.It does not have obvious inhibitory action to the growth of HepG2.2.15 cell under 40 mcg/ml concentration; And it suppresses activity to the HBeAg of HepG2.2.15 emiocytosis the 8th day the time and reaches 29.0% under the 100 mcg/ml concentration, surpasses positive control medicine 2 (alpha-interferons of 10000 units per ml) 72%; And positive control 1 (lamivudine) when maximum concentration (100 mcg/ml), HBeAg to be suppressed activity be zero.

Table 2. sample in the time of the 8th day to the excretory hepatitis B e antigen suppression ratio of HepG2.2.15

3.5 presentation of results: it does not have obvious inhibitory action to the growth of HepG2.2.15 cell the flavanolignan's chemical compound shown in the formula (1) under 40 mcg/ml concentration; Reach 29.0% but under the 100 mcg/ml concentration hepatitis B e antigen of HepG2.2.15 emiocytosis was suppressed activity the 8th day the time, surpass positive control medicine 2 (alpha-interferons of 10000 units per ml) 72%; And positive control 1 (lamivudine) when maximum concentration (100 mcg/ml), HBeAg to be suppressed activity be zero.At the flavanolignan's chemical compound shown in the 40 mcg/ml concentration following formulas (1) HBeAg of HepG2.2.15 emiocytosis is suppressed activity during at the 8th day and also can reach 16.6%, surpass positive control medicine 2 (alpha-interferons of 10000 units per ml) 52%; Suppress the HBeAg activity comparatively significantly it is thus clear that this flavanolignan has, thereby can expect and develop into the medicine that reduces hepatitis B e antigen, control Type B viral hepatitis symptom.

Embodiment 4:The inhibitory action that formula (1) chemical compound duplicates the hepatitis B virus DNA (HBV DNA) of HepG2.2.15 emiocytosis

4.1 cell culture: method is with embodiment 2.

Measure the inhibitory action of the flavanolignan's chemical compound shown in the formula (1) to the growth of HepG2.2.15 cell 4.2 adopt mtt assay: method is with embodiment 2.

4.3 the inhibitory action that the flavanolignan's chemical compound shown in the mensuration formula (1) duplicates hepatitis B virus DNA (HBV DNA): the HepG2.2.15 cell of the trophophase of taking the logarithm becomes 1 * 10 with culture medium with cell dilution ⁵Individual/milliliter, be inoculated in 96 porocyte culture plates, every hole 100 microlitres, at 37 ℃, 5%CO ₂, cultivate the flavanolignan's chemical compound that adds after 24 hours with shown in the formula (1) of culture medium dilution in the incubator of 100% relative humidity, concentration is respectively 100 mcg/ml; 20 mcg/ml and 4 mcg/ml, every hole 200 microlitres, each concentration is established three multiple holes; Place 37 ℃, 5%CO ₂, cultivate in the incubator of 100% relative humidity, changed the culture medium that contains the same concentrations sample in per 4 days, with the culture medium equal-volume mixing that swaps out of the same concentration of same sample, as testing sample.Measure HBV DNA concentration in the culture medium with HBV DNA quantitative PCR kit in the time of the 8th day.With the positive contrast 1 of lamivudine (3-TC) (test concentrations is 100 mcg/ml, 20 mcg/ml and 4 mcg/ml), with the positive contrast 2 of alpha-interferon (test concentrations is 10000 units per ml, 5000 units per ml and 1000 units per ml).

4.4 experimental result: experimental result illustrates as shown in table 3, and flavanolignan's formula (1) chemical compound has the effect of the inhibition HBV dna replication dna of strong effect.

Table 3 sample in the time of the 8th day to the suppression ratio of the HBV dna replication dna of HepG2.2.15 cell

4.5 presentation of results: the flavanolignan's chemical compound (±) shown in the formula (1)-2-[2; 3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1; 4-benzodioxane-6-]-2; 3-dihydro-3; 5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone has certain inhibitory action to duplicating of hepatitis B virus DNA (HBV DNA), and it demonstrates about 32.6% suppression ratio to HBV DNA under 100 mcg/ml concentration; Near alpha-interferon (positive control 2 had 38.2% the inhibition active to HBV DNA at the 8th day during the highest test concentrations 10000 units per ml); Therefore this flavanolignan's chemical compound belongs to effective non-nucleoside and suppresses the hepatitis B virus natural product, is worth further paying close attention to and further investigation, and can expects that further optimized development is for suppressing the non-nucleoside original new drug of HBV dna replication dna.

When above-mentioned description elaboration was of the present invention, the purpose that embodiment is provided simultaneously was to illustrate actual mechanical process of the present invention and meaning of the present invention.In the time of in getting into claim of the present invention and its equivalent scope, practical application of the present invention comprises all general variations, cooperates, or improves.

Claims (3)

1. have the E ring substituted silybin ester flavonolignan of iodine of structure shown in the formula (1) or the purposes that its officinal salt is used for preparation treatment hepatitis B medicine;

The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2R, 3R-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.

2. the E ring substituted silybin ester flavonolignan of iodine or its officinal salt that have structure shown in the formula (1) are used for the purposes that preparation reduces hepatitis B virus surface antigen HBsAg medicine;

The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2R, 3R-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.

3. the E ring substituted silybin ester flavonolignan of iodine or its officinal salt that have structure shown in the formula (1) are used for the purposes that preparation suppresses hepatitis B virus DNA HBV dna replication dna medicine,

The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3-iodo-4-hydroxy-5-methyl oxygen base phenyl)-2-methylol-1,4-benzodioxane-6-]-2R, 3R-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.