CN101829100A - Application of flavanonol lignanoid in preparing antiviral hepatitis B medicine - Google Patents
Application of flavanonol lignanoid in preparing antiviral hepatitis B medicine Download PDFInfo
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Abstract
The invention relates to application of flavanonol lignanoid in preparing an antiviral hepatitis B medicine, in particular to application of angle flavanolignan or pharmaceutically acceptable salts thereof in preparing a medicine which can be used for eliminating hepatitis B e antigen HBeAg, inhibiting HBV DNA replication and treating hepatitis B virus infection diseases. The flavanolignan has a certain HBeVg activity inhibition, the HBeAg elimination intensity of the flavanolignan is higher than that of a positive control first-line medicine as lamivudine in light concentration and is equivalent to that of alpha-interferon of 1000 unit/ml, and meanwhile, under the concentration of 20 microgram/ml, the flavanolignan displays an inhibition ratio which is larger than 45 percent for HBV DNA. The pharmacodynamics result indicates the application of the flavanolignan or the pharmaceutically acceptable salts thereof in preparing the medicine as expected for eliminating hepatitis B e antigen, inhibiting HBV DNA replication and treating hepatitis B virus infection diseases.
Description
Technical field
The present invention relates to medical technical field, particularly, the present invention relates to a corner-shape structure flavanolignan compounds shown in the formula (1) or its officinal salt and be used for preparation removing hepatitis B virus e antigen, suppress hepatitis B virus DNA (deoxyribonucleic acid) HBV dna replication dna, the purposes of treatment hepatitis B medicine, this flavanolignan finds to have certain inhibition hepatitis B virus core antigen HBeAg activity through the pharmacodynamics test, it is removed HBeAg intensity and just be higher than positive control one line medication lamivudine under low concentration 20 mcg/ml, and suitable with the alpha-interferon of 10000 units per ml; Simultaneously this chemical compound demonstrates suppression ratio greater than 45% to HBV DNA when 20 mcg/ml.Thereby above pharmacodynamic result show this flavanolignan or its officinal salt can expect be used to prepare remove the hepatitis B virus e antigen medicine, suppress the HBV dna replication dna, the purposes of the hepatitis b virus infected disease non-nucleoside medicine of treatment.
Background technology
Hepatitis B (hepatitis B) is the infectious disease that is caused by hepatitis b virus hbv, and 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 by hepatitis B virus carriers and hepatitis B patients'blood, saliva, seminal fluid, vaginal secretions, has chronic carrier state.Primary disease 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, to crowd infection rate's height, 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 easily develops into chronic hepatitis B (CHB) and liver cirrhosis, and a few patients can change primary hepatocarcinoma into.
Hepatitis B virus e antigen HBeAg is the structural protein of hepatitis B viruses (HBV) kernel, produces in a large number when hepatitis B virus is bred.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 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, and blood serum designated object HBeAg positive patient illustrates in its body that 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, suppresses the secretion of HBeAg and duplicate so become an important target in the research and development anti-hepatic-B virus medicine and 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 obtain HBeAg before liver cirrhosis, then its liver cirrhosis and hepatocarcinoma incidence rate will reduce by 10 times.All HBeAg serum is removed 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 as one of treatment terminal point determining standard.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 classes such as the liver protecting and ALT lowering, antiviral, anti-hepatic fibrosis and adjusting immunity.The research that still is the antiviral treatment aspect that made progress in the last few years; 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.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: the bioavailability height, and 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 HBVDNA, 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; And 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 human leukocyte 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 by 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, by 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 HBeAg serology conversion that interferon therapy CHB patient obtains is more more lasting than lamivudine, and " digestive tract " magazine the next item up studies show that in 2003: 3 years relapse rates of interferon therapy group HBeAg 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 for the treatment of chronic viral hepatitis B virus clinically, but its side effect and untoward reaction report 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 extensive use of; And the decompensated cirrhosis patient is not suitable for using.
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; It is the high risk factor that hepatocarcinoma (HCC) takes place that HBV DNA continues to exist.Particularly viral level 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, potent and low chemical sproof antiviral therapy along with the reduction of HBV DNA with turn out cloudy, in various degree reverse can occur and observe liver cirrhosis, and therefore present opinion liver cirrhosis also should carry out antiviral therapy.
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 difference treatment standard and the requirement of the HBeAg positive or HBeAg feminine gender 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 guidance and the foundation that changes 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.
By above-mentioned factor as can be known: suppress the basic link of another one that hepatitis B virus breeds in vivo and be 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 considered as one of the test event that must finish for the inhibition strength of HBV DNA in China's new drug development guide.Why lamivudine can become first-selected nucleoside medicine is because it has the activity of potent inhibition HBV dna replication dna.Therefore can suppress the novelty medicine that chemical compound that the HBV dna replication dna can suppress HBeAg again will more promise to be the treatment hepatitis B patient.
Mandatory declaration be: the present antiviral drugs of the using inhibitor of virus replication just in fact, directly kill virus and break virus body, otherwise will damage host cell.These antiviral drugs (mostly being nucleoside medicine) also exist above-mentioned toxic and side effects greatly, easily to cause after viral gene sudden change, the drug withdrawal shortcomings such as easily knock-on, so the development of new antiviral drugs is the task of top priority in current medicament research and development field; It all has extremely important social meaning and economic implications for a large amount of hepatitis B patient and virus carrier, the control sources of infection etc. of treatment China.So new non-nucleoside hepatitis B virus inhibitor and this type of lead compound that can reduce 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 finished the patent and the article of multinomial anti-hepatitis virus natural product and structure of modification derivant thereof in the past, multiple inhibition hepatitis B virus surface antigen HBsAg or hepatitis B virus e antigen HBeAg activity have been found, or the chemical compound of inhibition HBV dna replication dna, thereby filtering out, explanation can remove hepatitis B virus e antigen from natural product and synthesis of derivatives thereof, the novelty medicine of control hepatitis B virus infection is feasible [referring to " medical usage of a class mapping eucalyptus globulus alkanol type sesquiterpene for inhibiting hepatitis virus " (Zhao Yu, Liu Guangming, Yu Rongmin, Li Haibo etc.; 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.; ZL 200610053749.8); " 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.; ZL 200610053601.4); 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 new, Shi Shuyun, Wang Xiaoyu etc.; ZL200610053575.5); " 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 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.; CN1927197A); " 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.; CN 101293836); Inhibition HBeAg that the inventor has delivered and HBVDNA isoreactivity article are referring to " In VitroAntiviral Activity of Three Enantiomeric Sesquiterpene Lactones fromSenecio Species Against Hepatitis B Virus ", Haibo Li (Li Haibo), Changxin Zhou (girth is new), Xiumei Wu (Wu Xiumei), Yu Zhao* (Zhao Yu) etc., Antiviral Chemistry﹠amp; 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., JournalofChromatographyB, 2007,859,119-124].Undoubtedly, continuing to seek the lead compound that can remove HBeAg or inhibition HBV dna replication dna from natural product and structure of modification derivant thereof is that very therefore being necessary property is also classified as one of great special project of new drug development by the Ministry of Science and Technology with urgent.
In above-mentioned treatment CHB medicine, also having a class is to protect the liver the class medicine, its clinical a large amount of uses be typically 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 compounds surely belongs to flavanolignan's silibinin.Flavone lignin compound belongs to weedtree quality class, is the natural product that is contained the C6-C3-C6-C3-C6 construction unit by a class of a part phenylpropyl alcohol element and a part flavone be combined into.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 activity: 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 by 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 estradiol receptor after entering 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.Cancer Drug 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. as the inventor, " Design; Synthesis and Examinationof Neuron Protective Properties of Alkenylated and AmidatedDehydro-Silybin Derivatives ", 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﹠amp; Medicinal Chemistry, 2009,17 (17), 6380-6389; Yang Leixiang, Zhao Yu etc., " Synthesis and Antioxidant PropertiesEvaluation of Novel Silybin Analogues ", Journal ofEnzyme Inhibitionand Medicinal Chemistry, 2006,21 (4), 399-404; Or the like).In the above-mentioned article of inventor report, flavanolignan's compounds of the A ring of a plurality of series that design and synthesize out through the inventor, B ring, E ring, 23 replacements all demonstrates the activity of the potent DPPH of catching free radical and ultra-oxygen anion free radical, antioxidant activity and protection PC12 cell activity.But apparent: above-mentioned research only concentrates on antioxidation and the cytoprotection of studying the silibinin flavonolignan.
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.(2006) in the recent period, Xie Jun has reported that use in conjunction 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 than using the interferon effect separately to find that drug combination reduces ALT, AST value in patient's body, illustrates 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.
The compounds for treating DNA of flavanolignan viroid infects especially its new purposes that is used for anti-hepatitis virus aspect (comprise suppress hepatitis B virus e antigen HBeAg or suppress HBVDNA and duplicate) 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 the lead compound challenge that forefathers did not attempt especially of wherein finding to suppress HBeAg or suppressing the HBV dna replication dna.In order to explore this field, our design has also prepared and the silibinin structure a kind of new angle type flavanolignan derivant of difference to some extent, also promptly at B ring 2,3 digit pairs are synthesized dioxane, form C ring/B ring/D ring and be upset angie type ring system space structure, and silibinin is because of on the B ring being the synthetic dioxane modes of 3,4 digit pairs, so its C ring/B ring/D ring is linear stretch ring system space structure.So design can generate the plain flavanone alcohol compound (also being the novel flavanolignan of class chemical compound) of a class novel wooden that the new spatial structure is different from silibinin fully, in the hope of finding unusual inhibition hepatitis B virus e antigen or suppressing activity and even the lead compound that HBVDNA duplicates.
Below by illustrating the structural difference of angle type flavanolignan and silibinin class linear stretch flavanolignan in the design concept of the present invention.
Silibinin chemical compound (1)
(the C/B/D ring system is the linear stretch direction) (the C/B/D ring system is angle type direction of extension)
(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, 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, do not report that wherein any flavanolignan compounds has the active relative recording of anti-HBV, especially silibinin class natural product and derivant thereof, it is domestic that almost nobody relates to.Therefore, the present invention has carried out structure of modification and the anti-HBV activity research that forefathers do not add attention to it, one of our purpose is: flavanolignan's lead compound of wishing to find to reduce HBeAg or inhibition HBV dna replication dna, thereby it is developed further into to have can remove HBeAg or suppress the novelty medicine that HBVDNA duplicates treatment CHB, finishes the present invention in view of the above.
Summary of the invention
The purpose of this invention is to provide the angle type flavanolignan shown in the formula (1) or its officinal salt and be used for the new purposes that preparation reduces hepatitis B virus e antigen, inhibition HBV dna replication dna, treatment hepatitis B medicine.
The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.
The present invention also provides the method for the flavanonol lignin chemical compound of B epidioxy six rings shown in a kind of preparation formula (1), it is characterized in that: (±)-2-(2, the 3-dihydroxy phenyl)-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone under silver catalyst, with replace the hydroxyl cinnamyl alcohol is carried out coupling reaction and gets;
Wherein, R
1, R
2Be methoxyl group, silver salt can be Disilver carbonate or silver nitrate etc., has reported the example that uses Disilver carbonate among the present invention; Anhydrous solvent can make anhydrous aprotic solvent or their mixture such as anhydrous benzene, anhydrous propanone, anhydrous tetrahydro furan, reported the mixed solvent of anhydrous benzene, anhydrous propanone among the present invention.
Another object of the present invention has provided a kind of pharmaceutical composition that is used to reduce hepatitis B virus e antigen or suppresses HBV dna replication dna, treatment hepatitis B, it is characterized by by containing the mixture that (1) chemical compound of the formula as active component for the treatment of effective dose or its officinal salt and pharmaceutically acceptable auxiliaries are formed.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.
B ring 2 of the present invention, the angle type flavanolignan chemical compound (1) of 3 dioxane couplings is compared with natural flavone Lignanoids compounds silibinin, feature 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, electrical distribution center all have obviously different with silibinin; And chemical compound (1) molecular weight ratio silibinin has increased 30 mass units.Above-mentioned feature has all determined the three-dimensional conformation of chemical compound shown in the formula (1) all may produce bigger difference with the ligand-receptor that the 3d space structure of HBeAg or HBV DNA combines in conjunction with complex form and combination, its binding site and binding pattern, it all can produce bigger change in conjunction with free energy etc., thereby may suppress HBeAg or suppress aspect the HBV dna replication dna beyond thought effect arranged.
We have tested the growth inhibited effect of this chemical compound to the HepG2.2.15 cell, have tested it simultaneously to the hepatitis B e antigen HBeAg of HepG2.2.15 emiocytosis and the inhibition activity that HBVDNA is duplicated.Result of the test is found: the synthetic angle type lignin flavanone alcohol compound that obtains is (±)-2-[2 among the present invention, 3-dihydro-3-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone has certain inhibition activity to the hepatitis B e antigen HBeAg of HepG2.2.15 emiocytosis, it is removed HBeAg intensity and just be higher than positive control one line medication lamivudine under low concentration (20 mcg/ml), and suitable with the alpha-interferon of 10000 units per ml; Simultaneously, this chemical compound demonstrates suppression ratio greater than 45% to HBV DNA when 20 mcg/ml concentration.More than all formula (1) chemical compound beyond thought anti-HBV effect is arranged, thereby can expect that it can be used as reduces hepatitis B virus e antigen, suppresses the active lead compound that HBVDNA duplicated, treated hepatitis B and continue exploitation.
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 disease and preparation anti-hepatic-B virus medicine.Flavanolignan's formula (1) chemical compound all belongs to beyond thought discovery for HBeAg and the potent inhibition of HBV DNA, and definite originality is arranged.In sum, uniqueness on this flavanolignan's existing structure of our de novo synthesis, the novelty that the research of antivirus action aspect is arranged again, and in anti-hepatitis B activity test, found to be expected to the activity of uncommon inhibition hepatitis B virus e antigen become and to reduce HBeAg or suppress the HBV dna replication dna and the lead compound of treatment CHB.
Usefulness of the present invention is: the angle type flavanolignan shown in the discoverable type (1) has the reduction hepatitis B virus e antigen, suppresses HBV dna replication dna and the patent medicine potentiality aspect the control hepatitis B virus first, provides new material base for exploitation becomes the original new drug for the treatment of hepatitis B virus original new drug, exploitation reduction hepatitis B e antigen HBeAg or suppressing the HBV dna replication dna.The flavanonol lignin compound of B epidioxy six rings shown in the formula (1) has 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.Preparation method is simple, raw material sources conveniently are easy to get, cost is low, pollution is little, is beneficial to the large-scale production under the energy-saving and emission-reduction condition.The project industrialization prospect is very clear and definite.
The specific embodiment
The inventor is simply synthetic by multistep, and obtain this secretion that can effectively suppress hepatitis B virus e antigen (HBeAg) by the chromatography means and can effectively suppress the active flavanolignan's class reactive compound of HBV dna replication dna, derive its chemical constitution through integration analysis such as mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum again.The inventor finds, formula (1) chemical compound does not have obvious inhibitory action to the growth of HepG2.2.15 cell, and the secretion and the duplicating of HBVD NA of the hepatitis B virus e antigen (HBeAg) of HepG2.2.15 emiocytosis had significant inhibitory effect, point out this chemical compound have drug safety, definitely reduce hepatitis B virus e antigen, and suppress HBV dna replication dna characteristics of high efficiency.Therefore, according to the inventor's research, the angle type flavanolignan chemical compound shown in the designed and synthetic formula of inventor (1) can be used to prepare the medicine of treatment hepatitis B virus infection disease and be used for the treatment of the hepatitis B virus infection 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 the HBeAg of HepG2.2.15 emiocytosis and HBV dna replication dna.Embodiment has provided partial synthesis, the structure of formula (1) chemical compound and has identified and activity data that wherein OMe is meant that methoxyl group, OMOM are meant the methoxy methoxy base.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention, and essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1:Formula (1) chemical compound (±)-2-[2,3-dihydro-3-(3,5-dimethoxy 4-hydroxy phenyl)-2-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5, the preparation of 7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone
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 wherein the petroleum ether boiling range is 60-90 ℃; Thin layer preparative chromatography (PTLC) the aluminium foil silica gel plate of Merck company; Column chromatography adopts Sweden Amersham Pharmacia Biotech AB company product 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 iodine vapor, 10% sulphuric acid-ethanol and phosphorus molybdenum acid solution.
1.1 the preparation of starting material A:
2,3-4-dihydroxy benzaldehyde 4.8 grams are dissolved in 30 milliliters of acetone, stir to add potassium carbonate 17.5 grams after 10 minutes, drip 6 milliliters of chloromethyl ethers again, and reflux 1 hour is filtered filtrate concentrating and obtained yellow oil 7.0 grams.
1.2 the preparation of starting material B:
40 milliliters of DMF solution ice-water baths coolings with 2.6 sodium hydrides that restrain; Dropwise 5 .6 gram 2,4 under the nitrogen protection state, 60 milliliters of benzene of 6-trihydroxy-acetophenone and the mixed solution of 7.0 milliliters of DMF; the ice bath cooling drips 9.0 milliliters of chloromethyl ether solution down, stirs 24 hours under the room temperature.In 100 milliliter of 10% sodium hydrate aqueous solution of impouring, ether extraction 3 times, each 50 milliliters, the saturated sodium bicarbonate washing, anhydrous sodium sulfate drying, filter, concentrate, 40 gram 200-300 order silica gel column chromatographies, petroleum ether/ethyl acetate (4: 1) eluting, obtain 7.0 gram starting material B (2,4,6-trimethoxy methoxyacetophenone).Yellow oil; R
f(petroleum ether/ethyl acetate=3/1): 0.30; Proton nmr spectra (400MHz, deuterochloroform): δ 2.52 (unimodal, 3H, CH
3), 3.50 (unimodal, 9H, OCH
3), 5.17 (unimodal, 6H, OCH
2O), 6.52 (unimodal, 2H, H-3,5).
1.3 the preparation of intermediate chalcone derivative:
2.8 the gram potassium hydroxide dissolves in 30 ml methanol, stirring drips down 10 milliliters of the mixing methanol solutions of 1.4 gram starting material A and 1.3 gram starting material B, stirs 8 hours under the room temperature, removes solvent under reduced pressure, in residue, add 20 ml waters, ethyl acetate extraction (3 times, each 20 milliliters) merges organic layer, after removing solvent under reduced pressure, residue is through 30 gram 200-300 order silica gel column chromatographies, and petroleum ether/ethyl acetate (3: 1) eluting obtains 1.76 gram intermediate chalcone derivative.Yellow oil; R
f(petroleum ether/ethyl acetate=2/1): 0.38; UV:(methanol) λ max:209,300nm.Be used for next step reaction.
1.4 the preparation of intermediate epoxy chalcone derivative:
1.4 gram intermediate chalcone derivative is dissolved in 25 ml methanol, adds 1.6 milliliters of 2N potassium hydroxide aqueous solutions, adds 1.6 milliliter of 30% hydrogen peroxide solution again, stirring at room 2 hours.Add 25 ml waters, concentrating under reduced pressure, with ethyl acetate extraction (3 times, each 20 milliliters), merge organic layer, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure after, residue is through 20 gram 200-300 order silica gel column chromatographies, petroleum ether/ethyl acetate (3: 1) eluting obtains 1.1 gram intermediate epoxy chalcone derivative.Yellow oil; R
f(petroleum ether/ethyl acetate=2/1): 0.33; UV:(methanol) λ max:210,285nm.Be used for next step reaction.
1.5 adjoining, important intermediate (±)-2-(2, the 3-dihydroxy phenyl) 2,3-dihydro-3,5,7-trihydroxy-4H-1-benzo mutter-preparation of 4-ketone:
1.0 gram intermediate epoxy chalcone derivative is dissolved in 15 ml methanol, add under the stirring in the 10 ml methanol solution that are dissolved with 1.5 milliliters of concentrated hydrochloric acid, heat up 60 ℃ and react half an hour, remove heating, remove solvent after the cooling under reduced pressure, in residue, add 50 ml waters, with ethyl acetate extraction (3 times, each 20 milliliters), merge organic layer, saturated common salt washing 2 times, anhydrous sodium sulfate drying filters, after removing solvent under reduced pressure, residue is through 20 gram 200-300 order silica gel column chromatographies, and petroleum ether/ethyl acetate (3: 1) eluting obtains 97 milligrams (±)-2-(2, the 3-dihydroxy phenyl)-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.Yellow oil: R
f(chloroform/methanol=3/1): 0.23; Electrospray Mass Spectrometry ESI-MSm/z:303[M-H]
+
1.6 chemical compound (1) i.e. is (±)-2-[2,3-dihydro-3-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-benzo adjoin mutters-preparation of 4-ketone
In exsiccant reaction bulb, drop into Disilver carbonate 0.22 gram, add 20 milliliters of anhydrous benzene and 5 milliliters of anhydrous propanones, drip 90 milligrams (±)-2-(2 under the room temperature, the 3-dihydroxy phenyl)-2,3-dihydro-3,5,5 milliliters and 106 milligram 3 of the anhydrous benzene solution of 7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone, 3 milliliters of the anhydrous propanone solution of 5-dimethoxy-4 '-hydroxyl cinnamyl alcohol, insulation reaction is 12 hours in the time of 55 ℃.Leave standstill after being chilled to room temperature, the elimination insoluble matter, the mother solution concentrating under reduced pressure, yellow oil, through 20 gram 200-300 order silica gel column chromatography repeatedly, chloroform/methanol (10: 1) eluting through the gel filtration chromatography purification, finally obtains 26 milligrams of chemical compounds 1.R
f(chloroform/methanol/ethyl acetate/acetone/acetic acid=11: 0.5: 1: 1: 0.1): 0.24; Proton nmr spectra
1H NMR (400MHz, deuterated acetone) δ: 3.83 (unimodal, 6H, OMe), 3.93 (multiplets, 1H, H-23a), 4.18 (multiplet, 1H, H-23b), 4.84 (bimodal, J=8.0Hz, 1H, H-11), 4.99 is (bimodal, J=11.2Hz, 1H, H-3), 5.51 (multiplet, 1H, H-12), 5.66 (bimodal, J=11.2Hz, 1H, H-2), 5.84 (bimodal, J=1.2Hz, 1H, H-6), 5.88 is (bimodal, J=1.2Hz, 1H, H-8), 6.78～6.91 (multiplet, 3H, H-15,18,22), 7.02 is (bimodal, J=8.0Hz, 1H, H-14), 7.11 is (bimodal, J=8.0Hz, 1H, H-14), 10.22 is (wide unimodal, 1H, OH-20), 10.52 (wide unimodal, 1H, OH-7), 12.32 (unimodal, 1H, 5-OH); Electrospray Mass Spectrometry ESI-MS m/z:511[M-H]
+
Embodiment 2:Chemical compound (1) is to the inhibitory action of the hepatitis B e antigen (HBeAg) 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.
2.2 adopting mtt assay measures by the inhibitory action of chemical compound (1) 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, measures the OD value with microplate reader under the 570nm wavelength.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 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 20 mcg/ml, 4 mcg/ml and 0.8 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, 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 hepatitis B e antigen (HBeAg) concentration in the ELISA kit measurement culture medium, represent with P/N; With the positive contrast 1 of lamivudine (3-TC) (annotate: the lamivudine test concentrations is 100 mcg/ml, 20 mcg/ml and 4 mcg/ml); With the positive contrast 2 of alpha-interferon (annotate: the 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-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone has the effect of significant inhibition hepatitis B e antigen (HBeAg).Its growth to the HepG2.2.15 cell does not have obvious inhibitory action, reach 17.6% but the hepatitis B e antigen HBeAg of HepG2.2.15 emiocytosis was suppressed activity the 8th day the time, and positive control 1 lamivudine when maximum concentration (100 mcg/ml) HBeAg to be suppressed activity be zero; Positive control 2 is an alpha-interferon has 16.9% inhibition activity to HBeAg the 8th day test concentrations the highest when (10000 units per ml), and also slightly height is a bit for chemical compound (1) suppresses the highest test concentrations of specific activity (10000 units per ml) to HBeAg when 20 mcg/ml alpha-interferon.
Table 1. sample in the time of the 8th day to the excretory hepatitis B e antigen suppression ratio of HepG2.2.15
This embodiment presentation of results: flavanonol lignin compound (±)-2-[2 of B epidioxy six rings shown in the formula (1), 3-dihydro-3-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxanes-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone has significant inhibitory effect to the hepatitis B e antigen (HBeAg) of HepG2.2.15 emiocytosis, it suppresses activity to HBeAg and is higher than positive control lamivudine and the line medication alpha-interferon inhibition activity when the highest test concentrations (10000 units per ml) when 20 mcg/ml, as seen this flavanolignan has and suppresses hepatitis B virus secretion hepatitis B virus e antigen activity comparatively significantly, thereby can expect and be further development of the reduction hepatitis B e antigen, the medicine of control Type B viral hepatitis symptom.
Embodiment 3:The inhibitory action that formula (1) chemical compound duplicates the hepatitis B virus DNA (deoxyribonucleic acid) (HBV DNA) of HepG2.2.15 emiocytosis
3.1 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 3.2 adopt mtt assay: method is with embodiment 2.
3.3 the inhibitory action that the flavanolignan's chemical compound shown in the mensuration formula (1) duplicates hepatitis B virus DNA (deoxyribonucleic acid) (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 20 mcg/ml, 4 mcg/ml and 0.8 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.(annotate: the lamivudine test concentrations is 100 mcg/ml with the positive contrast 1 of lamivudine (3-TC), 20 mcg/ml and 4 mcg/ml), with the positive contrast 2 of alpha-interferon (annotate: the alpha-interferon test concentrations is 10000 units per ml, 5000 units per ml and 1000 units per ml).
3.4 experimental result:
Experimental result illustrates as shown in table 2, and flavanolignan's formula (1) chemical compound of de novo synthesis has the effect that potent inhibition hepatitis B virus DNA (deoxyribonucleic acid) (HBV DNA) is duplicated.
Table 2 sample in the time of the 8th day to the suppression ratio of the HBV dna replication dna of HepG2.2.15 cell
This embodiment presentation of results: the flavanolignan's chemical compound shown in the formula (1) has more intense inhibitory action to duplicating of hepatitis B virus DNA (deoxyribonucleic acid) (HBV DNA), it suppresses active to duplicating of hepatitis B viruses (HBV) DNA and just surpasses 45% than low dosage (20 mcg/ml) time, and still HBVDNA is demonstrated 20.9% remarkable inhibiting activity when extremely low concentration 0.8 mcg/ml.And the positive control alpha-interferon only has 38.2% inhibition activity to HBV DNA the 8th day test concentrations the highest when (10000 units per ml); Chemical compound (1) suppresses active near the inhibition activity of alpha-interferon when the maximum concentration 5000 units per ml concentration to HBV DNA when 4 mcg/ml.Therefore this 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 medicine of hepatitis B viruses (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 entering 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 angle type flavanolignan 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-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.
2. the angle type flavanolignan or its officinal salt that have structure shown in the formula (1) are used for the purposes that hepatitis B virus e antigen HBeAg medicine is removed in preparation;
The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.
3. the angle type flavanolignan or its officinal salt that have structure shown in the formula (1) are used for the purposes that preparation inhibition hepatitis B virus DNA (deoxyribonucleic acid) HBVDNA duplicates medicine;
The name of formula (1) chemical compound is called: (±)-2-[2,3-dihydro-3-(3,5-dimethoxy-4 '-hydroxy phenyl)-2-methylol-1,4 benzodioxane-5]-2,3-dihydro-3,5,7-trihydroxy-4H-1-.alpha.-5:6-benzopyran-4-ketone.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561992A (en) * | 2004-03-24 | 2005-01-12 | 中国药科大学 | Precursor liposome preparation containing silybum marianum extract and its preparing process |
| CN1990485A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | Silybin flavonolignan and their production method and use |
| WO2009002012A1 (en) * | 2007-06-28 | 2008-12-31 | Lee's Bio Tech Co., Ltd. | The composition and functional food containing extracts and fractions of genus hovenia for prevention and treatment of hepatitis b |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1561992A (en) * | 2004-03-24 | 2005-01-12 | 中国药科大学 | Precursor liposome preparation containing silybum marianum extract and its preparing process |
| CN1990485A (en) * | 2005-12-26 | 2007-07-04 | 浙江海正天华新药研发有限公司 | Silybin flavonolignan and their production method and use |
| WO2009002012A1 (en) * | 2007-06-28 | 2008-12-31 | Lee's Bio Tech Co., Ltd. | The composition and functional food containing extracts and fractions of genus hovenia for prevention and treatment of hepatitis b |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102018701A (en) * | 2010-10-27 | 2011-04-20 | 大理学院 | Application of angle flavonol lignans to preparing glucosidase inhibitors |
| CN102018701B (en) * | 2010-10-27 | 2012-05-23 | 大理学院 | Pharmaceutical application of angle flavonol lignans to preparing glucosidase inhibitors |
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